Thyroid hormone receptor agonists

Abstract

The present invention provides novel thyroid hormone receptor (TR) agonists, e.g., of Formula I, II or III. Also provided are methods of making the novel TR agonists and methods of using the novel TR agonists to treat diseases or conditions modulated by TR agonists, such as NAFLD, NASH, diabetes, hyperlipidemia and / or hypercholesterolemia. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980061525.7, application date October 11, 2019, and invention name “Thyroid Hormone Receptor Agonist”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to international application PCT / CN2018 / 109942 filed on October 12, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0004] In various embodiments, the present invention relates to novel thyroid hormone receptor agonists, pharmaceutical compositions, methods of making and methods of using the same, for example, to treat a disease or condition such as nonalcoholic fatty liver disease and / or nonalcoholic steatohepatitis. Background Art

[0005] Thyroid hormone (TH) plays a key role in the human endocrine system and controls energy metabolism by regulating protein synthesis, carbohydrate and fat metabolism in the liver, skeletal muscle and adipose tissue. In addition, TH affects cardiovascular, skeletal and renal function. The activity of TH is mediated by binding to thyroid hormone receptors (TRs), which include two isomers, TRα and TRβ. TRα is mainly expressed in the brain and heart, and less in the kidneys, skeletal muscle, and lungs, while TRβ is mainly expressed in the liver and kidneys, and less in the brain, heart, thyroid, skeletal muscle, lungs and spleen. Therefore, TRα mainly affects cardiac function, while TRβ controls carbohydrate and lipid metabolism in the liver.

[0006] TH regulates energy expenditure through central and peripheral actions. It maintains basal metabolic rate, promotes adaptive thermogenesis, regulates appetite and food intake, and regulates body weight. Upon binding to thyroid hormone, TRs bind to thyroid hormone response elements (TREs) of their downstream target genes to activate gene expression, thereby activating the TR signaling pathway. In the absence of hormone, binding of TRs to co-repressors prevents transcriptional regulation.

[0007] Nonalcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of more than 30% in adults in both developed and developing countries. NAFLD is considered the hepatic manifestation of the metabolic syndrome and is closely associated with the development of other metabolic risk factors such as type 2 diabetes, hyperlipidemia, and coronary artery disease. NAFLD represents a spectrum of liver diseases involving excessive accumulation of lipids in hepatocytes that is initially benign (hepatic steatosis) but progresses to more advanced stages with the development of inflammation (nonalcoholic steatohepatitis, NASH), culminating in fibrosis with inflammation, apoptosis, and scarring of the liver tissue (cirrhosis). Patients with cirrhosis will eventually develop hepatocellular carcinoma (HCC). Therefore, patients with NAFLD and / or NASH are at increased risk of developing HCC later in life. Summary of the invention

[0008] In various embodiments, the present invention provides novel TR agonists, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds, e.g., for treating diseases or conditions modulated by TR agonists, such as nonalcoholic fatty liver disease and / or NASH.

[0009] In various embodiments, the present disclosure provides novel TR agonists having Formula I, Formula II or Formula III, or pharmaceutically acceptable salts thereof:

[0010]

[0011]

[0012] wherein the variables Het, A, R in the compounds of formula I, II or III are defined as 1 , R 1 ', R 2 , R 3 , R 4 , R 5 , R 100 and n (if applicable). In some embodiments, the compound may have Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula II-1, Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-1A, Formula III-2A, Formula III-3A, Formula III-4A, Formula IX, Formula II-X or Formula III-X, any one of Compounds 1-99 as defined herein. In some specific embodiments, the compound may be any one of Compounds 1-99.

[0013] Certain embodiments of the present disclosure relate to a pharmaceutical composition comprising a compound of formula I as defined herein (e.g., formula I-1, formula I-2, formula I-3, formula I-4), a compound of formula II (e.g., formula II-1), a compound of formula III (e.g., formula III-1, formula III-2, formula III-3, formula III-4, any subformula thereof), a compound of formula IX, a compound of formula II-X or a compound of formula III-X, any one of compounds 1-99, or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions described herein can be formulated for different routes of administration, such as oral, parenteral administration or inhalation, etc.

[0014] Certain embodiments of the present disclosure relate to a method for treating a disease or condition associated with a TR agonist, such as non-alcoholic fatty liver disease. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as defined herein (e.g., formula I-1, formula I-2, formula I-3, formula I-4), a compound of formula II (e.g., formula II-1), a compound of formula III (e.g., formula III-1, formula III-2, formula III-3, formula III-4, any subformula thereof), a compound of formula IX, a compound of formula II-X or a compound of formula III-X, any one of compounds 1-99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, administration comprises administration by oral administration, parenteral administration, or inhalation administration. Non-limiting diseases or conditions suitable for treatment with the methods described herein include obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis, fatty liver, nonalcoholic fatty liver disease, bone disease, thyroid axis changes, atherosclerosis, cardiovascular disease, tachycardia, hyperkinesia, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disease, thyroid cancer, or a combination thereof.

[0015] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. DETAILED DESCRIPTION

[0016] TR agonists have shown significant promise in the treatment of hypercholesterolemia, hepatic steatosis, and weight loss. However, these nonselective TR agonists are associated with adverse cardiac, bone, and cartilage effects. Therefore, more selective and specific drugs targeting the TH signaling pathway are needed based on improved mechanistic understanding to more effectively and selectively target metabolic diseases.

[0017] Recent studies have shown that thyroid hormone analogs specific for TRβ have potential therapeutic benefits for metabolic diseases such as NAFLD and NASH. For example, MGL-3196 is reported to be a liver-directed thyroid hormone receptor β agonist with some selectivity for TR-α. MGL-3196 has also been found to be useful for reducing lipid content in clinical trials. See, for example, Atherosclerosis 230:373-380 (2013). Structurally, MGL-3196 is a pyridazinone compound with an azauracil ring that mimics the natural ligand triiodothyronine (T3). Limited structure activity relationships (SARs) of pyridazinone compounds similar to MGL-3196 have been published, J. Med. Chem. 57:3912-3923 (2014). The published SAR indicates that the best substituent on the pyridazinone ring is isopropyl, while the best substituent for the azauracil unit is CN, which enhances selectivity for TRα. The central benzene ring is usually substituted with two chloro groups.

[0018] In various embodiments, the inventors have surprisingly discovered that the CN group on the azauracil ring can be substituted with a hydrophobic group, such as an alkyl group, without reducing its selectivity for TRα. In addition, this substitution also provides compounds with minimal cellular shift compared to receptor binding assays, which means that the EC observed for cell-based assays is 50 Compared with the EC observed in the receptor binding assay 50 Similar (see the Specific Examples section). In various embodiments, the present invention is also based in part on the unexpected discovery that the reported optimal isopropyl group can be modified to various optionally substituted alkyl, cycloalkyl, phenyl or heterocyclic groups, and the resulting compounds can not only maintain efficacy against TRβ, but in some cases can improve efficacy and / or greatly reduce TRα activity. Therefore, such modifications can reduce side effects associated with undesirable TRα activity, for example in organs such as the heart. In addition, in various embodiments, the inventors have discovered that the central phenyl ring substituent, which is typically 2,6-dichlorophenyl, can be modified to obtain higher TRβ potency and / or better selectivity relative to TRα. In addition, representative compounds of the present disclosure also show enhanced stability in microsomal stability studies, which indicates better pharmacokinetic characteristics than MGL-3196. Therefore, in various embodiments, the present invention provides novel compounds comprising any one or more of these modifications.

[0019] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0020]

[0021] in:

[0022] R 1 and R 1’ are each independently hydrogen, OH, halogen (eg, fluorine), or an optionally substituted C 1-4 Alkyl (e.g. C 1-4 alkyl), or R 1 and R 1’ Together they form an oxo group (=O), R 2 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; or R 2 is -COOH or its ester, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0023] A is O, CH2, S, SO or SO2,

[0024] R 3 is hydrogen or optionally substituted alkyl,

[0025] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0026] n is 1, 2, 3 or 4,

[0027] R 4 is hydrogen, -CN, -COOH, optionally substituted alkyl (e.g., optionally substituted C 1-6 alkyl) or an optionally substituted carbocyclyl (e.g., an optionally substituted C 3-6 carbocyclic group).

[0028] In some embodiments, when -CR 1 R 1’ R 2 When R is isopropyl or -CH(CH3)(CH2-OH), 4 is not hydrogen, -COOH or -CN. In any embodiment according to Formula I herein, R 2 It may be optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl as further defined herein.

[0029] In some embodiments, the compound of Formula I can be represented as having Formula I-1:

[0030]

[0031] Where R 2 , R 100 , n and R 4 Defined in this article.

[0032] In some embodiments, the compound of Formula I can be represented as having Formula I-2:

[0033]

[0034] Where R 1 , R1 ’ , R 2 , R 4 , R 100 and n are defined herein.

[0035] In some embodiments, the compound of Formula I can be represented as having Formula I-3:

[0036]

[0037] Where R 2 , R 100 , n and R 4 As defined in this article. 2 When it is not methyl, for example, when R 2 When R is cyclohexyl or phenyl, the compound of formula I-3 has at least one chiral center, and when applicable, they can exist in the form of a single enantiomer or a mixture of two enantiomers in any proportion, including a racemic mixture. In the case of two or more chiral centers, the compound of formula I-3 can exist in the form of a single stereoisomer or any stereoisomer mixture thereof. As illustrated in the Examples section, having one chiral center (for example, when R 2 Representative compounds of Formula I-3 (when cyclohexyl or phenyl) can be prepared in racemic form or can be separated into individual enantiomers, for example, using chiral HPLC. When designated as a single enantiomer, such as enantiomer A or B, which optionally has a retention time from an analytical HPLC trace, determined to be the first or second eluting enantiomer, it is understood that a single enantiomer is enriched, for example, a single enantiomer can be substantially free of the other enantiomer (e.g., less than 20%, less than 15%, less than 10%, less than 5%, less than 2%, less than 1% or less than 0.5% or not detected by analytical chiral HPLC).

[0038] Typically, R in Formula I (e.g., Formula I-2) 1 and R 1’ are independently hydrogen or optionally substituted C1-4 Alkyl (e.g., C 1-4 In some embodiments, R 1 and R 1’ In some embodiments, R 1 and R 1’ One of them is hydrogen, and R 1 and R 1’ The other one is C 1-4 In some embodiments, R 1 and R 1’ One of them is hydrogen, and R 1 and R 1’ The other one is C 1-4 Alkyl (e.g., methyl, ethyl, etc.), which is optionally substituted with one or more substituents such as hydroxyl. 1 and R 1’ Both C 1-4 In some embodiments, R 1 and R 1’ Both C 1-4 Alkyl (eg, methyl, ethyl, etc.), optionally substituted with one or more substituents such as, for example, hydroxy.

[0039] The inventors also unexpectedly found that when R 1 and R 1’ When the oxo group (=O) is formed together, the resulting compound can bind to TRβ with a potency similar to the reasonable selectivity of MGL-3136 for TRα. Therefore, some embodiments of the present invention also relate to compounds having formula I, wherein R 1 and R 1’ Together they form an oxo group (=O), for example, a compound of formula I-4:

[0040]

[0041] In some embodiments, R in Formula I 1 and R 1’ One of (e.g., Formula I-2) may also be OH, and R 1 and R 1’ In some embodiments, R in Formula I is defined herein. 1 and R 1’ One of (e.g., Formula I-2) may also be a halogen (e.g., fluorine), and R 1 and R 1’ In some embodiments, R in Formula I (e.g., Formula I-2) is 1 and R1’ Both may be halogen (eg, fluorine).

[0042] Typically, A in Formula I is O, CH2, S, SO, or SO2. In some embodiments, A is O. In some embodiments, A is CH2. In some embodiments, A may also be S. It should be noted that in any of the embodiments described herein, if applicable, A is CO, CF2, NH, N(C 1-4 alkyl) or protected NH, and are novel compounds of the present invention.

[0043] In some embodiments, R 3 In some embodiments, R 3 can be metabolized into R 3 In some embodiments, R 3 Can be optionally substituted C 1-4 For example, in some embodiments, R 3 Can be C 1-4 Alkyl, such as methyl, which may be substituted with one or more groups (e.g., one) independently selected from -OH, protected hydroxyl, and -OR, wherein R may be any feasible group that can be stably attached to oxygen (e.g., an oxygen atom substituent described herein). For example, in some embodiments, -OR may be an O-attached amino acid, -OP(O)(OH)2, or -OC(O)-R 101 , where R 101 It may be an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted -C 1-6 Alkylene-COOH, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted aryl. 3 Can be C 1-4Alkyl, such as methyl, is optionally substituted with one or more, such as -OH or protected hydroxyl groups. Suitable hydroxyl protecting groups are well known in the art and are included in those described in detail in "Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. As used herein, the term "O-linked amino acid" refers to any naturally occurring or synthetic amino acid linked to a molecule through the oxygen of the carboxyl group of the amino acid, preferably through the carboxyl terminal of the amino acid. Preferred examples of amino acids are (S)-2-amino-3-methylbutyric acid, (2S, 3S)-2-amino-3-methylpentanoic acid and (S)-2-aminopropionic acid.

[0044] Various acyclic or cyclic groups are suitable for R in Formula I. 2 (For example, Formula I-1, I-2, I-3 or I-4). In some embodiments, R 2 It can be an optionally substituted carbocyclic group. For example, in some embodiments, R 2 It may be an optionally substituted C 3-6 Cycloalkyl, for example, has one or two substituents independently selected from C 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R 2 It may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted by 1 or 2 substituents independently selected from fluoro, methyl and hydroxy.

[0045] In some embodiments, R 2 It may be an alkyl group, for example a C 1-4 Alkyl, the substituents being independently selected from optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl (e.g., piperidinyl or tetrahydropyranyl), optionally substituted 5-10 membered heteroaryl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 is an oxygen protecting group. For example, in some embodiments, R 2 It can be a C substituted with a substituent 1-4 Alkyl (e.g., methyl), the substituent is selected from optionally substituted C 3-6In some embodiments, R 2 may be an optionally substituted C 3-6 Cycloalkyl substituted C 1-4 alkyl (eg methyl), the optionally substituted C 3-6 Cycloalkyl, for example, has one or two substituents independently selected from C 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R 2 may be substituted by one optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 1-4 In some embodiments, R 2 It can be C substituted with a phenyl group 1-4 The phenyl group is optionally substituted by 1-5 (eg, 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), optionally substituted with 1 to 3 fluorine atoms 1-4 In some embodiments, R 2 It can be C substituted with a phenyl group 1-4 The phenyl group is optionally substituted by 1-5 (eg, 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C substituted with one or two hydroxyl groups 1-4 Alkyl, optionally substituted by 1-3 fluorine groups 1-4 In some embodiments, R 2 It may be C substituted with a 5- or 6-membered heteroaryl (e.g., pyridyl, pyrazolyl, isoxazolyl, etc. as described herein). 1-4 The heteroaryl group is optionally substituted by 1-5 (eg, 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C substituted with one or two hydroxyl groups 1-4 Alkyl, optionally substituted by 1-3 fluorine groups 1-4 In some embodiments, R 2 It may be C substituted with a 5,6- or 6,6-bicyclic heteroaryl (eg, as described herein, such as indazolyl, etc.) 1-4 The heteroaryl group is optionally substituted by 1-5 (eg, 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C substituted with one or two hydroxyl groups 1-4 Alkyl, optionally substituted by 1-3 fluorine groups 1-4 In some embodiments, R 2 may be C substituted by an optionally substituted 4-7 membered heterocyclic group (e.g. piperidinyl or tetrahydropyranyl) 1-4 alkyl (e.g. methyl), if applicable, the optionally substituted 4-7 membered heterocyclyl, for example, has one or two substituents independently selected from the substituents of the nitrogen protecting group, C optionally substituted by 1-3 fluorine 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, where Pg 1 It is an oxygen protecting group.

[0046] In some embodiments, R 2 It may be an optionally substituted heterocyclic group, preferably an optionally substituted 4-7 membered heterocyclic group (e.g., piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, where Pg 1 When the 4-7 membered heterocyclic group has NH, it may be optionally substituted with a nitrogen atom substituent as described herein, such as a nitrogen protecting group, for example, benzyl or substituted benzyl, -C(O)-C 1-4 Alkyl or -C(O)-OC 1-4 For example, in some embodiments, R 2It may be an optionally substituted 5- or 6-membered saturated heterocyclic group containing one or two heteroatoms, such as one oxygen, one oxygen and one nitrogen, one nitrogen, two nitrogen atoms, etc. In some embodiments, R 2 It may be piperidinyl or tetrahydropyranyl, which may be optionally substituted. For example, in some embodiments, piperidinyl may be substituted with a nitrogen atom substituent as described herein, such as a nitrogen protecting group, such as -C(O)-C 1-4 Alkyl or -C(O)-OC 1-4 alkyl.

[0047] In some embodiments, R 2 It may be optionally substituted aryl, such as optionally substituted phenyl, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, where Pg 1 In some embodiments, R 2 It may be an optionally substituted phenyl group, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, C1-4 alkyl substituted with one or two hydroxy groups, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, where Pg 1 is an oxygen protecting group. For example, in some embodiments, R 2 It may be phenyl optionally substituted by 1-5 (e.g. 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C optionally substituted by 1-3 fluorine 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), optionally substituted with 1 to 3 fluorine atoms 1-4 Alkoxy (eg methoxy, ethoxy, etc.), hydroxyl and CN.

[0048] Heteroaryl is also suitable as R of formula I 2 In some embodiments, R 2 It may be an optionally substituted 5-10 membered heteroaryl, for example a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S, wherein the heteroaryl is substituted, for example, by 1-5 substituents, for example, optionally substituted by one or two substituents independently selected from C optionally substituted by 1-3 fluorine 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 In some embodiments, R 2 It may be an optionally substituted 5- or 6-membered heteroaryl, for example, pyridyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, for example, substituted by 1-5 substituents, for example, optionally substituted by one or two substituents, the substituents being independently selected from C optionally substituted by 1-3 fluorine 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 is an oxygen protecting group. Bicyclic heteroaryl is also suitable. For example, in some embodiments, R 2 It may be a 5,6-bicyclic or 6,6-bicyclic heteroaryl, for example, indolyl, pyrrolopyridinyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnamyl, quinoxalinyl, phthalazinyl and quinazolinyl, for example, which is substituted with 1-5 substituents, for example, optionally substituted with one or two substituents independently selected from C optionally substituted with 1-3 fluorine. 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 is an oxygen protecting group. 2 It may be pyridinyl (eg 2-, 3- or 4-pyridinyl), indazolyl, isoxazolyl or pyrazolyl, which may be optionally substituted as described herein.

[0049] In some embodiments, R 2 Can be selected from the following:

[0050]

[0051] In some embodiments, R 2 Can be selected from the following:

[0052]

[0053] The benzene ring in Formula I (e.g., Formula I-1, I-2, I-3 or I-4) is generally substituted by 2 or 3 independently selected R 100 In some embodiments, R 100 Each occurrence is independently fluorine, chlorine, bromine, CF3 or methyl. 100 An example of is CF3. Various substitution patterns of the benzene ring in Formula I (e.g., Formula I-1, I-2, I-3 or I-4) are suitable. Generally, when there are 2 or 3 independently selected R 100 When the two R 100 The group is attached to the ortho position of the linker A in Formula I, for example, as follows:

[0054]

[0055] In some embodiments, R 100 Together with a benzene ring, it forms one of the following:

[0056]

[0057] In some embodiments, R 100 Together with the benzene ring, In some embodiments, R 100 Together with the benzene ring,

[0058] The substituent R on the azapyrimidine ring of Formula I (eg, Formula I-1, I-2, I-3 or I-4) is 4 Can vary. For example, in some embodiments, R 4 Can be C 1-6 Alkyl or C 3-6 Cycloalkyl, each optionally substituted with 1-3 fluorine. 4 It can be hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula I-1 4 It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula I-1 4 It can be methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula I-2 4 It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula I-2 4 It can be methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula I-3 4It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula I-3 4 It can be methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula I-4 4 It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula I-4 4 It may be methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0059] In some embodiments, the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof:

[0060]

[0061] in:

[0062] R 5 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl; or R 5 is -COOH or its ester, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0063] A is O, CH2, S, SO or SO2,

[0064] R 3 is hydrogen or optionally substituted alkyl,

[0065] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0066] n is 1, 2, 3 or 4,

[0067] R 4 is hydrogen, -CN, -COOH, optionally substituted alkyl (e.g., optionally substituted C 1-6 alkyl) or an optionally substituted carbocyclyl (e.g., an optionally substituted C 3-6 carbocyclic group).

[0068] In any embodiment according to Formula II herein, R 5 It may be optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl as further defined herein.

[0069] In some embodiments, the compound of formula II can be represented as having formula II-1:

[0070]

[0071] Where R 5 , R 100 , n and R 4 Defined in this article.

[0072] Various cyclic groups are suitable for use as R in Formula II (e.g., Formula II-1). 5 In some embodiments, R 5 It may be an optionally substituted C 3-6 Cycloalkyl, for example, has one or two substituents independently selected from C 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R 5 It may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted by 1 or 2 substituents independently selected from F, methyl and hydroxy.

[0073] In some embodiments, R 5 It may be an optionally substituted 4-7 membered heterocyclyl (e.g., piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-OC 1-4 Alkyl, and halogen, where Pg 1 is an oxygen protecting group. For example, in some embodiments, R 5 It may be an optionally substituted 5- or 6-membered saturated heterocyclic group containing one or two heteroatoms, such as one oxygen, one oxygen and one nitrogen, one nitrogen, two nitrogen atoms, etc. In some embodiments, R 5 It may be piperidinyl or tetrahydropyranyl, which may be optionally substituted. For example, in some embodiments, the piperidinyl may be substituted with a nitrogen atom substituent as described herein, such as a nitrogen protecting group (e.g., benzyl or substituted benzyl, -C(O)-C 1-4 Alkyl or -C(O)-OC 1-4 alkyl, such as acetyl).

[0074] In some embodiments, R 5 It may be an optionally substituted phenyl group, for example, having one or more substituents, for example 1 or 2, independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, where Pg 1 is an oxygen protecting group. For example, in some embodiments, R 5 It may be phenyl, which is optionally substituted by 1-5 (e.g., 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C optionally substituted by 1-3 fluorine 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), optionally substituted with 1 to 3 fluorine atoms 1-4 Alkoxy (eg methoxy, ethoxy, etc.), hydroxyl and CN.

[0075] In some embodiments, R 5 can be an optionally substituted 5-10 membered heteroaryl (e.g., as described herein). For example, in some embodiments, R 5 It may be a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S, wherein, for example, the heteroaryl is substituted by 1-5 substituents, for example, optionally substituted by one or two substituents, for example, the substituents are independently selected from C optionally substituted by 1-3 fluorine 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 In some embodiments, R 5 It can be, for example, an optionally substituted 5- or 6-membered heteroaryl as described herein, such as pyridyl, pyrazolyl or isoxazolyl, etc. In some embodiments, R 5 It may be, for example, an optionally substituted 5,6- or 6,6-bicyclic heteroaryl group as described herein, such as indazolyl and the like.

[0076] In some embodiments, R 5 Can be selected from the following:

[0077]

[0078] Applicable to A, R of Formula II (e.g., Formula II-1) 3 , R 100 , n and R 4The definitions of include any definitions described herein in the context of Formula I.

[0079] For example, generally, A in Formula II is O or CH2, more preferably O. In some embodiments, A in Formula II is S. In some embodiments, R in Formula II is 3 can be hydrogen or an optionally substituted alkyl group which can be metabolically converted to R 3 For example, in some embodiments, R 3 Can be C 1-4 Alkyl, such as methyl, is independently selected from -OH, O-linked amino acids, -OP(O)(OH)2 and -OC(O)-R 101 One or more (eg one) of the groups of is optionally substituted, wherein R 101 is an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted -C 1-6 Alkylene-COOH, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted aryl. The benzene ring in Formula II (e.g., Formula II-1) is also typically substituted by 2 or 3 independently selected R 100 In some embodiments, R 100 is independently fluorine, chlorine, bromine, CF3 or methyl at each occurrence. 100 An example of is CF3. In some embodiments, R 100 Together with a benzene ring, it forms one of the following:

[0080] In some embodiments, R 100 Together with the benzene ring, In some embodiments, R 100 Together with the benzene ring,

[0081] In some embodiments, the substituent R on the azapyrimidine ring in Formula II (eg, Formula II-1) is 4 Can be C 1-6 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted with 1-3 fluorine. 4 It can be hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula II (e.g., Formula II-1) 4It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula II (e.g., Formula II-1) 4 It may be methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0082] Other suitable A, R 3 , R 100 , n and R 4 Including those described herein.

[0083] In some embodiments, the present invention also relates to TRβ agonists without pyridazinone structural units. The inventors unexpectedly found that various heterocyclic structures can be used to replace pyridazinone structural units and obtain similar or better efficacy. In some embodiments, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof:

[0084]

[0085] in:

[0086] Het is a bicyclic heteroaryl, such as a 5,6-bicyclic or 6,6-bicyclic heteroaryl, substituted by 1-2 substituents independently selected from nitrogen protecting groups, -OH, -OPg 1 , optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted; wherein Pg 1 is an oxygen protecting group, wherein the bicyclic heteroaryl, such as 5,6-bicyclic or 6,6-bicyclic heteroaryl, is optionally further substituted where valence permits;

[0087] A is empty, O, CH2, S, SO or SO2,

[0088] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0089] n is 1, 2, 3 or 4,

[0090] Where R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C3-6 Carbocyclic group.

[0091] Any of the 5,6-bicyclic or 6,6-bicyclic heteroaryl groups described herein can be used as Het in Formula III. In some embodiments, the 5,6-bicyclic or 6,6-bicyclic heteroaryl group can be selected from indolyl, pyrrolopyridine and indazolyl. A in Formula III is typically S, O or CH2. In some embodiments, A is O. In some embodiments, A is S. In some embodiments, A is CH2. However, in the case where the nitrogen atom of the 5,6-bicyclic or 6,6-bicyclic heteroaryl group is directly attached to the phenyl group in Formula III, A is understood to be empty.

[0092] In some embodiments, Het in Formula III is indolyl. For example, in some embodiments, the present invention provides a compound of Formula III-1 or a pharmaceutically acceptable salt thereof:

[0093]

[0094] in:

[0095] R 6 is a hydrogen or nitrogen protecting group,

[0096] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0097] A is O, CH2, S, SO or SO2,

[0098] R 100 and R 102 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0099] n is 1, 2, 3 or 4,

[0100] p is 0, 1, 2, 3 or 4,

[0101] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6Carbocyclic group.

[0102] In some embodiments, the compound of formula III-1 can be represented as having formula III-1A:

[0103]

[0104] Where R 7 , R 100 , n and R 4 Defined in this article.

[0105] In some embodiments, Het in Formula III is pyrrolopyridine. For example, in some embodiments, the present invention provides a compound of Formula III-2 or a pharmaceutically acceptable salt thereof:

[0106]

[0107] in:

[0108] R 6 is a hydrogen or nitrogen protecting group,

[0109] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0110] A is O, CH2, S, SO or SO2,

[0111] R 100 and R 102 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0112] n is 1, 2, 3 or 4,

[0113] p is 0, 1, 2, 3 or 4,

[0114] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0115] In some embodiments, the compound of formula III-2 can be represented as having formula III-2A:

[0116]

[0117] Where R 7 , R 100 , n and R 4 Defined in this article.

[0118] In some embodiments, Het in Formula III is indazolyl. For example, in some embodiments, the present invention provides a compound of Formula III-3 or a pharmaceutically acceptable salt thereof:

[0119]

[0120] in:

[0121] R 6 is a hydrogen or nitrogen protecting group,

[0122] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0123] A is O, CH2, S, SO or SO2,

[0124] R 100 and R 102 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0125] n is 1, 2, 3 or 4,

[0126] p is 0, 1, 2, 3 or 4,

[0127] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0128] In some embodiments, the compound of formula III-3 can be represented as having formula III-3A:

[0129]

[0130] Where R 7 , R 100 , n and R 4 Defined in this article.

[0131] In some embodiments, Het in Formula III is an indazole group directly connected to a phenyl group, that is, A is empty. For example, in some embodiments, the present invention provides a compound of Formula III-4 or a pharmaceutically acceptable salt thereof:

[0132]

[0133] in:

[0134] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0135] R 102 In each case, -OH, -OPg 1 , fluorine, chlorine, bromine, iodine, C optionally substituted with 1 to 3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy, where Pg 1 It is an oxygen protecting group.

[0136] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0137] n is 1, 2, 3 or 4,

[0138] p is 0, 1, 2, 3 or 4,

[0139] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0140] In some embodiments, the compound of formula III-4 can be represented as having formula III-4A:

[0141]

[0142] Where R 102 Is OH or O-Pg 1 , R 7 , R 100 , n and R 4 Defined in this article.

[0143] A in formula III-1 to III-3 is typically S, O or CH2. For example, in some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH2.

[0144] In some embodiments, the indole ring in formula III-1 is not further substituted, i.e., p is 0. However, in some embodiments, the indole ring may be further substituted with up to 4 substituents. 102 ) p It is understood to include substitution at any available position of the indole ring, including the 2-position, and not just the benzene portion of the indole ring. 102 Each substituent of may be independently selected from, for example, F, Cl, methyl, CF3, cyclopropyl, cyclobutyl, methoxy, cyclopropyloxy and cyclobutyloxy.

[0145] In some embodiments, the pyrrolopyridine ring in formula III-2 is not further substituted, that is, p is 0. However, in some embodiments, the pyrrolopyridine ring may also be further substituted with up to 3 substituents. 102 ) p It is understood to include substitution at any available position in the pyrrolopyridine ring, not limited to the pyridine ring. 102 Each substituent of may be independently selected from, for example, F, Cl, methyl, CF3, cyclopropyl, cyclobutyl, methoxy, cyclopropyloxy and cyclobutyloxy.

[0146] In some embodiments, the indazole ring in formula III-3 is not further substituted, i.e., p is 0. However, in some embodiments, the indazole ring may also be further substituted with up to 3 substituents. 102 Each substituent of may be independently selected from, for example, F, Cl, methyl, CF3, cyclopropyl, cyclobutyl, methoxy, cyclopropyloxy and cyclobutyloxy.

[0147] The indazole ring in formula III-4 is usually further substituted, for example, p is 1. In some embodiments, R102 At least one example is a hydroxyl group or a protected hydroxyl group (ie, O-Pg 1 In some embodiments, the indazole ring may be further substituted with up to 3 substituents, which may be independently selected from, for example, F, Cl, methyl, CF3, cyclopropyl, cyclobutyl, methoxy, cyclopropyloxy, and cyclobutyloxy.

[0148] R in Formulas III-1 to III-3 6 Typically, it is hydrogen. For example, in some embodiments, R 6 may be a nitrogen protecting group which can be deprotected (metabolic cleaved) in vitro or in vivo to provide a 6 For example, in some embodiments, R 6 Can be -C(O)-C 1-4 Alkyl or -C(O)-OC 1-4 Suitable nitrogen protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0149] Various acyclic and cyclic groups are suitable for R in formulae III-1 to III-4. 7 (including applicable subformulae). In some embodiments, R 7 It may be isopropyl or C optionally substituted, for example, by one or two substituents. 3-6 Cycloalkyl, the substituents are independently selected from C 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R 7 CONH2, -CONH(C 1-4 alkyl) or -CON(C 1-4 Alkyl)(C 1-4 alkyl), wherein each C 1-4 The alkyl groups are independently selected and optionally substituted, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R7 It may be an optionally substituted 4-7 membered heterocyclyl (e.g., piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 In some embodiments, R in Formulas III-1 to III-4 7 (including subformulae, if applicable) may be -CR as defined in Formula I 1 R 1’ R 2 part, or R defined in formula II 5 , including applicable subformulae, see e.g. above.

[0150] In formula III-1 to III-4, R 7 Non-limiting exemplary useful groups (including applicable sub-formulas) include (1) C 1-6 Alkyl, such as isopropyl; (2) C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be optionally substituted with 1 or 2 substituents independently selected from F, methyl and hydroxy; (3) phenyl or 5 or 6 membered heteroaryl (e.g., as described herein, such as pyridyl, pyrazolyl, isoxazolyl, etc.), each of which may be optionally substituted with 1-5 (e.g., 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), optionally substituted with 1 to 3 fluorine atoms 1-4 Alkoxy (e.g. methoxy, ethoxy, etc.), hydroxyl and CN; (4) by a C 3-6 Cycloalkyl substituted C 1-4 alkyl (e.g., methyl), 4-7 membered heterocyclyl, 5 or 6 membered heteroaryl (e.g., as described herein, such as pyridyl, pyrazolyl, isoxazolyl, etc.), or phenyl, wherein each of the cycloalkyl, heterocyclyl, heteroaryl or phenyl is optionally substituted with 1-5 (e.g., 1, 2 or 3) substituents independently selected from fluorine, chlorine, bromine, C 2-3 fluorine-substituted cycloalkyl ... 1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), optionally substituted with 1 to 3 fluorine atoms 1-4 Alkoxy (e.g., methoxy, ethoxy, etc.), hydroxy and CN; and (5) 4-7 membered heterocyclyl (e.g., piperidinyl or tetrahydropyranyl), which may be optionally substituted, for example, in some embodiments, piperidinyl may be substituted with a nitrogen atom substituent (e.g., a nitrogen protecting group) as described herein.

[0151] R applicable to Formula III (e.g., Formula III-1 to III-4, including any applicable subformulae) 100 , n and R 4 The definitions of include any definitions described herein in the context of Formula I or II.

[0152] For example, typically, the benzene ring (not the indole ring) in Formula III (e.g., Formulas III-1 to III-4) is also typically replaced by 2 or 3 independently selected R 100 In some embodiments, R 100 is independently fluorine, chlorine, bromine, CF3 or methyl at each occurrence. 100 An example of is CF3. In some embodiments, R 100 Together with a benzene ring, it forms one of the following:

[0153] In some embodiments, R 100 Together with the benzene ring, In some embodiments, R 100 Together with the benzene ring,

[0154] In some embodiments, the substituent R on the azapyrimidine ring of Formula III (eg, Formula III-1 to Formula III-4) is 4 Can be C 1-6 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted with 1-3 fluorine. 4 It can be hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl. In some preferred embodiments, R in Formula III (e.g., Formula III-1 to III-4) 4 It can be hydrogen, -CN or methyl. In some preferred embodiments, R in Formula III (e.g., Formula III-1 to III-4) 4 It may be methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0155] Other suitable A, R 100 , n and R 4 Including those described herein.

[0156] In some embodiments, the present invention also provides a compound that does not contain an aza-uracil unit but has a phosphoric acid or an ester thereof. For example, in some embodiments, the present invention provides a compound of formula IX or II-X or a pharmaceutically acceptable salt or ester thereof:

[0157]

[0158] in:

[0159] R 1 and R 1’ are each independently hydrogen, -OH, halogen (eg, fluorine), or an optionally substituted C 1-4 Alkyl (e.g. C 1-4 alkyl), or R 1 and R 1’ Together they form an oxo group (=O),

[0160] R 2 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or R 2 is -COOH or its ester, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0161] A is O, CH2, S, SO or SO2,

[0162] R 3 is hydrogen or optionally substituted alkyl,

[0163] R 5 is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or R 5 is -COOH or its ester, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0164] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0165] n is 1, 2, 3 or 4,

[0166] L is J 1 -J 2 -J 3 , where J 1 , J 2 and J3 are each independently empty, O, NH or optionally substituted C 1-6 Alkylene, provided that J 1 , J 2 and J 3 At least one of them is a substitutable C 1-6 Alkylene, L does not contain OO or ON bonds.

[0167] In some embodiments, L is C 1-4 Alkylene or -OC 1-4 Alkylene, for example, L is vinyl or -O-CH2-, wherein CH2 is attached to the phosphorus atom.

[0168] In some embodiments, esters of compounds of formula IX or II-X are provided, including monoesters or diesters, such as pharmaceutically acceptable esters. For example, in some embodiments, the invention provides ethyl esters (e.g., diethyl esters) of compounds of formula IX or II-X. In some embodiments, the ester can be a cyclic ester, which can be derived from a diol, such as a 1,2-diol or a 1,3-diol.

[0169] Where applicable, R of Formula IX or II-X 1 , R 1 ', R 2 , R 3 , R 5 ,A,R 100 Further definitions of and n include those described and / or preferred in Formula I or II.

[0170] In some embodiments, the present invention provides a compound of Formula III-X or a pharmaceutically acceptable salt or ester thereof:

[0171]

[0172] in:

[0173] Het is a bicyclic heteroaryl, such as a 5,6-bicyclic or 6,6-bicyclic heteroaryl, substituted by 1-2 substituents independently selected from nitrogen protecting groups, -OH, -OPg 1 , optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted; wherein Pg 1is an oxygen protecting group, wherein the bicyclic heteroaryl, such as 5,6-bicyclic or 6,6-bicyclic heteroaryl, is optionally further substituted when valence permits;

[0174] A is empty, O, CH2, S, SO or SO2,

[0175] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0176] n is 1, 2, 3 or 4,

[0177] Where L is J 1 -J 2 -J 3 , where J 1 , J 2 and J 3 are each independently empty, O, NH or optionally substituted C 1-6 Alkylene, provided that J 1 , J 2 and J 3 At least one of them is a substitutable C 1-6 Alkylene, L does not contain OO or ON bonds.

[0178] In some embodiments, L is C 1-4 Alkylene or -OC 1-4 Alkylene, for example, L is vinyl or -O-CH2-, wherein CH2 is attached to the phosphorus atom.

[0179] In some embodiments, esters of compounds of formula III-X are provided, including monoesters or diesters, such as pharmaceutically acceptable esters. For example, in some embodiments, the invention provides ethyl esters (e.g., diethyl esters) of compounds of formula III-X. In some embodiments, the esters can be cyclic esters, which can be derived from diols, such as 1,2-diols or 1,3-diols.

[0180] Where applicable, Het, A, R of formula III-X 100 Further definitions of and n include those described and / or preferred in the context of formula III-1, III-2, III-3 or III-4.

[0181] In some specific embodiments, the present invention provides a compound selected from Compound Nos. 1-99 or a pharmaceutically acceptable salt thereof:

[0182]

[0183]

[0184]

[0185] Synthesis method

[0186] Given this disclosure, one skilled in the art can readily synthesize the disclosed compounds. Exemplary syntheses are also shown in the Examples section.

[0187] The following synthesis method for formula I-2 is illustrative and can be similarly used by those skilled in the art to synthesize other compounds of formula I, II and III. For example, compounds having S as a linker A can be prepared according to a similar scheme, except that the phenolic raw material used to synthesize formula I-2 is replaced by the corresponding -SH analog. An example is shown in Example 27 herein. Compounds having CH2 as a linker A can also be prepared according to a similar scheme. In this case, suitable raw materials with "CH2 nucleophiles" can be used. For example, in some cases, such CH2 linkers can be prepared from cyanomethylene raw materials, which can be deprotonated to generate carbon anions, reacted with chloropyridazine derivatives, and then can be hydrolyzed and decarboxylated to generate CH2 linkers. See, for example, J.Med.Chem.57:3912-3923 (2014). The corresponding analogs with S as a linker A can be oxidized to prepare compounds having SO or SO2 as a linker A.

[0188] As shown in Scheme 1, a typical synthesis of compounds of Formula I-2 can be initiated by reacting aminophenol S-1 with pyridazine S-2 to form aryl ether S-3. The conditions for this transformation are known in the art and are also illustrated in the Examples section. 1 Typically Cl, although other leaving groups, such as F, may also be used and may sometimes be advantageous. Hydrolysis of the chloropyridazine S-3 can then produce the pyridazinone compound S-4. The aniline functionality in S-4 can then be converted to an azapyrimidine ring according to known methods or those described herein to provide compounds of formula I-2. Variable R in Scheme 1 1 , R 1 ', R 2 , R 4 , R 100 and n are as defined herein.

[0189]

[0190] In some embodiments, R 4If -CN is present, S-4 can be converted to cyanuracil by diazotizing S-4 and then reacting with a cyanoacetamide derivative S-5 to form intermediate IM-1, which can then be cyclized to provide compounds of Formula I-2, Formula I-2-A. See Scheme 2 below. Variable R in Scheme 2 1 , R 1′ , R 2 , R 100 and n are as defined herein.

[0191] Solution 2

[0192]

[0193] For R 4 In embodiments where S-4 is an optionally substituted alkyl or cycloalkyl group, such as methyl, ethyl, isopropyl, cyclopropyl, etc., the azapyrimidine ring can be converted by first converting the aniline to a hydrazine S-6, followed by reaction with an acid S-7 to form an intermediate IM-2, which can then be converted to an intermediate IM-3 by reaction with a carbamate S-8. Intermediate IM-3 can then be cyclized to an azapyrimidine under similar conditions as described in Scheme 2. The conditions for the conversion in Scheme 3 are known in the art and are also exemplified herein. The variable R in Scheme 3 is 1 , R 1 ', R 2 , R 100 and n are as defined herein.

[0194] Solution 3

[0195]

[0196] Various starting materials for S-2 can be prepared by known methods. 1 In the case where R is Cl, S-2 can be prepared by reacting a dichloropyridazine with a carboxylic acid in the presence of an oxidant under decarboxylative coupling conditions. Example 6 shows a typical procedure for such a coupling reaction. Alternatively, S-2 can be prepared by first coupling 4-bromo-1,2,3,6-tetrahydropyridazine-3,6-dione with a suitable reagent (e.g., an organoboron reagent or other suitable reagent) to form a pyridazine-dione derivative, which can be converted to S-2 according to known procedures. An example of this method is shown in Example 19. Example 24 shows another method for preparing S-2, in which a suitable precursor (in Example 24, a benzyl substituted dichloropyridazine) can be deprotonated and then reacted with R 1 -Lg reaction (in Example 24, Me-I). Other compounds can be prepared similarly.

[0197] Alternatively, as shown in Scheme 4, compound S-4 can be prepared by first reacting compound S-1 with dichloropyridazine. Thus, compound S-1 is first converted to compound S-9, and then the chloropyridazine is hydrolyzed and the aniline NH2 is protected to form compound S-10. This is followed by the introduction of the appropriate C(R 1 )(R 1 ')(R 2 ) group, for example, by reacting compound S-10 with an appropriate Grignard reagent followed by oxidation. After deprotection, compound S-4 can be obtained. An example of this method is shown in Example 7. Variable R in Scheme 4 1 , R 1 ', R 2 , R 100 and n are as defined herein. 2 This may be any suitable amine protecting group, for example benzoyl.

[0198] Solution 4

[0199]

[0200] The present disclosure also provides methods for preparing compounds of formula I-1 as shown in Scheme 1A. For example, pyridazinone IM-4 can be reduced to IM-5, which can be reacted with an appropriate aldehyde (or other appropriate reactant) under appropriate conditions to provide IM-6, which can be oxidized to provide a compound of formula I-1. Example 25 provides a representative process. Alternatively, an appropriate S-10 can be reduced and then reacted with an appropriate aldehyde to form a compound of S-4, wherein R 1 and R 1 ' are all hydrogen, and can also be converted into compounds of formula I-1. A representative process is shown in Example 26.

[0201] Option 1A

[0202]

[0203] Indole derivatives of formula III-1A can be synthesized according to the general strategy described herein. Examples of the synthesis are also described in detail in the Examples section. In short, as shown in Scheme 5 below, 5-hydroxyindole derivative S-13 can be reacted with para-F nitrophenyl compound S-14 (or a similar nitrobenzene derivative having a leaving group in the para position of the nitro group) to give aryl ether S-15. The nitro group is reduced to an NH2 group, which can then be converted to an azapyrimidine ring according to the general strategy described herein to obtain compounds of formula III-1A. As will be appreciated by those skilled in the art, indole S-13 can be readily synthesized by various indole syntheses, such as the Fischer indole synthesis. Reduction of the nitro group to NH2 is also well known. The variable R in Scheme 5 4 , R6 , R 7 , R 100 , R 102 , n and p are as defined herein. Compounds of formula III-2A and III-3A can be prepared similarly, except that the corresponding pyrrolopyridine or indazole starting materials are used. It should be noted that the corresponding intermediates (i.e., the indole units in intermediates S-15 or S-16 are substituted with the corresponding pyrrolopyridine or indazole) that can lead to compounds of formula III-2A and III-3A are also new compounds of the present invention. A similar method can be used to prepare compounds of formula III-4, except that, for example, indazole nitrogen is reacted with the corresponding S-14. Representative processes are shown in the Examples section.

[0204] Solution 5

[0205]

[0206] Compounds having a phosphate unit in place of the azapyrimidine, for example compounds of Formula IX, can be prepared in analogy to the procedures outlined in Examples 23 and 28.

[0207] It will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, "Protecting Groups in Organic Synthesis", 4th edition, PGM Wuts; TW Greene, John Wiley, 2007 describes many protecting groups, as well as references cited therein. The reagents for the reactions described herein are generally known compounds, or can be prepared by known methods or obvious modifications thereof. For example, many reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Other compounds can be prepared by methods 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 Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), or obvious modifications thereof, as well as any available updates in this document.

[0208] Drug ingredients

[0209] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0210] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., a compound of formula I (e.g., formula I-1, formula I-2, formula I-3, formula I-4), a compound of formula II (e.g., formula II-1), a compound of formula III (e.g., formula III-1, formula III-2, formula III-3, formula III-4, any subformula thereof), a compound of formula IX, formula II-X or formula III-X, any one of compounds 1-99 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 absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, release agents, sterilants, sweeteners, solubilizers, wetting agents and mixtures thereof. See Remington's "Remington's The Science and Practice of Pharmacy", 21st edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Maryland, 2005; incorporated herein by reference), which discloses various excipients used to formulate pharmaceutical compositions and known techniques for their preparation.

[0211] The pharmaceutical composition may include any one or more compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition includes, for example, a therapeutically effective amount of a compound selected from compounds 1-99 or a pharmaceutically acceptable salt thereof, a compound of any one of formula I (e.g., formula I-1, formula I-2, formula I-3, formula I-4), formula II (e.g., formula II-1), formula III (e.g., formula III-1, formula III-2, formula III-3, formula III-4, any subformula thereof), formula IX, a compound of formula II-X or formula III-X, any one of compounds 1-99, or a pharmaceutically acceptable salt thereof. In any embodiment described herein, the pharmaceutical composition may include a therapeutically effective amount of a compound selected from compounds 1-99 or a pharmaceutically acceptable salt thereof.

[0212] The pharmaceutical compositions may also be formulated for delivery by any known delivery route, including but not limited to oral, parenteral, inhalation, and the like.

[0213] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be present as discrete units, such as capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing oral compositions 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, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-polyvidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0214] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral preparations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral preparations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, glucose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0215] In some embodiments, the pharmaceutical composition is formulated for inhalation. Inhalable formulations can be formulated, for example, as nasal sprays, dry powders or aerosols that can be administered by a metered dose inhaler. Excipients for preparing inhalation formulations are known in the art. Suitable non-limiting excipients include, for example, lactose, talcum powder, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, and mixtures of these substances. Sprays can additionally contain propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0216] Depending on various factors, such as the intended use of the compound and the efficacy and selectivity, the pharmaceutical composition may contain various amounts of the compounds of the present disclosure. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compounds of the present disclosure. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compounds of the present disclosure and a pharmaceutically acceptable excipient. As used herein, the therapeutically effective amount of the compounds of the present invention is an amount that is effective for treating the diseases or conditions described herein, which may depend on the recipient of the treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound, the clearance rate, and whether another drug is used simultaneously.

[0217] Treatment

[0218] The compounds of the present disclosure are useful as therapeutically active substances for the treatment and / or prevention of diseases or disorders modulated by thyroid hormone receptor agonists.

[0219] In some embodiments, the present disclosure provides a method for treating a disease or condition in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a compound of the present invention (e.g., a compound of formula I (e.g., formula I-1, formula I-2, formula I-3, formula I-4), formula II (e.g., formula II-1), formula III (e.g., formula III-1, formula III-2, formula III-3, formula III-4, any subformula thereof), formula IX, a compound of formula II-X or formula III-X, any one of compounds 1-99, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0220] Administration herein is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intralingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In some embodiments, oral administration is performed.

[0221] Various diseases or conditions can be treated by the methods herein. Non-limiting examples include obesity, hyperlipidemia, hypercholesterolemia, diabetes (e.g., type 2 diabetes), nonalcoholic steatohepatitis (NASH), fatty liver, nonalcoholic fatty liver disease (NAFLD), bone disease, thyroid axis changes, atherosclerosis, cardiovascular disease, tachycardia, hyperkinetic behavior, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, bone age delay, neurological or mental illness, thyroid cancer and combinations thereof. In some embodiments, the disease or condition can be a metabolic disease, such as type 2 diabetes or hyperlipidemia. In some embodiments, cardiovascular disease is coronary artery disease.

[0222] In some embodiments, the method is used to treat obesity, hyperlipidemia, hypercholesterolemia, diabetes (e.g., type 2 diabetes), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism or thyroid cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of any one of Formula I (e.g., Formula I-1, Formula I-2, Formula I-3, Formula I-4), Formula II (e.g., Formula II-1), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3, Formula III-4, any subformula thereof), a compound of Formula IX, Formula II-X or Formula III-X, any of Compounds 1-99 described herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein.

[0223] In some embodiments, the present disclosure provides a method for treating a liver disease or condition such as non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., Formula I (e.g., Formula I-1, Formula I-2, Formula I-3, Formula I-4), Formula II (e.g., Formula II-1), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3, Formula III-4, any of its subformulas), Formula IX, Formula II-X or Formula III-X, any of Compounds 1-99 described herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some preferred embodiments, the liver disease or condition is liver fibrosis, hepatocellular carcinoma or hepatic steatosis. In some preferred embodiments, the liver disease or condition is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0224] In some embodiments, the disclosure provides a method for treating a lipid disease or condition in a subject in need. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., Formula I (e.g., Formula I-1, Formula I-2, Formula I-3, Formula I-4), Formula II (e.g., Formula II-1), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3, Formula III-4, any subformula thereof), Formula IX, a compound of Formula II-X or Formula III-X, any of Compounds 1-99 described herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some preferred embodiments, the lipid disease or condition is hyperlipidemia and / or hypercholesterolemia.

[0225] The administration regimen including dosage can be varied and adjusted depending on the recipient of treatment, the disease or condition being treated and its severity, the composition comprising the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate and whether another drug is used simultaneously.

[0226] Non-limiting exemplary embodiments

[0227] Some exemplary embodiments of the present disclosure are provided below.

[0228] 1. A compound of formula III or a pharmaceutically acceptable salt thereof:

[0229]

[0230] in:

[0231] Het is a 5,6-bicyclic or 6,6-bicyclic heteroaryl group substituted by 1-2 substituents independently selected from nitrogen protecting groups, -OH, -OPg 1 , optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted; wherein Pg 1 is an oxygen protecting group, wherein the 5,6-bicyclic or 6,6-bicyclic heteroaryl group is optionally further substituted when valence permits;

[0232] A is empty, O, CH2, S, SO or SO2,

[0233] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0234] n is 1, 2, 3 or 4,

[0235] Where R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0236] 2. The compound of embodiment 1 or a pharmaceutically acceptable salt or ester thereof, wherein the 5,6-bicyclic or 6,6-bicyclic heteroaryl group is selected from indolyl, pyrrolopyridine and indazolyl.

[0237] 3. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, characterized by being of formula III-4:

[0238]

[0239] in,

[0240] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0241] R 102 In each case, -OH, -OPg 1 , fluorine, chlorine, bromine, iodine, C optionally substituted with 1 to 3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy, where Pg 1 It is an oxygen protecting group.

[0242] wherein p is 0, 1, 2, 3 or 4, as valency permits.

[0243] 4. The compound of embodiment 3 or a pharmaceutically acceptable salt thereof, wherein R 7 isopropyl or C optionally substituted by one or two substituents 3-6 Cycloalkyl, the substituents are independently selected from C 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0244] 5. The compound of embodiment 3 or a pharmaceutically acceptable salt thereof, wherein R 7 -CONH2, -CONH(C 1-4 alkyl) or -CON(C 1-4 Alkyl)(C 1-4 alkyl), wherein each C 1-4The alkyl groups are independently selected and optionally substituted, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0245] 6. The compound of embodiment 3 or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted 4-7 membered heterocyclyl (eg, piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0246] 7. A compound according to any one of embodiments 1-2, or a pharmaceutically acceptable salt thereof, wherein A is void, S, O or CH2.

[0247] 8. The compound according to any one of embodiments 3-7, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0248] 9. The compound according to embodiment 8, or a pharmaceutically acceptable salt thereof, wherein R 102 OH or -OPg 1 .

[0249] 10. The compound according to any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

[0250] 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 100 is independently at each occurrence fluoro, chloro, bromo, CF3 or methyl.

[0251] 12. The compound according to any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein R 100 Together with a benzene ring, it forms one of the following:

[0252]

[0253] 13. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl or C 3-6cycloalkyl, each of which is optionally substituted by 1 to 3 fluorine atoms, or R 4 It is hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0254] 14. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0255] 15. A method for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1-13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 14, wherein the disease or condition is obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis, fatty liver, non-alcoholic fatty liver, bone disease, thyroid axis changes, atherosclerosis, cardiovascular disease, tachycardia, hyperkinesia, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disease, thyroid cancer, or a combination thereof.

[0256] 16. A method for treating a liver disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-13 or a pharmaceutical composition as described in Embodiment 14.

[0257] 17. The method of embodiment 16, wherein the liver disease or disorder is non-alcoholic steatohepatitis.

[0258] 18. The method of embodiment 16, wherein the liver disease or disorder is non-alcoholic fatty liver disease.

[0259] 19. A method for treating a lipid disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13 or a pharmaceutical composition according to embodiment 14.

[0260] 20. The method according to embodiment 19, wherein the lipid disease or condition is hyperlipidemia and / or hypercholesterolemia.

[0261] Some exemplary embodiments of the present disclosure are provided below.

[0262] 1. A compound of formula I or a pharmaceutically acceptable salt thereof:

[0263]

[0264] in:

[0265] R 1 and R 1’ are each independently hydrogen, -OH, halogen (eg, fluorine), or an optionally substituted C 1-4 Alkyl (e.g. C 1-4 alkyl), or R 1 and R 1’ Together they form an oxo group (=O),

[0266] R 2 is an optionally substituted alkyl group, an optionally substituted carbocyclyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group,

[0267] A is O, CH2, S, SO or SO2,

[0268] R 3 is hydrogen or optionally substituted alkyl,

[0269] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0270] n is 1, 2, 3 or 4,

[0271] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group,

[0272] The premise is that when -CR 1 R 1’ R 2 When R is isopropyl or -CH(CH3)(CH2-OH), 4 Not hydrogen, -COOH or -CN.

[0273] 2. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

[0274] R 1 and R 1’ are each independently hydrogen or optionally substituted C 1-4 Alkyl (e.g., C 1-4 alkyl).

[0275] 3. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

[0276] R 1 and R 1’ All are hydrogen.

[0277] 4. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1’ is hydrogen, R 1 It is methyl.

[0278] 5. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1’ and R 1 An oxo group (=O) is formed.

[0279] 6. The compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted C 3-6 Cycloalkyl, for example, has one or two substituents independently selected from C 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0280] 7. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 is C optionally substituted by one or more substituents 1-4 Alkyl, the substituents being independently selected from optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl (e.g., piperidinyl or tetrahydropyranyl), optionally substituted 5-10 membered heteroaryl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0281] 8. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-4 Alkyl, the C 1-4 The alkyl group is substituted with a substituent selected from the group consisting of: optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 4-7 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0282] 9. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2is an optionally substituted 4-7 membered heterocyclyl (eg, piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0283] 10. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted phenyl group, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0284] 11. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted phenyl group, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0285] 12. A compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted 5-10 membered heteroaryl, for example a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S, wherein the heteroaryl is optionally substituted, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0286] 13. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 2is an optionally substituted 5- or 6-membered heteroaryl, for example, pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl and pyrazinyl, for example, which is optionally substituted by one or two substituents independently selected from C optionally substituted by 1-3 fluorine 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0287] 14. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5,6-bicyclic or 6,6-bicyclic heteroaryl group, for example, indolyl, pyrrolopyridinyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizine, purine, naphthyridine, pterygium, quinolyl, isoquinolyl, cinnamyl, quinoxalinyl, phthalazinyl and quinazolinyl, for example, which is optionally substituted by one or two substituents independently selected from C optionally substituted by 1-3 fluorine groups. 1-4 Alkyl, C substituted with one or two hydroxyl groups 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0288] 15. The compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 Select from the following:

[0289]

[0290] 16. The compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2 Select from the following:

[0291]

[0292] 17. A compound according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen.

[0293] 18. A compound according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C 1-4 alkyl.

[0294] 19. The compound according to embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from -OH, O-linked amino acids, -OP(O)(OH)2 and -OC(O)-R 101 One or more optionally substituted C 1-4 Alkyl, where R 101 is an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted -C 1-6 Alkylene-COOH, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted aryl.

[0295] 20. A compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein A is O or CH2.

[0296] 21. A compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein A is S.

[0297] 22. A compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein A is O.

[0298] 23. A compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

[0299] 24. A compound according to any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein R 100 is independently at each occurrence fluoro, chloro, bromo, CF3 or methyl.

[0300] 25. A compound according to any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein R 100 Together with a benzene ring, it forms one of the following:

[0301]

[0302] 26. A compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl or C 3-6Cycloalkyl, each optionally substituted by 1 to 3 fluorine groups.

[0303] 27. A compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0304] 28. A compound of formula II or a pharmaceutically acceptable salt thereof:

[0305]

[0306] in:

[0307] R 5 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0308] A is O, CH2, S, SO or SO2,

[0309] R 3 is hydrogen or optionally substituted alkyl,

[0310] R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0311] n is 1, 2, 3 or 4,

[0312] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0313] 29. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5 is an optionally substituted C 3-6 Cycloalkyl, for example, has one or two substituents independently selected from C 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0314] 30. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5is an optionally substituted 4-7 membered heterocyclyl (eg, piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-OC 1-4 Alkyl, and halogen, where Pg 1 It is an oxygen protecting group.

[0315] 31. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted piperidinyl or tetrahydropyranyl, for example, having one or two substituents independently selected from nitrogen protecting groups (such as benzyl or substituted benzyl, if applicable), C optionally substituted with 1-3 fluorine 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)-OC 1-4 Alkyl, and halogen, where Pg 1 It is an oxygen protecting group.

[0316] 32. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted phenyl, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine 1-4 Alkyl, -OH, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, -CN, and halogen, among which Pg 1 It is an oxygen protecting group.

[0317] 33. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5 Select from the following:

[0318]

[0319] 34. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein R 5 Select from the following:

[0320]

[0321] 35. A compound according to any one of embodiments 28-34, or a pharmaceutically acceptable salt thereof, wherein R3 For hydrogen.

[0322] 36. A compound according to any one of embodiments 28-34, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C 1-4 alkyl.

[0323] 37. The compound according to embodiment 36, or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from -OH, O-linked amino acids, -OP(O)(OH)2 and -OC(O)-R 101 One or more optionally substituted C 1-4 Alkyl, where R 101 is an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted -C 1-6 Alkylene-COOH, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted aryl.

[0324] 38. A compound according to any one of embodiments 28-37, or a pharmaceutically acceptable salt thereof, wherein A is O or CH2.

[0325] 39. A compound according to any one of embodiments 28-37, or a pharmaceutically acceptable salt thereof, wherein A is S.

[0326] 40. A compound according to any one of embodiments 28-37, or a pharmaceutically acceptable salt thereof, wherein A is O.

[0327] 41. A compound according to any one of embodiments 28-40, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

[0328] 42. A compound according to any one of embodiments 28-41, or a pharmaceutically acceptable salt thereof, wherein R 100 is independently at each occurrence fluoro, chloro, bromo, CF3 or methyl.

[0329] 43. A compound according to any one of embodiments 28-41, or a pharmaceutically acceptable salt thereof, wherein R 100 Together with a benzene ring, it forms one of the following:

[0330]

[0331] 44. A compound according to any one of embodiments 28-43, or a pharmaceutically acceptable salt thereof, wherein R 4C 1-6 Alkyl or C 3-6 Cycloalkyl, each optionally substituted by 1 to 3 fluorine groups.

[0332] 45. A compound according to any one of embodiments 28-43, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0333] 46. ​​A compound of formula III-1, III-2 or III-3 or a pharmaceutically acceptable salt thereof:

[0334]

[0335] in:

[0336] R 6 is a hydrogen or nitrogen protecting group,

[0337] R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted;

[0338] A is O, CH2, S, SO or SO2,

[0339] R 100 and R 102 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy,

[0340] n is 1, 2, 3 or 4,

[0341] Where valence permits, p is 0, 1, 2, 3 or 4,

[0342] R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

[0343] 47. The compound according to embodiment 46, or a pharmaceutically acceptable salt thereof, wherein R 7isopropyl or C optionally substituted by one or two substituents 3-6 Cycloalkyl, the substituents are independently selected from C 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0344] 48. The compound according to embodiment 46, or a pharmaceutically acceptable salt thereof, wherein R 7 CONH2, -CONH(C 1-4 alkyl) or -CON(C 1-4 Alkyl)(C 1-4 alkyl), wherein each C 1-4 The alkyl groups are independently selected and optionally substituted, for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups. 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0345] 49. The compound according to embodiment 46, or a pharmaceutically acceptable salt thereof, wherein R 7 is an optionally substituted 4-7 membered heterocyclyl (eg, piperidinyl or tetrahydropyranyl), for example, having one or two substituents independently selected from C optionally substituted with 1-3 fluorine groups 1-4 Alkyl, hydroxyl, -OPg 1 , C optionally substituted by 1-3 fluorine 1-4 Alkoxy, and halogen, among which Pg 1 It is an oxygen protecting group.

[0346] 50. A compound according to any one of embodiments 46-49, or a pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

[0347] 51. A compound according to any one of embodiments 46-50, or a pharmaceutically acceptable salt thereof, wherein R 6 -C(O)-C 1-4 Alkyl or -C(O)-OC 1-4 alkyl.

[0348] 52. A compound according to any one of embodiments 46-51, or a pharmaceutically acceptable salt thereof, wherein A is O or CH2.

[0349] 53. A compound according to any one of embodiments 46-52, or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0350] 54. A compound according to any one of embodiments 46-53, or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3.

[0351] 55. A compound according to any one of embodiments 46-54, or a pharmaceutically acceptable salt thereof, wherein R 100 is independently at each occurrence fluoro, chloro, bromo, CF3 or methyl.

[0352] 56. A compound according to any one of embodiments 46-54, or a pharmaceutically acceptable salt thereof, wherein R 100 Together with a benzene ring, it forms one of the following:

[0353]

[0354] 57. A compound according to any one of embodiments 46-56, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-6 Alkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1 to 3 fluorine groups.

[0355] 58. A compound according to any one of embodiments 46-56, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen, -CN, -COOH, methyl, ethyl, cyclopropyl, isopropyl or propyl.

[0356] 59. A compound selected from Compound No. 1-99 or a pharmaceutically acceptable salt thereof.

[0357] 60. A pharmaceutical composition comprising a compound according to any one of embodiments 1-59 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0358] 61. A method for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of embodiments 1-59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in embodiment 60, wherein the disease or condition is obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis, fatty liver, nonalcoholic fatty liver disease, bone disease, thyroid axis changes, atherosclerosis, cardiovascular disease, tachycardia, hyperkinesia, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disease, thyroid cancer, or a combination thereof.

[0359] 62. A method of treating a liver disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 60.

[0360] 63. A method according to embodiment 62, wherein the liver disease or condition is non-alcoholic fatty liver disease.

[0361] 64. A method according to embodiment 62, wherein the liver disease or condition is non-alcoholic fatty liver disease.

[0362] 65. A method of treating a lipid disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 60.

[0363] 66. A method according to embodiment 65, wherein the lipid disease or condition is hyperlipidemia and / or hypercholesterolemia.

[0364] definition

[0365] It is to be understood that all moieties and combinations thereof maintain proper valence.

[0366] It should also be understood that a specific embodiment of a variable portion herein may be the same as or different from another specific embodiment having the same identifier.

[0367] Where applicable, in the compounds of formula I, II or III or subformulae thereof, Het, A, R 1 , R 1 ', R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 100 , R 102 Suitable groups for Het, A, R and p are independently selected. The embodiments of the invention described may be combined. Such combinations are contemplated and within the scope of the invention. For example, when applicable, it is contemplated that for Het, A, R 1 , R 1 ', R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 100 , R 102, n and p can be implemented as Het, A, R 1 , R 1 ', R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 100 , R 102 , any one of the defined embodiments of n and p is combined.

[0368] The definitions of specific functional groups and chemical terms are described in more detail below. According to the "Periodic Table of the Elements" (CAS version, "Handbook of Chemistry and Physics", 75th edition), the chemical elements in the cover are identified, and specific functional groups are generally defined as described herein. In addition, Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March, "March's Advanced Organic Chemistry", 5th edition, John Wiley & Sons, New York, 2001; Larock, "Comprehensive Organic Transformations," VCH Publishing Co., Ltd., New York, 1989; and Carruthers, "Some Modern Methods of Organic Synthesis", 3rd edition, Cambridge University Press, Cambridge, 1987 describes the general principles of organic chemistry as well as specific functional parts and reactivity, and the present disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0369] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture 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 may be prepared by asymmetric synthesis. See, e.g., 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, New York, 1962); and Wilen, "Tables of Resolving Agents and Optical Resolutions", 268 pages (ELEliel, Ed., Notre Dame University Press, 1972, Notre Dame). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, as well as as mixtures of various isomers, including racemic mixtures.

[0370] When a range of values ​​is listed, it is intended to include every value and subrange within that range. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, 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 .

[0371] As used herein, the term "compounds of the present disclosure" or "compounds of the present invention" refers to compounds according to Formula I (e.g., Formula I-1, Formula I-2, Formula I-3, Formula I-4), Formula II (e.g., Formula II-1), Formula III (e.g., Formula III-1, Formula III-2, Formula III-3, Formula III-4, any subformula thereof), Formula IX, Formula II-X or Formula III-X, or any compound of Compounds 1-99, isotope-labeled compounds (e.g., deuterium atom analogs in which one hydrogen atom is replaced by a deuterium atom, the abundance of which is higher than its natural abundance), possible stereoisomers (including diastereomers, enantiomers and racemic mixtures), tautomers thereof, conformational isomers thereof and / or pharmaceutically acceptable salts thereof (e.g., acid addition salts, such as HCl salts or base addition salts, such as Na salts) as described herein. Hydrates and solvates of the compounds of the present invention are considered compositions of the present invention, wherein the compounds are associated with water or a solvent, respectively.

[0372] The compounds of the present disclosure may exist in isotopically labeled or enriched form, which contains one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number most commonly found in nature. Isotopes may be radioactive isotopes or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 Oh, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of the invention.

[0373] As used herein, the phrases "administration" of a compound, "administering" a compound or other variations thereof, means providing the compound or a prodrug of the compound to a subject in need of treatment.

[0374] As used herein, the term "alkyl" by itself or as part of another group refers to a straight or branched aliphatic hydrocarbon. In some embodiments, an alkyl group (e.g., C 1-12 In one embodiment, the alkyl group is a straight chain C 1-10 In another embodiment, the alkyl group is a branched C 3-10 In another embodiment, the alkyl group is a straight chain C 1-6In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight chain C 1-4 For example, the C 1-4 Alkyl refers to a group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl and isobutyl. 1-4 Alkyl refers to the defined C 1-4 Alkyl, which is optionally substituted with one or more substituents as described herein. As used herein, the term "alkylene" by itself or as part of another group refers to a divalent group derived from an alkyl. For example, non-limiting straight chain alkylene includes -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like.

[0375] As used herein, the term "alkenyl" by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-carbon double bonds. 2-6 In another embodiment, alkenyl is C 2-4 Alkenyl. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0376] As used herein, the term "alkynyl" by itself or as part of another group refers to the above alkyl groups containing one to three carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 In another embodiment, the alkynyl group is C 2-4 Alkynyl. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

[0377] As used herein, the term "alkoxy" by itself or as part of another group refers to a radical of the formula OR a1 A group in which R a1 It is an alkyl group.

[0378] As used herein, the term "cycloalkoxy" by itself or as part of another group refers to a cycloalkyloxy group of the formula OR a1 A group in which R a1 It is a cycloalkyl group.

[0379] As used herein, the term "haloalkyl" by itself or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In a preferred embodiment, the haloalkyl group is an alkyl group substituted with one, two or three fluorine atoms. In one embodiment, the haloalkyl group is C1-10 In one embodiment, the haloalkyl group is C 1-6 In one embodiment, the haloalkyl group is C 1-4 Halogenated alkyl.

[0380] "Carbocyclyl" or "carbocyclic" used alone or as a fragment of another group refers to a non-aromatic cyclic hydrocarbon radical ("C 3-10 "Carbocyclyl" also includes ring systems in which a carbocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, in which case the number of carbon atoms continues to specify the number of carbon atoms in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0381] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-10 In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 "cycloalkyl").

[0382] "Heterocyclyl" or "heterocyclic" as used by itself or as another group refers to a radical of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclic bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on the carbocyclyl or heterocycle, or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocycle, in which case the number of ring members continues to specify the number of ring members in the heterocycle system.

[0383] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxirane, thiirane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiofuranyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thienyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithienyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0384] "Aryl" as used by itself or as part of another group refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms (e.g., sharing 6, 10, or 14 π electrons in the cyclic array) and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system.

[0385] "Aralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more aryl groups, preferably with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, and the like. When the aralkyl group is optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be optionally substituted.

[0386] "Heteroaryl" when used by itself or as part of another group refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms (e.g., sharing 6 or 10 pi electrons in the cyclic array) and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as described above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0387] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepaninyl, oxepinyl, and thiapepaninyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzodiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnamyl, quinoxalinyl, phthalocyaninyl and quinazolinyl.

[0388] "Heteroaralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more heteroaryl groups, preferably with one heteroaryl group. When the heteroaralkyl group is optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl group may be optionally substituted.

[0389] It is generally understood by those skilled in the art that alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, respectively.

[0390] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic radical, optionally substituted heterocyclic radical, optionally substituted aryl and optionally substituted heteroaryl, refer to each group that is unsubstituted or substituted. In general, whether or not starting with the term "optionally", the term "substituted" means that at least one hydrogen present on a group (such as a carbon or nitrogen atom) is replaced by an allowed substituent, such as a substituent that produces a stable compound when substituted, for example, a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination or other reactions. Unless otherwise indicated, a "substituted" group has a substituent on one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position. Typically, when substituted, the optionally substituted group herein may be substituted by 1-5 substituents. If applicable, the substituent may be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent.

[0391] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa ,-ON(R bb )2,-N(R bb )2,-N(R bb )3 + X – ,-N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa ,-OC(=O)R aa , -OCO2R aa ,-C(=O)N(R bb )2,-OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2,-C(=NR bb )R aa ,-C(=NR bb )OR aa ,-OC(=NR bb )R aa ,-OC(=NR bb)OR aa ,-C(=NR bb )N(R bb )2,-OC(=NR bb )N(R bb )2,-NR bb C(=NR bb )N(R bb )2,-C(=O)NR bb SO2R aa ,-NR bb SO2R aa ,-SO2N(R bb )2,-SO2R aa ,-SO2ORaa,-OSO2R aa ,-S(=O)R aa ,-OS(=O)R aa ,-Si(R aa )3,-OSi(R aa )3,-C(=S)N(R bb )2,-C(=O)SR aa ,-C(=S)SR aa ,-SC(=S)SR aa ,-SC(=O)SR aa ,-OC(=O)SR aa ,-SC(=O)OR aa ,-SC(=O)R aa ,-P(=O)(R aa )2,-P(=O)(OR cc )2,-OP(=O)(R aa )2,-OP(=O)(OR cc )2,-P(=O)(N(R bb )2)2,-OP(=O)(N(R bb )2)2,-NR bb P(=O)(R aa )2,-NR bb P(=O)(OR cc )2,-NR bb P(=O)(N(R bb ) 2 ) 2 ,-P(R cc ) 2 ,-P(OR cc ) 2 ,-P(R cc ) 3+ X - ,-P(OR cc )3+ X - , -P(R cc ) 4 ,-P(OR cc )4,-OP(R cc )2, -OP(R cc )3 + X - ,-OP(OR cc )2, -OP(OR cc )3 + X - ,-OP(R cc )4, -OP(OR cc )4,-B(R aa )2,-B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is a counterion; or the two double-bonded hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN (R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or = NOR cc Instead; each R aa Examples are independently selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0392] R bb Each instance of is independently selected from hydrogen, -OH, -OR aa , -N(R cc )2,-CN,-C(=O)R aa ,-C(=O)N(R cc )2, -CO2R aa , -SO2R aa ,-C(=NR cc )OR aa ,-C(=NR cc )N(R cc )2,-SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa ,-C(=S)N(R cc )2,-C(=O)SR cc , -C(=S)SR cc ,-P(=O)(R aa )2,-P(=O)(OR cc )2,-P(=O)(N(R cc )2)2,C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X- is a counterion;

[0393] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0394] R dd Each instance of is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee ,-ON(R ff )2,-N(R ff )2,-N(R ff )3 + X – ,-N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee ,-OC(=O)R ee , -OCO2R ee ,-C(=O)N(R ff )2,-OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2,-C(=NR ff )OR ee ,-OC(=NR ff )R ee ,-OC(=NR ff )OR ee ,-C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff S02R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee ,-OSO2R ee , -S(=O)R ee , -Si(R ee )3,-OSi(R ee )3, -C(=S)N(R ff )2,-C(=O)SR ee , -C(=S)SR ee , -SC(=S)SRee ,-P(=O)(OR ee )2,-P(=O)(R ee )2,-OP(=O)(R ee )2, -OP(=O)(OR ee )2,C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Substitution groups, or two double bonds R dd Substituents may be linked to form =O or =S; where X – is the counter ion;

[0395] R ee Each instance of is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0396] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0397] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X – , -NH(C 1-6 Alkyl)2 + X – , -NH2(C 1-6 alkyl) + X - , -NH3 + X – , -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -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), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2,-NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3,-OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 Alkyl)2,-P(=O)(C 1-6 alkyl)2,-OP(=O)(C 1-6 alkyl)2,-OP(=O)(OC 1-6 Alkyl)2,C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two R gg The diradical substituents may be linked to form =O or =S; wherein X- is a counterion.

[0398] "Counterions" or "anionic counterions" are negatively charged groups associated with positively charged groups to maintain electrical neutrality. Anionic counterions can be monovalent (i.e., include one formal negative charge). Anionic counterions can also be multivalent (i.e., include more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halides (e.g., F – , Cl – ,Br – , I – ), NO3 – , ClO4 – , OH – , H2PO4 – , HSO4 – , sulfonate ions (e.g., toluenesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 – , PF4 –, PF6 – , AsF6 – , SbF6 – ,B[3,5-(CF3)2C6H3]4] – , BPh4 – ,Al(OC(CF3)3)4 – , and carborane anions (e.g. CB 11 H 12 – or (HCB 11 Me5Br6) – ). Exemplary counterions that may be multivalent include CO3 2- , HPO4 2- ,PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carborane.

[0399] "Halo" or "halogen" refers to fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br) or iodine (I, -I).

[0400] "Acyl" refers to a group selected from -C(=O)R aa , -CHO, -CO2R aa ,-C(=O)N(R bb )2,-C(=NR bb )R aa ,-C(=NR bb )OR aa ,-C(=NR bb )N(R bb )2,-C(=O)NR bb S02R aa ,-C(=S)N(R bb )2,-C(=O)SR aa or -C(=S)SR aa A group in which R aa and R bb As defined herein.

[0401] The nitrogen atoms may be substituted or unsubstituted where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(Rcc )2,-CN,-C(=O)R aa ,-C(=O)N(R cc )2, -CO2R aa , -SO2R aa ,-C(=NR bb )R aa ,-C(=NR cc )OR aa ,-C(=NR cc )N(R cc )2,-SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa ,-C(=S)N(R cc )2,-C(=O)SR cc , -C(=S)SR cc ,-P(=O)(OR cc )2,-P(=O)(R aa )2,-P(=O)(N(R cc )2)2,C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R attached to the nitrogen atom cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution, where R aa , R bb , R cc and R dd As defined above.

[0402] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa ,-C(=O)N(R cc )2, -CO2R aa , -SO2R aa ,-C(=NR cc )R aa ,-C(=NR cc )ORaa ,-C(=NR cc )N(R cc )2,-SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa ,-C(=S)N(R cc )2,-C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl, Aryl-C 1-10 Alkyl, Heteroaryl-C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heterocyclyl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution, where R aa , R bb , R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0403] Exemplary oxygen atom substituents include, but are not limited to, -R aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa ,-C(=O)N(R bb )2,-C(=NR bb )R aa ,-C(=NR bb )OR aa ,-C(=NR bb )N(R bb )2,-S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2,-P(R cc )3 + X - ,-P(ORcc )2,-P(OR cc )3 + X - ,-P(=O)(R aa )2,-P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where X - , R aa , R bb and R cc As defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art, including those described in detail in "Protecting Groups in Organic Synthesis", TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl, such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like, silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and the like, acetals or ketals, such as tetrahydropyranyl (THP), esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like, carbonates, sulfonates, such as methanesulfonates (mesylate), benzylsulfonates, and tosylate (Ts), and the like.

[0404] The term "leaving group" has its common meaning in the field of synthetic organic chemistry and refers to an atom or group that can be substituted by a nucleophilic reagent. See, for example, Smith, March Advanced Organic Chemistry, 6th edition (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., fluorine, chlorine, bromine or iodine), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxyamino, phenylxanthine and haloformate.

[0405] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0406] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., a reaction that provides a tautomeric pair) can be catalyzed by an acid or a base. Exemplary tautomerism includes ketone to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerism.

[0407] As used herein, the term "subject" (alternatively referred to herein as "patient") refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0408] As used herein, the terms "treat," "treating," "treatment," and the like refer to the elimination, alleviation or amelioration of a disease or condition and / or the symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the likelihood of re-development of a disease or condition, as well as the recurrence of a previously controlled disease or condition, in a subject who is not, is at risk or susceptible to a disease or condition, or to a recurrence of a disease or condition. The terms "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0409] Example

[0410] Where appropriate, conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation and chromatography, can be used to separate and purify the various starting materials, intermediates and compounds in the preferred embodiments. The characterization of these compounds can be carried out using conventional methods, such as by melting point, mass spectrum, nuclear magnetic resonance and various other spectral analyses. Exemplary embodiments of the steps for carrying out the synthesis of the products described herein are described in more detail below.

[0411] Example 1. Synthesis of Compound 42

[0412]

[0413] Step 1. 4-amino-2-chloro-6-fluorophenol (2.50 g, 15.5 mmol), dimethyl sulfoxide (DMSO) (40 mL), potassium carbonate (6.40 g, 46.3 mmol), 3,6-dichloro-4-(propan-2-yl)pyridazine (3.00 g, 15.7 mmol) and CuI (1.75 g, 9.2 mmol) were added to a 250 mL flask. The resulting solution was heated at 85 ° C overnight. The solution was diluted with water (200 mL) and adjusted to pH = 8 with HCl (1 M). The mixture was extracted with 2×300 mL of ethyl acetate. The combined organic layers were washed with brine (2×300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase column chromatography with 0.05% NH4HCO3 aqueous solution / acetonitrile (gradient of 50% to 60% in 10 minutes) to give 42-1.

[0414] Step 2. 42-1 (1.0 g, 3.16 mmol) and sodium acetate (0.78 g, 9.49 mmol) in acetic acid (30 mL) were added to a 250 mL flask. The mixture was heated at 100° C. overnight, cooled to room temperature, diluted with water (200 mL), and adjusted to pH=9 with sodium hydroxide (1 M). The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product of 42-2, which was used in the next step without further purification.

[0415] Step 3. 42-2 (1.2 g, 2.83 mmol), MeOH (15 mL) and sodium hydroxide (1 M, 15 mL) were added to a 100 mL flask. The resulting solution was heated at 95 ° C overnight. The mixture was cooled to room temperature, adjusted to pH = 6 with HCl (1 M), diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1: 1) to give 42-3.

[0416] Step 4. To a solution of 42-3 (140 mg, 0.47 mmol) in concentrated HCl (2.8 mL) and H2O (8 mL) was slowly added a solution of NaNO2 (37 mg, 0.53 mmol) in water (0.3 mL) at 0°C. The resulting solution was stirred at 0°C for 1 hour. N-(2-cyanoacetyl)ethyl carbamate (81 mg, 0.52 mmol) in pyridine (2.8 mL) and H2O (9.4 mL) was added to a second flask and the resulting solution was stirred at 0°C for 30 minutes. The first reaction mixture was then filtered and transferred to the second reaction mixture, and the resulting suspension was stirred at 0°C for 0.5 hours. The mixture was filtered, and the filter cake was washed with water and petroleum ether and dried to give 42-4.

[0417] Step 5. 42-4 (100 mg, 0.22 mmol), potassium acetate (24 mg, 0.25 mmol) and N,N-dimethylacetamide (DMA) (3 mL) were added to a 50 mL flask. The resulting solution was heated at 120 ° C for 3 hours. The reaction mixture was cooled to room temperature and then purified by preparative HPLC (NH4HCO3 aqueous solution (10 mmol / L) / acetonitrile (21%-38%)) to give compound 42 (42 mg). LCMS (ES, m / z): [M+H] + =419.1; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.23 (s, 1H), 7.66-7.62 (m, 2H), 7.43 (s, 1H), 3.12-3.00 (m, 1H), 1.19 (d, J=6.9 Hz, 6H).

[0418] Example 2. Synthesis of Compound 43

[0419]

[0420] Step 1. At room temperature, 2,6-difluoro-4-nitrophenol (100 mg, 0.57 mmol), acetic anhydride (0.1 mL) and acetic acid (2.0 mL) were added to an 8 mL flask. The suspension was degassed 3 times with a nitrogen stream, and 10% Pd / C (30.0 mg, 0.085 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours under a H2 atmosphere, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to obtain 43-1.

[0421] Step 2. Under nitrogen at room temperature, 3,6-dichloro-4-(isopropyl)pyridazine (2.0 g, 10.7 mmol), CuI (3.46 g, 18.2 mmol) and potassium carbonate (4.43 g, 32.1 mmol) were added to a stirred solution of 43-1 (2.02 g, 10.7 mmol) in dimethyl sulfoxide (DMSO) (20 mL) in a 100 mL three-necked round-bottom flask. The resulting mixture was stirred at 85 ° C for 16 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain 43-2.

[0422] 43 was synthesized according to a similar procedure as in Example 1. LCMS (ES, m / z): [M+H] +=403.0; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.26 (s, 1H), 7.49-7.56 (m, 2H), 7.42 (s, 1H), 3.09-3.00 (m, 1H), 1.19 (d, J=6.9 Hz, 6H).

[0423] Example 3. Synthesis of Compound 44

[0424]

[0425] Step 1. 4-amino-2,6-dichlorophenol (2 g, 11.24 mmol), dimethyl sulfoxide (DMSO) (20 mL), potassium carbonate (6.21 g, 44.94 mmol), 3,6-dichloro-4-(propan-2-yl) pyridazine (2.15 g, 11.25 mmol) and CuI (1.28 g, 6.72 mmol) were added to a 100 mL flask. The resulting mixture was heated at 90 ° C for 16 hours, cooled to room temperature, neutralized with HCl (1 M) to pH = 8, and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain 44-1.

[0426] Step 2. Under nitrogen atmosphere, at 0°C, to a stirred solution of 44-1 in acetonitrile (100 mL) was added fluorine reagent (2.24 g, 6.33 mmol) in batches. The mixture was stirred at 0°C for 10 minutes and then at 40°C for 40 minutes. The mixture was cooled to room temperature, quenched with saturated NaHCO3 aqueous solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give 44-2.

[0427] 44 was synthesized according to a similar procedure as in Example 1. LCMS (ES, m / z): [M+H] + =453.0; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.27 (s, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.48 (s, 1H), 3.18-3.03 (m, 1H), 1.26 (d, J=7.2 Hz, 6H).

[0428] Example 4. Synthesis of Compound 41

[0429]

[0430] Step 1. 2,6-dichloro-3-methylphenol (1.5 g, 8.47 mmol) and dichloromethane (15 mL) were added to a 50 mL flask. The mixture was cooled to 0 ° C, and concentrated nitric acid (0.46 mL) was added dropwise. The resulting solution was stirred at 0 ° C for 0.5 hours, then quenched with water and extracted with dichloromethane. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=15:100) to obtain 41-1.

[0431] Step 2. A solution of 41-1 (1.4 g, 6.31 mmol), Zn powder (2.06 g, 31.53 mmol), NH4Cl (2.70 g, 50.45 mmol) in ethanol (14 mL) and water (7 mL) was added to a 50 mL flask. The resulting mixture was stirred at room temperature for 16 hours, filtered, and the filtrate was extracted with ethyl acetate. The combined organic layers were concentrated to give 41-2.

[0432] 41 was synthesized according to a similar procedure as in Example 1. LCMS (ES, m / z): [M+H] + =449.1; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.30 (br s, 1H), 12.21 (s, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 3.18-3.01 (m, 1H), 2.27 (s, 3H), 1.16 (d, J=6.9 Hz, 6H).

[0433] Example 5. Synthesis of Compound 35

[0434]

[0435] Step 1. 3,5-dichloro-4-[[6-chloro-5-(propan-2-yl)pyridazin-3-yl]oxy]aniline (1.5 g, 4.51 mmol), sodium acetate (1.29 g, 15.72 mmol) and acetic acid (15 mL) were added to a 100 mL flask. The mixture was heated at 100 ° C for 16 hours, cooled to room temperature, and adjusted to pH = 8 with aqueous sodium hydroxide solution (1 M). The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 35-1.

[0436] Step 2. 35-1 (1 g, 2.81 mmol), MeOH (10 mL) and sodium hydroxide (1 M, 10 mL) were added to a 100 mL flask. The resulting mixture was heated at 100 ° C for 16 hours, cooled to room temperature, and adjusted to pH = 5 with HCl aqueous solution (1 M). The solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:1) to give 35-2.

[0437] Step 3. Sodium nitrite (90 mg, 1.3 mmol) was added to a solution of 35-2 (407 mg, 1.3 mmol) in water (8 mL) and concentrated hydrochloric acid (4 mL) at 0 ° C. The mixture was stirred for 0.5 hours. A solution of stannous chloride (983 mg, 5.2 mmol) in concentrated hydrochloric acid (2 mL) was added to the above mixture. The reaction mixture was then stirred for 0.5 hours and filtered. The filter cake was collected to give 35-3, which was used in the next step without further purification.

[0438] Step 4. To a solution of 35-3 (700 mg, 1.3 mmol) in ethanol (5 mL) and water (15 mL) was added pyruvic acid (229 mg, 2.6 mmol) at room temperature. The mixture was stirred for 0.5 h and filtered. The filter cake was washed with water, collected, and slurried with dichloromethane (15 mL). The slurry was filtered, the filter cake was collected and dried to give 35-4.

[0439] Step 5. At room temperature, thionyl chloride (212 mg, 1.8 mmol) was added to a solution of 35-4 (360 mg, 0.9 mmol) in toluene (60 mL). The mixture was stirred at 110 ° C for 2 hours, concentrated and dissolved in toluene (60 mL) again. Ethyl carbamate (160 mg, 1.8 mmol) was added to the above mixture at room temperature. The mixture was then stirred at 110 ° C for 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane / methanol = 10: 1) to obtain 35-5.

[0440] Step 6. Potassium acetate (59 mg, 0.6 mmol) was added to a solution of 35-5 (55 mg, 0.12 mmol) in dimethylacetamide (3 mL) at room temperature. The mixture was stirred at 60°C for 16 hours, cooled, and purified by preparative HPLC (acetonitrile in water containing 0.05% TFA: 25% to 95%) to give 35. LCMS: (ESI, m / z): [M+H] +=424.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.38 (br s, 1H), 12.18 (s, 1H), 7.76 (s, 2H), 7.40 (s, 1H), 3.05-2.97 (m, 1H), 2.13 (s, 3H), 1.16 (d, J=6.8 Hz, 6H).

[0441] Example 6. Synthesis of Compound 1

[0442]

[0443] Step 1. Concentrated sulfuric acid (5.74 mL, 105.0 mmol), silver nitrate (1.19 g, 7.0 mmol) and cyclopropanecarboxylic acid (7.24 mL, 91.0 mmol) were added to a suspension of 3,6-dichloropyridazine (10.43 g, 70.0 mmol) in water (210 mL) at room temperature. The mixture was heated to 65 ° C, and a solution of ammonium persulfate (23.94 g, 105.0 mmol) in water (70 mL) was added dropwise over 20 minutes (T < 72 ° C). The mixture was then stirred at 70 ° C for 0.5 hours, cooled to room temperature, and poured into ice water (50 mL). The pH of the mixture was adjusted to 9 with ammonium hydroxide and extracted with dichloromethane. The combined organic layer was washed with aqueous sodium hydroxide solution (1 M), water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1:1) to give 1-1.

[0444] Step 2. 4-amino-2,6-dichlorophenol (1.5 g, 8.43 mmol), 1-1 (1.67 g, 8.85 mmol), potassium carbonate (3.49 g, 25.3 mmol), CuI (0.80 g, 4.21 mmol) and dimethyl sulfoxide (DMSO) (30 mL) were added to a 100 mL flask purged with nitrogen. The resulting solution was stirred at 90 ° C for 18 hours, cooled to room temperature, diluted with water, adjusted to pH = 8 with HCl (1M) solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1:3 to 1:1) to obtain the product as a mixture of isomers, which was purified by recrystallization from ether and hexane to obtain 1-2.

[0445] 1 was synthesized according to a similar procedure as in Example 1. LCMS: (ESI, m / z): [M+H] +=433.2; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.30 (br s, 1H), 12.21 (s, 1H), 7.77 (s, 2H), 7.18 (s, 1H), 2.27-2.13 (m, 1H), 1.24-1.07 (m, 4H).

[0446] Example 7. Synthesis of Compound 25

[0447]

[0448] Step 1. Under nitrogen, a mixture of 4-amino-2,6-dichlorophenol (18.2 g, 102 mmol), 3,6-dichloropyridazine (15 g, 100 mmol) and cesium carbonate (37 g, 115 mmol) in N,N-dimethylacetamide (100 mL) was stirred at 110 ° C for 3 hours and then at 70 ° C for 16 hours. After cooling to room temperature, the mixture was filtered with celite, and the filtrate was poured into water (600 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 25-1, which was used directly in the next step.

[0449] Step 2. To a solution of 25-1 (14 g, 38.6 mmol) in acetic acid (120 mL) was added benzoic anhydride (9.6 g, 42.5 mmol), and the mixture was stirred at 100°C for 1 hour. After the reaction mixture was cooled to room temperature, sodium acetate (6.3 g, 77 mmol) was added, and the mixture was stirred at 110°C for 16 hours. After the mixture was cooled to 70°C, water (120 mL) was added dropwise, and the mixture was then cooled to room temperature and filtered. The filter cake was washed with water and recrystallized from acetic acid (220 mL) and water (200 mL) to give 25-2.

[0450] Step 3. Under nitrogen, at 35°C, benzylmagnesium chloride (1M in tetrahydrofuran, 35 mL, 35 mmol) was added dropwise to a stirred solution of 25-2 (2.2 g, 5.8 mmol) in tetrahydrofuran (45 mL). The mixture was stirred at 35°C for 1 hour, cooled to 10°C, adjusted to pH = 4 with 1M hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2:1) to give 25-3.

[0451] Step 4. At room temperature, bromine (1.6 g, 10 mmol) was added to a solution of 25-3 (1.2 g, 2.5 mmol) in acetic acid (120 mL). The mixture was stirred at 90 ° C for 3 hours and then cooled to room temperature. Water (220 mL) was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2: 1) to obtain 25-4.

[0452] Step 5. To a solution of 25-4 (0.35 g, 0.75 mmol) in tetrahydrofuran (5 mL) was added potassium hydroxide aqueous solution (10 wt%, 5 mL) at room temperature. The mixture was stirred at 80°C for 72 hours, cooled, concentrated to remove tetrahydrofuran, and adjusted to pH = 8 with 1M hydrochloric acid. The mixture was filtered, and the filter cake was washed with water, dried, and purified by preparative TLC (petroleum ether / ethyl acetate = 3:2) to give 25-5.

[0453] 25 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =483.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.30 (s, 1H), 7.73 (s, 2H), 7.32-7.30 (m, 5H), 7.25-7.22 (m, 1H), 3.83 (s, 2H).

[0454] Example 8. Synthesis of Compound 45

[0455]

[0456] Step 1. A solution of 5-fluoro-2-methylphenol (15 g, 118.9 mmol) in acetone (150 mL) in a 500 mL flask was cooled to 0 ° C and potassium carbonate (41.1 g, 297.3 mmol) was added. After stirring for 2 hours, chloro(methoxy)methane (10.5 g, 130.8 mmol) was added and the mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 45-1.

[0457] Step 2. Under nitrogen, at -78 ° C, n-butyl lithium (1.6M hexane solution, 70 mL, 112.9 mmol) was added to a stirred solution of 45-1 (16 g, 94.0 mmol) in tetrahydrofuran (160 mL), and the mixture was stirred at -78 ° C for 2 hours. MeI (17.4 g, 122.2 mmol) was added dropwise at -78 ° C, and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 45-2.

[0458] Step 3. To a stirred solution of 45-2 (21 g, 114.0 mmol) in MeOH (200 mL) was added concentrated HCl (4.50 mL) dropwise. The mixture was stirred at 50 °C for 3 hours and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether) to give 45-3.

[0459] Step 4. At 0 ° C, concentrated nitric acid (8.09 g, 128.43 mmol) was added dropwise to a stirred solution of 45-3 (15 g, 107.0 mmol) in dichloromethane (150 mL), and the mixture was stirred for 1 hour and then quenched with ice water at 0 ° C. The mixture was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=5:1) to obtain 45-4.

[0460] Step 5. Under nitrogen, 10% Pd / C (250 mg) was added in batches to a stirred solution of 45-4 (2.5 g, 13.5 mmol) and acetic anhydride (2.5 mL) in acetic acid (50 mL). The mixture was exchanged with hydrogen and stirred at room temperature for 3 hours, then filtered. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to give 45-5.

[0461] Step 6. Potassium carbonate (3.18 g, 22.8 mmol) and CuI (450 mg, 4.6 mmol) were added in batches to a stirred solution of 45-5 (1.45 g, 7.6 mmol) and 3,6-dichloro-4-(propan-2-yl)pyridazine (1.5 g, 7.61 mmol) in dimethyl sulfoxide (DMSO) (10 mL) at 90 ° C. The mixture was stirred at 90 ° C for 14 hours and then cooled to room temperature. After filtration, the filter cake was washed with ethyl acetate and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=5:1) to give 45-6.

[0462] Step 7. Sodium acetate (880 mg, 10.73 mmol) was added in batches to a stirred solution of 45-6 (1.2 g, 3.4 mmol) in acetic acid (10 mL). The mixture was stirred at 100 ° C for 14 hours, cooled to room temperature, and adjusted to pH = 8 with sodium hydroxide (1 M). The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5: 1) to give 45-7.

[0463] 45 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =413.2; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.08 (s, 1H), 7.35-7.32 (m, 2H), 3.11-3.02 (m, 1H), 2.12 (s, 3H), 2.08 (s, 3H), 1.20 (d, J=6.9 Hz, 6H).

[0464] Example 9. Synthesis of Compound 39

[0465]

[0466] 39-1 was synthesized according to a similar procedure as in Example 1.

[0467] Step 1. 39-1 (200 mg, 0.46 mmol), acetic acid (6 mL) and concentrated HCl (0.6 mL, 19.75 mmol) were added to a 100 mL flask, and the mixture was heated at 120 ° C for 24 hours. The resulting mixture was cooled to room temperature, diluted with 50 mL of water, and adjusted to pH = 5 with sodium hydroxide (1 M). The solution was extracted with ether, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (0.1% formic acid in water / acetonitrile = 61% to 80%) to give 39 (6.4 mg). LCMS (ESI, m / z): [M + H] + =454.2; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.18 (s, 1H), 8.14 (s, 1H), 7.81 (s, 2H), 7.44 (s, 1H), 3.14-2.95 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

[0468] Example 10. Synthesis of Compound 37

[0469]

[0470] Step 1. Add 35-3 (600 mg, 1.21 mmol), 2-oxobutanoic acid (247 mg, 2.42 mmol), ethanol (5 mL) and water (15 mL) to a 50 mL flask at room temperature. Stir the resulting mixture at room temperature for 1 hour and filter. Wash the filter cake with water, collect, and dilute with dichloromethane. Stir the slurry, filter, and dry the filter cake to obtain 37-1.

[0471] 37 was synthesized according to the similar procedure as in Example 5. LCMS (ESI, m / z): [M+H] + =438.2; HNMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.22 (s, 1H), 7.82 (s, 2H), 7.45 (s, 1H), 3.10-3.00 (m, 1H), 2.62-2.55 (m, 2H), 1.24 (s, 1H), 1.20 (d, J=6.9 Hz, 6H), 1.19-1.13 (m, 3H).

[0472] Example 11. Synthesis of Compound 40

[0473]

[0474] Step 1. To a suspension of 3,6-dichloropyridazine (10.0 g, 67.56 mmol) in water (200 mL) was added concentrated sulfuric acid (5.5 mL, 101.36 mmol), silver nitrate (1.15 g, 6.76 mmol) and 2-ethylbutyric acid (10.2 g, 87.84 mmol) at room temperature. The mixture was heated to 65 ° C, and a solution of ammonium persulfate (23.2 g, 101.36 mmol) in water (70 mL) was added dropwise over 20 minutes (T < 72 ° C). The mixture was stirred at 70 ° C for 0.5 hours, cooled to room temperature, and poured into ice water. The pH of the solution was adjusted to 9 with ammonium hydroxide and extracted with dichloromethane. The combined organic layers were washed with aqueous sodium hydroxide solution (1 M), water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 40-1, which was used in the next step without further purification.

[0475] Step 2. At room temperature, cesium carbonate (7.8 g, 23.98 mmol) and 4-amino-2,6-dichlorophenol (3.7 g, 20.85 mmol) were added to a solution of 40-1 (5.0 g, 22.94 mmol) in dimethylacetamide (50 mL). The mixture was stirred at 90 ° C for 6 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2: 1) to give a crude product, which was slurried with diethyl ether at 0 ° C. The slurry was filtered, the filter cake was collected and dried to give 40-2.

[0476] 40 was synthesized according to a similar procedure as in Example 5. LCMS (ESI, m / z): [M+H] + =452.3; HNMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.37 (s, 1H), 12.18 (s, 1H), 7.76 (s, 2H), 7.40 (s, 1H), 2.78-2.71 (m, 1H), 2.12 (s, 3H), 1.63-1.56 (m, 4H), 0.75 (t, J=7.2 Hz, 6H).

[0477] Example 12. Synthesis of Compound 33

[0478]

[0479] To a solution of 32 (75 mg, 0.15 mmol) in dichloromethane (5 mL) was added boron tribromide (0.5 mL) at 0°C. The mixture was stirred at 0°C for 2 hours and then poured into ice water. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile in water containing 0.05% trifluoroacetic acid: 20% to 95%) to give 33. LCMS (ESI, m / z): [M+H] + =499.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.14 (br s, 1H), 12.25 (s, 1H), 9.28 (s, 1H), 7.74 (s, 2H), 7.21 (s, 1H), 7.11 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.70 (s, 2H).

[0480] Example 13. Synthesis of Compound 27

[0481]

[0482] Step 1. At room temperature, concentrated sulfuric acid (12.6 g, 126 mmol), silver nitrate (1.4 g, 8.4 mmol) and 2-phenylacetic acid (15 g, 110 mmol) were added to a suspension of 3,6-dichloropyridazine (12.5 g, 84 mmol) in water (160 mL). The mixture was heated to 65 ° C, and a solution of ammonium persulfate (28 g, 126 mmol) in water (100 mL) was added dropwise over 20 minutes (T < 72 ° C). After stirring at 70 ° C for 0.5 hours, the reaction mixture was cooled to 0 ° C and separated. The organic layer was diluted with dichloromethane and washed with aqueous sodium hydroxide solution (1 M), water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate / petroleum ether = 0 to 12%) to give 27-1.

[0483] Step 2. A mixture of 4-amino-2,6-dichlorophenol (2.3 g, 13 mmol), 27-1 (2.8 g, 11.7 mmol) and cesium carbonate (4.3 g, 13 mmol) in dimethylacetamide (50 mL) was stirred at 90 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1:2) to give 27-2.

[0484] 27 was synthesized according to a similar procedure as in Example 5. LCMS (ESI, m / z): [M+H] + =472.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.38 (s, 1H), 12.28 (s, 1H), 7.76 (s, 2H), 7.33-7.32 (m, 4H), 7.26 (s, 1H), 7.25-7.24 (m, 1H), 3.83 (s, 2H), 2.13 (s, 3H).

[0485] Example 14. Synthesis of Compound 28

[0486]

[0487] Zinc cyanide (8.7 mg, 0.075 mmol), Pd2(dba)3 (9.1 mg, 0.01 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11.6 mg, 0.02 mmol) were added to a solution of 29 (30 mg, 0.05 mmol) in N,N-dimethylformamide (DMF) (4 mL), and the mixture was stirred at 110 °C for 6 hours under nitrogen. The reaction mixture was cooled to room temperature and purified by preparative HPLC (acetonitrile in water containing 0.05% TFA: 15% to 65%) to give 28. LCMS (ESI, m / z): [M+H] + =508.3; HNMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.24 (br s, 1H), 12.35 (s, 1H), 7.78 (d, J=8.4 Hz, 2H) 7.74 (s, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.46 (s, 1H), 3.93 (s, 2H).

[0488] Example 15. Synthesis of Compound 16

[0489]

[0490] Step 1. At room temperature, 3-oxocyclobutane-1-carboxylic acid (23g, 201mmol), ammonium persulfate (30.6g, 134mmol), silver nitrate (11.4g, 67mmol) and trifluoroacetic acid (1.5g, 13.4mmol) were added to a solution of 3,6-dichloropyridazine (10g, 67mmol) in acetonitrile (150mL) and water (150mL). The reaction mixture was stirred at 70°C for 2 hours under a nitrogen atmosphere. The mixture was cooled and filtered. The filtrate was neutralized with ammonium hydroxide to pH=8 and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=3:1) to obtain 16-1.

[0491] Step 2. Potassium borohydride (180 mg, 3.4 mmol) was added to a solution of 16-1 (560 mg, 2.6 mmol) in methanol (10 mL) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 1 hour and then quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 16-2.

[0492] Step 3. Cesium carbonate (1.8 g, 5.7 mmol) and 4-amino-2,6-dichlorophenol (342 mg, 1.9 mmol) were added to a solution of 16-2 (420 mg, 1.9 mmol) in dimethylacetamide (15 mL). The reaction mixture was stirred at 90 ° C for 2 hours under nitrogen, cooled to room temperature, and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1: 1) to obtain 16-3.

[0493] 16 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =463.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): 13.24 (br s, 1H), 12.17 (s, 1H), 7.75 (s, 2H), 7.41 (d, J=0.8 Hz, 1H), 5.12-5.08 (m, 1H), 4.08-4.02 (m, 1H), 2.97-2.85 (m, 1H), 2.65-2.43 (m, 2H), 1.89-1.71 (m, 2H).

[0494] Example 16. Synthesis of Compound 21

[0495]

[0496] Step 1. Under nitrogen atmosphere, at -78 ° C, methylmagnesium bromide (3M in ether, 8.5 mL, 25.5 mmol) was added to a solution of 16-1 (2.2 g, 10.2 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 0 ° C for 1 hour, then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 3: 1) to obtain 21-1.

[0497] 21 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =477.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): 13.26 (br s, 1H), 12.18 (s, 1H), 7.75 (s, 2H), 7.43 (d, J=1.2 Hz, 1H), 5.00 (s, 1H), 3.05-3.00 (m, 1H), 2.30-2.25 (m, 2H), 2.09-2.03 (m, 2H), 1.30 (s, 3H).

[0498] Example 17. Synthesis of Compound 34

[0499]

[0500] 34-1 was synthesized according to a similar procedure as in Example 22.

[0501] Step 1. Boron tribromide (0.5 mL) was added to a solution of 34-1 (20 mg, 0.04 mmol) in dichloromethane (10 mL) at 0°C. The mixture was stirred at 0°C for 2 hours and then poured into ice water (10 mL). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile aqueous solution containing 0.05% trifluoroacetic acid: 20% to 95%) to give 34. LCMS (ESI, m / z): [M+H] + =499.3; H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.24 (br s, 1H), 12.29 (s, 1H), 9.36 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.73-6.69 (m, 2H), 6.63-6.60 (m, 1H), 3.73 (s, 2H).

[0502] Example 18. Synthesis of Compound 36

[0503]

[0504] Step 1. To a stirred suspension of cyclopropyl methyl ketone (0.5 g, 5.94 mmol) in water (5 mL) of sodium hydroxide (0.29 g, 7.25 mmol) was slowly added a solution of KMnO4 (1.88 g, 11.9 mmol) in water (40 mL) at 0°C. The resulting mixture was stirred at room temperature for 24 hours and the solids were removed by filtration. The filtrate was concentrated in vacuo to about 10 mL at 50°C and acidified to pH = 3 with concentrated HCl, then extracted with CH2Cl2. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 36-1.

[0505] Step 2. 36-1 (59 mg, 0.52 mmol), ethanol (2 mL) and 35-3 (170 mg, 0.52 mmol) were added to a 25 mL flask purged with nitrogen. The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:2) to give 36-2.

[0506] 36 was synthesized according to a similar procedure as in Example 5. LCMS (ESI, m / z): [M+H] + =450.1; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.20 (s, 1H), 7.76 (s, 2H), 7.43 (s, 1H), 3.06-3.20 (m, 1H), 2.10-2.20 (m, 1H), 1.18-1.24 (m, 1H), 1.20 (m, 6H), 0.88-0.95 (m, 3H).

[0507] Example 19. Synthesis of Compound 19

[0508]

[0509] Step 1. 4-bromo-1,2,3,6-tetrahydropyridazine-3,6-dione (500 mg, 2.62 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethan-1-one (789 mg, 3.142 mmol), potassium carbonate (729 mg, 5.24 mmol), 1,2-dimethoxyethane (8 mL), water (2 mL) and Pd(dtbpf)Cl2 (171 mg, 0.26 mmol) were added to a 20 mL sealed tube purged with nitrogen. The reaction mixture was irradiated at 100 ° C for 1 hour under microwave. The mixture was cooled to room temperature, filtered and concentrated. The residue was purified by reverse phase column chromatography with 0.1% formic acid in water-acetonitrile (gradient of 20% to 40% in 5 minutes) to give 19-1.

[0510] Step 2. To a 250 mL flask purged with nitrogen was added 19-1 (1.0 g, 4.25 mmol), 10% Pd / C (150 mg, 1.41 mmol) and N-methylpyrrolidone (NMP) (60 mL). The resulting mixture was stirred at room temperature for 2 hours under H2 atmosphere. The mixture was filtered and the filtrate was concentrated to give 19-2.

[0511] Step 3. 19-2 (1.0 g, 4.22 mmol) and POCl3 (10 mL) were added to a 40 mL flask, and the resulting solution was stirred at 120 ° C for 3 hours. The mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:2) to obtain 19-3.

[0512] 19 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] +=517.9; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.26 (br s, 1H), 12.30 (s, 1H), 7.78 (s, 2H), 7.45 (s, 1H), 4.52-4.56 (m, 1H), 3.91-3.95 (m, 1H), 2.96-3.54 (m, 2H), 2.59-2.81 (m, 1H), 2.03 (s, 3H), 1.81-1.89 (m, 2H), 1.49-1.62 (m, 2H).

[0513] Example 20. Synthesis of Compound 47

[0514]

[0515] Step 1. A solution of 3,6-dichloro-4-(propan-2-yl)pyridazine (5.0 g, 26.17 mmol) in tetrabutylammonium fluoride (TBAF) (1.0 M solution in tetrahydrofuran (THF), 78.5 mL) was heated at 50 ° C overnight. Tetrabutylammonium fluoride (TBAF) (1.0 M solution in tetrahydrofuran (THF), 13.0 mL) was then added, and the mixture was heated at 60 ° C for another 2 hours. The reaction mixture was then cooled to room temperature and quenched with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:5) to give 47-1.

[0516] Step 2. To a suspension of 4-nitro-2-(trifluoromethyl)phenol (5.00 g, 24.14 mmol) and Cs2CO3 (15.73 g, 48.28 mmol) in acetonitrile (50 mL) was added N-chlorosuccinimide (NCS) (9.67 g, 72.43 mmol). The resulting mixture was stirred at 80 °C for 3 hours. The solution was concentrated in vacuo to remove the solvent, and water (100 mL) was added. The resulting solution was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=3:10) to give 47-2.

[0517] Step 3. To a solution of 47-2 (3.00 g, 12.42 mmol) and NH4Cl (6.64 g, 124.20 mmol) in water (15 mL) and ethanol (30 mL) was added Zn powder (4.06 g, 62.10 mmol). The resulting mixture was stirred at room temperature overnight and then filtered. The filtrate was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 47-3, which was used in the next step without further purification.

[0518] Step 4. A solution of 47-3 (1.40 g, 6.62 mmol) in acetic anhydride (10 mL) was heated at 100 ° C for 2 hours. The reaction mixture was then cooled to room temperature and quenched with water (50 mL). The resulting solution was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 47-4, which was used in the next step without further purification.

[0519] Step 5. To a solution of 47-4 (1.40 g, 4.74 mmol) in tetrahydrofuran (THF) (14 mL) and water (7 mL) was added LiOH.H2O (0.40 g, 9.471 mmol). The resulting solution was stirred at room temperature for 2 hours and then diluted with water. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 47-5, which was used in the next step without further purification.

[0520] Step 6. To a solution of 47-5 (1.14 g, 4.50 mmol) in dimethyl sulfoxide (DMSO) (10 mL) was added 47-1 (1.96 g, 11.24 mmol), potassium carbonate (1.24 mg, 8.99 mmol) and CuI (514 mg, 2.70 mmol). The resulting solution was heated at 90 ° C overnight. The reaction mixture was cooled to room temperature and then quenched with water. The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1:2) to give 47-6.

[0521] 47 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): [M+H] + =469.1; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.37 (br s, 1H), 12.28 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 3.10-3.00 (m, 1H), 1.20 (d, J=6.6 Hz, 6H).

[0522] Example 21. Synthesis of Compound 56

[0523]

[0524] Step 1. To a solution of 4-(benzyloxy)phenylhydrazine (10.0 g, 46.67 mmol) and 3-methylbutanal (4.02 g, 46.67 mmol) in ethanol (100 mL) was added 1% H2SO4 (66 mL) dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at 80°C for 3 hours and then cooled to room temperature. The mixture was partially concentrated under reduced pressure and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 8) to give 56-1.

[0525] Step 2. Under nitrogen atmosphere, 10% Pd / C (0.4 g) was added to a solution of 56-1 (4.0 g, 15.07 mmol) in methanol (120 mL). The resulting mixture was stirred at room temperature for 16 hours under H2 atmosphere, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:3) to give 56-2.

[0526] Step 3. To a solution of 56-2 (322 mg, 1.84 mmol) in dimethyl sulfoxide (DMSO) (3.2 mL) was added 1,3-dichloro-2-fluoro-5-nitrobenzene (425 mg, 2.02 mmol) and potassium carbonate (508 mg, 3.68 mmol) at room temperature. The mixture was heated at 125 ° C for 2 hours under a nitrogen atmosphere. The resulting mixture was then cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:50) to give 56-3.

[0527] Step 4. To a solution of 56-3 (600 mg, 1.64 mmol) in toluene (6 mL) was added p-toluenesulfonyl chloride (376 mg, 1.97 mmol) in toluene (3 mL), 50% aqueous KOH (6 mL) and Bu4NHSO4 (56 mg, 0.16 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, then water (25 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:60) to give 56-4.

[0528] Step 5. To a suspension of 56-4 (1.07 g, 2.06 mmol) in ethanol (22 mL) and water (11 mL) was added NH4Cl (882 mg, 16.48 mmol) and iron powder (575 mg, 10.30) in batches. Under a nitrogen atmosphere, the resulting mixture was stirred at 50 ° C for 2 hours, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:6) to give 56-5.

[0529] 56-6 was synthesized according to a similar procedure as in Example 1.

[0530] Step 6. To a stirred solution of 56-6 (190 mg, 0.31 mmol) in tetrahydrofuran (THF) (4 mL) was added tetrabutylammonium fluoride (TBAF) (1 M in tetrahydrofuran (THF), 4.0 mL) in portions under nitrogen atmosphere at room temperature. The resulting mixture was heated at 65° C. for 48 hours under nitrogen atmosphere, then cooled and quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC with 0.05% NH3·H2O aqueous solution / acetonitrile to give 56. LCMS (ESI, m / z): [M+H] + =455.8; H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ10.79 (s, 1H), 7.80 (s, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.11-7.12 (m, 1H), 6.90 (s, 1H), 6.67 (dd, J=8.7, 2.5 Hz, 1H), 2.98-3.03 (m, 1H), 1.22-1.24 (d, J=6.9 Hz, 6H).

[0531] Example 22. Synthesis of Compound 58

[0532]

[0533] Step 1. To a suspension of 2,6-dichloro-4-nitrophenol (41.6 g, 200 mmol) and potassium carbonate (110.4 g, 800 mmol) in dimethylformamide (200 mL) was added iodomethane (56.8 g, 400 mmol) at 0°C. The mixture was stirred at 60°C for 1.5 hours, then cooled to room temperature and quenched with water (1 L). The resulting slurry was stirred for 10 minutes and filtered. The filter cake was washed with water and dried to give 58-1.

[0534] Step 2. To a solution of 58-1 (18 g, 81 mmol) in ethanol (250 mL) at room temperature, stannous chloride (76.8 g, 405 mmol) was added in portions. The resulting mixture was heated at 80°C for 2 hours, cooled to room temperature, and then poured into ice water (500 mL). The solution was adjusted to about pH = 9 with 2N aqueous sodium hydroxide solution and filtered through celite. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 58-2.

[0535] 58-3 was synthesized according to a similar procedure as in Example 5.

[0536] Step 3. Boron tribromide (0.2 mL) was added to a solution of 58-3 (178 mg, 0.59 mmol) in dichloromethane (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, then quenched with saturated aqueous sodium bicarbonate at 0° C. and adjusted to pH=5 with HCl (1 M). The mixture was filtered and the solid was dried to give 58-4.

[0537] Step 4. To a suspension of 3,6-dichloropyridazine (455 mg, 3.0 mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (970 mg, 4.0 mmol), silver nitrate (510 mg, 3.0 mmol) and trifluoroacetic acid (68 mg, 0.6 mmol) in acetonitrile (20 mL) and water (20 mL) was added a solution of ammonium persulfate (1.37 g, 6 mmol) at 65°C. The reaction mixture was then heated at 75°C for 2 hours, then cooled to room temperature and neutralized with NH3·H2O. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to ethyl acetate / petroleum ether = 0 to 30% to give 58-5.

[0538] Step 5. A mixture of 58-5 (500 mg, 1.45 mmol) and potassium fluoride (336 mg, 5.8 mmol) in dimethyl sulfoxide (40 mL) was heated at 120° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate / petroleum ether=0 to 30%) to give 58-6.

[0539] Step 6. Potassium fluoride (84 mg, 1.44 mmol) was added to a solution of 58-6 (234 mg, 0.71 mmol) and 58-4 (68 mg, 0.24 mmol) in dimethyl sulfoxide (40 mL) at room temperature. The reaction mixture was heated at 100 ° C for 2 days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate / petroleum ether = 0 to 70%) to give 58-7.

[0540] Step 7. Sodium acetate (27 mg, 0.34 mmol) was added to a solution of 58-7 (50 mg, 0.084 mmol) in acetic acid (5 mL) at room temperature, and the mixture was heated at 100 ° C overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 58-8, which was used in the next step without further purification.

[0541] Step 8. To a solution of 58-8 (30 mg, 0.052 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (59 mg, 0.52 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by preparative HPLC (acetonitrile in water containing 0.05% TFA: 25% to 50%) to give 58. LCMS (ESI, m / z): [M+H] + =479.4.HNMR(400MHz,CD3OD): δ7.76(s,2H),7.45(s,1H),3.40-3.37(m,2H),3.00-2.94(m,2H ), 2.62 (d, J = 6.8 Hz, 2H), 2.24 (s, 3H), 2.12-2.07 (m, 1H), 1.95-1.92 (m, 2H), 1.54-1.43 (m, 2H).

[0542] Example 23. Synthesis of Compound 70

[0543]

[0544] Step 1. Under N2 atmosphere, at 70°C, a solution of 2-(4-hydroxyphenyl)acetic acid methyl ester (5 g, 30 mmol) and diisobutylamine (388 mg, 3.0 mmol) in toluene (50 mL) was added dropwise with a solution of sulfonyl chloride (8.1 g, 60 mmol) in toluene (16 mL). The mixture was then stirred at 70°C for 1 hour, poured into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 70-1.

[0545] Step 2. Under N2 atmosphere, at -10°C, to a solution of 70-1 (4.9 g, 20.94 mmol) in tetrahydrofuran (100 mL) was added dropwise LiAlH4 (8.4 mL, 2.5 M solution in tetrahydrofuran, 20.94 mmol). The mixture was then stirred at -10°C for 15 minutes and then quenched with water and 15% aqueous sodium hydroxide solution at 0°C. The mixture was diluted with ethyl acetate and filtered. The filter cake was rinsed with ethyl acetate, and the filtrate was washed with aqueous hydrochloric acid (1N), water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give 70-2.

[0546] Step 3. Under N2 atmosphere, a mixture of 70-2 (2.75 g, 13.35 mmol), 3,6-dichloro-4-(propan-2-yl)pyridazine (3.06 g, 16.02 mmol), potassium carbonate (3.68 g, 26.70 mmol) and cuprous iodide (1.27 g, 6.68 mmol) in dimethyl sulfoxide (14 mL) was stirred at 90 ° C for 4 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1: 1) to give a crude product, which was slurried with ether at 0 ° C. The slurry was filtered, and the filter cake was washed with ether and dried to give 70-3.

[0547] Step 4. CBr4 (815 mg, 2.49 mmol) was added to a solution of 70-3 (600 mg, 1.66 mmol) and triphenylphosphine (653 mg, 2.49 mmol) in dichloromethane (10 mL) at room temperature. The mixture was stirred for 1 hour and then concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1:1) to give 70-4.

[0548] Step 5. A mixture of 70-4 (300 mg, 0.71 mmol) in triethyl phosphite (1 mL) was heated at 130 °C for 5 hours and then concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 1:1) to give 70-5.

[0549] Step 6. To a solution of 70-5 (250 mg, 0.52 mmol) in acetic acid (2 mL) was added sodium acetate (255 mg, 3.11 mmol) at room temperature. The mixture was heated at 120°C for 16 hours, then poured into water and filtered. The filter cake was dried to give 70-6.

[0550] Step 7. To a solution of 70-6 (190 mg, 0.41 mmol) in acetonitrile (3 mL) was added bromo(trimethyl)silane (0.5 mL) at room temperature. The mixture was heated at 70°C for 3 hours, then poured into water and filtered. The filter cake was purified by preparative HPLC (acetonitrile in water containing 0.05% TFA: 15% to 95%) to give 70. LCMS (ESI, m / z): 407.3 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.15 (s, 1H), 7.45 (s, 2H), 7.33 (d, J = 0.8 Hz, 1H), 3.05-2.94 (m, 1H), 2.80-2.73 (m, 2H), 1.88-1.79 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H).

[0551] Example 24. Synthesis of Compounds 71 ​​and 72

[0552]

[0553] Step 1. At -5 ° C, NaH (60% in oil, 2.51 g, 62.74 mmol) was added to a solution of 27-1 (10.0 g, 41.82 mmol) in N, N-dimethylformamide (DMF) (100 mL) in batches. To the mixture was added dropwise iodomethane (10.09 g, 71.10 mmol) at -5 ° C. The resulting solution was stirred at -5 ° C for 3 hours and then quenched with NH4Cl (aqueous solution). The mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:10) to give 71-1.

[0554] 71-2 was synthesized according to the similar steps in Example 13, and 71-3 was synthesized according to the similar steps in Example 5. The racemic compound 71-3 was separated by chiral preparative HPLC (analysis conditions: chiral column: Whelk-O 1-(R,R), column size: 0.46*5cm, particle size: 3.5μm, mobile phase: NH3·H2O (pH=9.5):MeOH=10:90, flow rate 1.0mL / min), and 71 (enantiomer A, first elution, retention time 1.562 minutes) and 72 (enantiomer B, second elution, retention time 2.145 minutes) were obtained respectively. 71.LCMS(ESI,m / z):486.2[M+H] +.HNMR (300MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.42 (s, 1H), 12.26 (s, 1H), 7.84-7.75 (m, 2H), 7.53 (s, 1H), 7.34-7.43 (m 4H), 7.25 (s, 1H), 4.35-4.22 (m, 1H), 2.16 (s, 3H), 1.61-1.44 (m, 3H). 72. LCMS (ESI, m / z): 486.2 [M+H] + .H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.42 (s, 1H), 12.26 (s, 1H), 7.86-7.74 (m, 2H), 7.53 (s, 1H), 7.34-7.43 (m 4H), 7.25 (s, 1H), 4.38-4.24 (m, 1H), 2.16 (s, 3H), 1.61-1.44 (m, 3H).

[0555] Example 25. Synthesis of Compound 74

[0556]

[0557] 74-1 was synthesized according to a similar procedure as in Example 5.

[0558] Step 1. To a solution of 74-1 (1.6 g, 4 mmol) in acetic acid (20 mL) was added sodium acetate (1.64 g, 20 mmol) at room temperature. The mixture was heated at 120°C for 8 hours, then poured into water and filtered. The filter cake was washed with water and dried to give 74-2.

[0559] Step 2. Zinc powder (780 mg, 12 mmol) was added to a suspension of 74-2 (305 mg, 0.8 mmol) in acetic acid (20 mL). The mixture was then heated at 85 °C for 48 hours under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 74-3.

[0560] Step 3. Under a nitrogen atmosphere, a mixture of 74-3 (200 mg, 0.5 mmol), 2-pyridinecarboxaldehyde (80 mg, 0.75 mmol) and potassium hydroxide (140 mg, 2.5 mmol) in ethanol (10 mL) was heated at 80 ° C for 1 hour. After cooling to room temperature, the mixture was neutralized with acetic acid to pH ~ 4, diluted with water, and extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol=10:1) to give 74-4.

[0561] Step 4. To a solution of 74-4 (25 mg, 0.05 mmol) in ethanol (30 mL) was added (diacetoxyiodo)benzene (32 mg, 0.1 mmol) at room temperature. The mixture was stirred for 24 hours and then concentrated to give a residue, which was purified by preparative HPLC (acetonitrile aqueous solution containing 0.05% trifluoroacetic acid (TFA): 12% to 95%) to give 74. LCMS (ESI, m / z): 473.3 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.38 (s, 1H), 12.32 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 7.92-7.88 (m, 1H), 7.76 (s, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.41-7.37 (m, 1H), 4.06 (s, 2H), 2.12 (s, 3H).

[0562] Example 26. Synthesis of Compound 73

[0563]

[0564] Step 1. To a suspension of 25-2 (4.5 g, 12 mmol) in acetic acid (150 mL) was added zinc powder (4.6 g, 70 mmol). The mixture was then heated to 80 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water, aqueous NaHCO3 and brine, then dried over sodium sulfate, filtered and concentrated to give 73-1.

[0565] Step 2. At 0°C, to a suspension of 1H-indazole-5-carboxaldehyde (1.46 g, 10 mmol) in dichloromethane (100 mL), potassium hydroxide aqueous solution (50%, 20 mL) was added, followed by tetrabutylammonium bromide (32 mg, 0.1 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (2.13 mL, 12 mmol). Under N2 atmosphere, the mixture was stirred at 0°C for 4 hours. The mixture was then washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether to dichloromethane / petroleum ether=1:1) to give 73-2.

[0566] Step 3. To a solution of 73-2 (440 mg, 1.6 mmol) in ethanol (10 mL) was added 73-1 (500 mg, 1.3 mmol) and potassium hydroxide (260 mg, 3.9 mmol) at room temperature. The mixture was heated at 80 ° C overnight under a N2 atmosphere. Aqueous potassium hydroxide solution (50%, 10 mL) was then added, and the mixture was heated at 90 ° C for 5 hours and then concentrated. The residue was diluted with dichloromethane, neutralized with acetic acid to pH ~ 3 and separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane to ethyl acetate / dichloromethane = 1: 1) to give 73-3.

[0567] 73 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): 523.3 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.26 (br s, 1H), 13.01 (s, 1H), 12.30 (s, 1H), 8.01 (s, 1H), 7.73 (s, 2H), 7.69 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.28 (s, 1H), 3.92 (s, 2H).

[0568] Example 27. Synthesis of Compound 80

[0569]

[0570] Step 1. At 25°C, a solution of 2,6-dichloro-4-nitrophenol (10.0 g, 48 mmol) in N,N-dimethylformamide (200 mL) was treated with 1,4-diazabicyclo[2.2.2]octane (10.0 g, 96 mmol) and dimethylthiocarbamoyl chloride (9.5 g, 76 mmol). The reaction was stirred at 25°C for 18 hours. The mixture was then diluted with ethyl acetate, washed with aqueous hydrochloric acid, water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give 80-1.

[0571] Step 2. Neat 80-1 (6.6 g, 23 mmol) was heated to 180-200° C. for 20 min and then cooled to give 80-2.

[0572] Step 3. A mixture of 80-2 (5.0 g, 17 mmol) in acetic acid (30 mL), 2-propanol (60 mL) and water (30 mL) was heated to 50 ° C, and iron powder (2.63 g, 47.3 mmol) was then added. The resulting mixture was heated to 95 ° C for 2 hours. The reaction mixture was then filtered through a celite pad, and the filter cake was washed with hot water and ethyl acetate. The filtrate was concentrated, diluted with water, and neutralized with ammonium hydroxide to pH = 8. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was slurried with diethyl ether, filtered and concentrated to give 80-3.

[0573] Step 4. An ethanol solution of 80-3 (2.0 g, 7.5 mmol) was treated with aqueous potassium hydroxide solution (3N, 5 mL). The mixture was heated to 95° C. for 2 days, then cooled to 25° C. and neutralized to pH=2 with hydrochloric acid (3N). The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give a residue, which was purified by flash chromatography to give 80-4.

[0574] Step 5. A mixture of 80-4 (500 mg, 2.6 mmol), 27-1 (2.3 g, 10 mmol), cesium carbonate (5.2 g, 16.0 mmol) in dimethylacetamide (2 mL) was heated at 90 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 100 to 50%) to give 80-5.

[0575] 80 was synthesized according to a similar procedure as in Example 1. LCMS (ESI, m / z): 499.3 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.27 (bs, 1H), 12.93 (s, 1H), 7.76 (s, 2H), 7.27-7.19 (m, 5H), 7.09 (s, 1H), 3.74 (s, 2H).

[0576] Example 28. Synthesis of Compound 85

[0577]

[0578] Step 1. At 0°C, a solution of (4-methoxy-2,6-dimethylphenyl)methanol (1.0 g, 6.0 mmol) in diethyl ether (15 mL) was added dropwise with phosphorus tribromide (1.9 g, 7.2 mmol) in diethyl ether (2 mL). The mixture was stirred at 0°C to room temperature for 40 minutes and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 85-1.

[0579] Step 2. At 0°C, trimethylsilyl cyanide (437 mg, 4.9 mmol) and tetrabutylammonium fluoride (1M in tetrahydrofuran (THF) solution, 4.4 mL, 4.4 mmol) were added to a solution of 85-1 (600 mg, 2.6 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 2 hours and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 10:1) to give 85-2.

[0580] Step 3. At room temperature, potassium tert-butoxide (290 mg, 2.6 mmol) was added to a solution of 85-2 (350 mg, 2.0 mmol) and 3,6-dichloro-4-(propan-2-yl)pyridazine (380 mg, 2.0 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at 60 ° C for 3 hours and then quenched with water. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 8: 1) to give 85-3.

[0581] Step 4. To a solution of 85-3 (300 mg, 0.91 mmol) in acetic acid (3 mL) was added concentrated HCl (15 mL). The mixture was then heated to 120 ° C overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 8: 1) to give 85-4.

[0582] Step 5. Cesium carbonate (362 mg, 1.11 mmol) was added to a solution of 85-4 (100 mg, 0.37 mmol) and 4-methylbenzenesulfonic acid (diethoxyphosphoryl) methyl ester (95 mg, 0.29 mmol) in N, N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate = 3:1) to give 85-5.

[0583] Step 6. Bromotrimethylsilane (0.5 mL) was added dropwise to a solution of 85-5 (20 mg, 0.05 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and the residue was purified by preparative HPLC (acetonitrile aqueous solution containing 0.05% trifluoroacetic acid (TFA): 25% to 50%) to give 85. LCMS (ESI, m / z): 367.3 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.53 (s, 1H), 6.97 (s, 1H), 6.61 (s, 2H), 3.94 (d, J = 10.0 Hz, 2H), 3.80 (s, 2H), 2.91 (t, J = 6.8 Hz, 1H), 2.14 (s, 6H), 1.05 (d, J = 6.8 Hz, 6H).

[0584] Example 29. Synthesis of Compound 84

[0585]

[0586] Step 1. Under nitrogen, 5-methoxy-1H-pyrrolo[2,3-b]pyridine (10.0 g, 67.5 mmol) was added to a suspension of AlCl3 (45.0 g, 337.5 mmol) in dichloromethane (DCM) (150 mL). The reaction mixture was stirred at ambient temperature for 1 hour, during which acetyl chloride (26.5 g, 337.5 mmol) was added dropwise, and the resulting mixture was stirred for 5 hours. The reaction was cooled to 0 ° C, quenched with MeOH and concentrated. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to give 84-1.

[0587] Step 2. At -10 ° C, MeMgBr (21 mL, 42.0 mmol) was added to a solution of 84-1 (2.0 g, 10.52 mmol) in tetrahydrofuran (THF) (5 mL). The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere and then quenched with a saturated NH4Cl aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 1) to give 84-2.

[0588] Step 3. Triethylsilane (1.69 g, 14.53 mmol) and trifluoroacetic acid (2.76 g, 24.21 mmol) were added dropwise to a solution of 84-2 (1.0 g, 4.85 mmol) in anhydrous dichloromethane (20 mL) at 0 ° C. The mixture was stirred at room temperature overnight and then poured into ice water. The mixture was neutralized to pH 4 to 5 with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (3% to 10% ethyl acetate in petroleum ether) to give 84-3.

[0589] Step 4. At 0°C, NaH (60%, 315 mg, 7.89 mmol) was added to a solution of 84-3 (1.25 g, 6.57 mmol) in tetrahydrofuran (THF) (25 mL), and the mixture was stirred for 0.5 hours, and then TsCl (1.5 g, 7.89 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Ice water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10:1) to give 84-4.

[0590] Step 5. To a solution of 84-4 (980 mg, 2.85 mmol) in dichloromethane (DCM) (20 mL) was added dropwise BBr3 (1.0 M in dichloromethane (DCM), 5.38 mL) at 0°C. The mixture was stirred at 0°C for 1.5 hours and then quenched with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 84-5.

[0591] Step 6. Potassium carbonate (1.41 g, 10.20 mmol) was added in batches to a solution of 84-5 (1.12 g, 3.39 mmol) and 1,3-dichloro-2-fluoro-5-nitrobenzene (0.71 g, 3.38 mmol) in dimethyl sulfoxide (DMSO) (10 mL). The mixture was stirred for 2 hours and then diluted with water. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give 84-6.

[0592] Step 7. A mixture of 84-6 (1.20 g, 2.31 mmol), iron powder (644 mg, 11.53 mmol) and NH4Cl (987 mg, 18.45 mmol) in ethanol / water (2:1, 30 mL) was heated at 70 °C for 3 hours. The mixture was then filtered and the filter cake was washed with EtOAc. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give 84-7.

[0593] 84-8 was synthesized following a similar procedure as in Example 1.

[0594] Step 8. Under nitrogen atmosphere, a mixture of 84-8 (100 mg, 0.16 mmol) and tetrabutylammonium fluoride (TBAF) (1 M in tetrahydrofuran (THF), 0.8 mL, 0.80 mmol) in tetrahydrofuran (THF) (6 mL) was heated at 65 ° C overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (ethyl acetate) to give a crude product, which was purified by preparative HPLC to give 84. LCMS (ESI, m / z): 457.2 [M+H] + .H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ13.28 (bs, 1H), 11.40 (s, 1H), 7.95 (s, 1H), 7.86 (s, 2H), 7.40 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 3.11-3.02 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H).

[0595] Example 30. Synthesis of Compound 86

[0596]

[0597] Step 1. Under N2 atmosphere, a mixture of 29 (108 mg, 0.19 mmol), isopropenylboronic acid pinacol ester (39 mg, 0.23 mmol), potassium carbonate (53 g, 0.38 mmol) and tetrakis (triphenylphosphine) palladium (6 mg, 0.005) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was heated at 90 ° C for 4 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol=8 / 1) to give 86-1.

[0598] Step 2. A solution of 86-1 (70 mg, 0.13 mmol) and 3-chloroperbenzoic acid (28 mg, 0.16 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. The mixture was then quenched with aqueous sodium thiosulfate, diluted with water and extracted with dichloromethane / tetrahydrofuran (2: 1). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was slurried with dichloromethane (1 mL) to give a crude product, which was purified by preparative HPLC (acetonitrile in water containing 0.05% TFA: 10% to 75%) to give 86. LCMS (ESI, m / z): 557.4 [M+H] + .H NMR (400 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.28 (s, 1H), 7.73 (s, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 4.81 (s, 1H), 4.65-4.59 (m, 1H), 3.78 (s, 2H), 1.34 (s, 3H).

[0599] Example 31. Synthesis of Compounds 90 and 91

[0600]

[0601] Step 1. At -78 ° C, 5- (benzyloxy) -2-nitrobenzaldehyde (9.50 g, 36.93 mmol) in tetrahydrofuran (THF) (20 mL) solution was added bromo (prop-1-en-2-yl) magnesium (7.51 g, 51.69 mmol). The mixture was stirred at -78 ° C for 3 hours under nitrogen atmosphere and then quenched with aqueous HCl to pH 5. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1) to give 90-1.

[0602] Step 2. A mixture of 90-1 (7.40 g, 24.72 mmol) and Dess-Martin reagent (12.58 g, 29.66 mmol) in dichloromethane (DCM) (100 mL) and pyridine (5 mL) was stirred at room temperature for 2 hours. Aqueous Na2CO3 solution was added and the mixture was filtered. The filtrate was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100:1) to give 90-2.

[0603] Step 3. To a solution of 90-2 (3.50 g, 11.77 mmol) in ethanol (20 mL) was added 10% Pd / C (2.51 g, 2.36 mmol), and the mixture was stirred under H2 atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give 90-3.

[0604] Step 4. At 0°C, a solution of 90-3 (1.70 g, 9.49 mmol) in HCl (concentrated, 10 mL) was added with a solution of NaNO2 (720 mg, 10.43 mmol) in water (5 mL). After stirring for 1 hour, a solution of SnCl2·2H2O (5.14 g, 22.77 mmol) in HCl (concentrated, 5 mL) was added, and the mixture was stirred at 0°C for 2 hours. The mixture was then diluted with water and neutralized to pH 7 with a saturated aqueous NaHCO3 solution. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to give 90-4.

[0605] Step 5. A mixture of 90-4 (2.0 g, 11.35 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (2.38 g, 11.33 mmol) and potassium carbonate (1.88 g, 13.60 mmol) in N,N-dimethylformamide (DMF) (10 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give 90-5 and 91-1, respectively.

[0606] 90 was synthesized according to a similar procedure as in Example 29. LCMS (ESI, m / z): 457.1 [M+H] + .H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ12.62 (s, 1H), 7.84 (s, 2H), 7.47 (d, J = 9.3 Hz, 1H), 7.05-6.99 (m, 2H), 3.33-3.23 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H).

[0607] 91 was synthesized according to a similar procedure as in Example 29. LCMS (ESI, m / z): 457.1 [M+H] +1H NMR (300 MHz, dimethyl sulfoxide (DMSO)-d6, ppm): δ9.33 (s, 1H), 7.90 (s, 2H), 7.12 (d, J = 1.5 Hz, 1H), 7.06-6.94 (m, 2H), 3.41-3.43 (m, 1H), 1.39 (d, J = 7.2 Hz, 6H).

[0608] Other exemplary thyroid hormone receptor beta agonist compounds described herein can be prepared according to similar methods and techniques described herein. The characterization of the compounds is provided in Table 1 below:

[0609] Table 1. Characterization of selected compounds

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618] Biological Example 1. Thyroid Hormone Receptor Binding Assay

[0619] The TR-FRET binding assay was used to test representative compounds herein.

[0620] The ligand binding domain of thyroid hormone receptor α and thyroid hormone receptor β with GST tag were purchased from Invitrogen, biotin-SRC2-2 coactivator peptide was purchased from Sangon Biotech, and Europium anti-GST and streptavidin-D2 were purchased from Cisbio.

[0621] 5 μL of 4X compound serial dilutions were added to 384-well plates (white, small volume, round bottom assay plates). 5 μL of TRβLBD (2nM) or TRαLBD (4nM) in 50mM Tris-HCl (pH7.4) (reaction buffer) containing 100mM NaCl, 1mM EDTA, 50mM KF, 1mM DTT, 1mM MgCl2, 10% glycerol, 0.01% NP-40, 0.1% BSA was mixed with 10 μL of 400nM Biotin-SRC2-2 (2X) and anti-GST Eu (1:200) (2X) and 50nM streptavidin-d2 (2X) in the reaction buffer of the same assay plate. The assay plate was centrifuged at 1000g for 1 minute and incubated at room temperature in the dark for 1 hour. The plate was then read at 665nm and 615nm wavelengths on an Envision 2104 plate reader. EC was calculated using Graphpad 5.0 by fitting the logarithm of percent activity values ​​and compound concentration to a nonlinear regression (dose response – variable slope). 50 .

[0622] The results are shown in the following table.

[0623] Table 2. Binding activity of representative compounds

[0624]

[0625]

[0626] Biological Example 2. Thyroid Hormone Receptor Cell Assay

[0627] The TRα-LBD or TRβ-LBD coding sequence was inserted into the pBIND expression vector (Promega, E1581) to express the TRβ-GAL4 binding domain chimeric receptor. The expression vector was transfected into HEK293-LUC host cells with a reporter vector (pGL4.35 carrying a stably integrated GAL4 promoter-driven luciferase reporter gene). After the agonist binds to the corresponding TRa-GAL4 or TRb-GAL4 chimeric receptor, the chimeric receptor binds to the GAL4 binding site and stimulates the reporter gene.

[0628] 2.5×10 6HEK293-LUC cells were inoculated into 60 mm dishes and incubated at 37 °C for 16 h in a 5% CO2 atmosphere. 12 μL of Lipo LTX reagent was mixed with 250 μL of Opti-MEM medium by inversion. 6 μg of DNA was mixed with 250 μL of Opti-MEM medium, and then 6 μL of Lipo PLUS reagent was added. The diluted DNA was added to each test tube of the diluted Lipo LTX reagent (1:1 ratio), mixed with a pipette and incubated at room temperature for 10 minutes. The reagent mixture was added to a 60 mm dish and incubated with cells at 37 °C for 4-7 hours in a 5% CO2 atmosphere.

[0629] 75 nL of compound was added to a 384-well assay plate using ECHO550, and HEK293-LUC cells (transfected, 17,000 cells / well) were added to the plate using phenol red-free DMEM containing 5% charcoal / dextran treated FBS and incubated at 37°C for 16-20 hours in a 5% CO2 atmosphere. 25 μL of Steady-Glo luciferase assay reagent was added to each well. Shake for 5 minutes and then record the luminescence value on the Envision 2104 plate reader.

[0630] The results are shown in the following table.

[0631] Table 3. Cellular activities of representative compounds

[0632]

[0633]

[0634] Biological Example 3. Human Hepatocyte Clearance Study

[0635] In vitro human hepatocyte clearance of the compounds described herein was studied using pooled human hepatocytes purchased from Bioreclamation IVT (Westbury, NY, Cat. No. X008001, Lot No. TQJ). The assay was performed according to the manufacturer's instructions. Briefly, 10 mM stock solutions of test compounds and positive control (verapamil) were prepared in 100% dimethyl sulfoxide (DMSO). The thawing medium (50 mL) used in the study consisted of the following components: 31 mL Williams E medium (GIBCO Catalog No. 12551-032); 15 mL isotonic percoll (GE Healthcare Catalog No. 17-0891-09); 500 μL 100XGlutaMax (GIBCO Catalog No. 35050); 750 μL HEPES (GIBCO Catalog No. 15630-080); 2.5 mL FBS (Corning Catalog No. 35-076-CVR); 50 μL human insulin (GIBCO Catalog No. 12585-014) and 5 μL dexamethasone (NICPBP). The incubation medium was made of Williams E medium supplemented with 1xGlutaMax. Both the thawing medium and the incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes before use. Compound stocks were diluted to 100 μM by combining with 198 μL of 50% acetonitrile / 50% water and 2 μL of the 10 mM stock. Verapamil was used as a positive control in the assay. The vial of cryopreserved hepatocytes was removed from storage and thawed with gentle shaking in a 37°C water bath. The contents of the vial were poured into a 50 mL conical tube of thawing medium. The vial was centrifuged at 100 g for 10 minutes at room temperature. The thawing medium was aspirated and the hepatocytes were resuspended in serum-free incubation medium to obtain ~1.5 × 10 6 The viability and density of hepatocytes were counted using the trypan blue exclusion method, and then the cells were diluted with serum-free culture medium to a working cell density of 0.5×10 6 Then, a portion of 0.5×10 6Live cells / mL of hepatocytes were boiled for 5 minutes before being added to the plate as a negative control to eliminate enzyme activity, whereby little or no substrate turnover should be observed. Boiled hepatocytes were used to prepare negative samples. An aliquot of 198 μL of hepatocytes was distributed to each well of a 96-well uncoated plate. The plate was placed in an incubator on an orbital shaker at 500 rpm for approximately 10 minutes. An aliquot of 2 μL of 100 μM test compound or positive control was added to each well of an uncoated 96-well plate to start the reaction. The assay was performed in duplicate. The plate was incubated in an incubator on an orbital shaker at 500 rpm for the specified time points. 25 μL of the contents were transferred and mixed with 6 volumes (150 μL) of cold acetonitrile containing IS (200 nM imipramine, 200 nM labetalol and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90, 120 minutes. The samples were centrifuged at 3,220 g for 25 minutes and aliquots of 150 μL of the supernatant were used for LC-MS / MS analysis. For data analysis, all calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms. The in vitro half-life (t) of the parent compound was determined by regression analysis of the percent disappearance of the parent compound vs. time curve. 1 / 2 The in vitro half-life (in vitro t 1 / 2 ): in vitro 1 / 2 =0.693 / k. The following formula (average of repeated measurements) was used to convert the in vitro t 1 / 2 (in minutes) converted to scaled-up unbound intrinsic clearance (scaled-up unbound CL int , in mL / min / kg): unbound CL int = kV / N × magnification factor, where V = incubation volume (0.5 mL); N = number of hepatocytes per well (0.25 × 10 6 cells). The scaling factors for the prediction of in vivo intrinsic clearance using human hepatocytes are as follows: liver weight (g liver / kg body weight): 25.7; hepatocyte concentration (10 6 cells / g liver): 99; magnification factor: 2544.3.

[0636] The results are shown in the following table:

[0637] Table 4: Human hepatocyte clearance of exemplary compounds

[0638]

[0639] * If the calculated CL int <0, then T 1 / 2and CLint are reported as ""∞"" and "0.00" respectively.

[0640] 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.

[0641] The present invention has been described above with the help of functional building blocks showing the implementation of specific functions and their relationships. For the convenience of description, the boundaries of these functional building blocks have been arbitrarily defined in this article. As long as the specified functions and their relationships are properly performed, other boundaries can be defined.

[0642] With respect to aspects of the invention described as being genus, all individual species are considered separately as independent aspects of the invention. If aspects of the invention are described as "comprising" features, "consisting of" or "consisting essentially of" the features is also contemplated.

[0643] The foregoing description of specific embodiments will reveal the general nature of the invention very fully, so that others can easily modify and / or change the specific embodiments for various applications by applying the knowledge of those skilled in the art without departing from the general concept of the invention, without excessive experimentation. Therefore, based on the teachings and guidance set forth herein, such changes and modifications should be within the meaning and scope of the equivalent forms of the disclosed embodiments. It should be understood that the words or terms herein are for the purpose of description rather than limitation, and the terms or words of this specification will be interpreted by the technician based on the teachings and guidance.

[0644] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0645] All of the various aspects, embodiments, and options described herein may be combined in any and all variations.

[0646] All publications, patents, and patent applications mentioned in this specification are incorporated herein 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. If 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 of the term given in this document shall prevail.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R 1 and R 1’ are each independently hydrogen, -OH, halogen (eg, fluorine), or an optionally substituted C 1-4 Alkyl (e.g. C 1-4 alkyl), or R 1 and R 1’ Together they form an oxo group (=O), R 2 is an optionally substituted alkyl group, an optionally substituted carbocyclyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, A is O, CH2, S, SO or SO2, R 3 is hydrogen or optionally substituted alkyl, R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy, n is 1, 2, 3 or 4, R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group, The premise is that when -CR 1 R 1’ R 2 When R is isopropyl or -CH(CH3)(CH2-OH), 4 Not hydrogen, -COOH or -CN.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ are each independently hydrogen or optionally substituted C 1-4 Alkyl (e.g., C 1-4 alkyl).

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ All are hydrogen.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1’ is hydrogen, R 1 It is methyl.

5. A compound of formula II or a pharmaceutically acceptable salt thereof: in: R 5 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl; A is O, CH2, S, SO or SO2, R 3 is hydrogen or optionally substituted alkyl, R 100 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy, n is 1, 2, 3 or 4, R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

6. A compound of formula III-1, III-2 or III-3 or a pharmaceutically acceptable salt thereof: in: R 6 is a hydrogen or nitrogen protecting group, R 7 is an optionally substituted alkyl, -COOH or an ester thereof, -CONH2, -CONH(C 1-6 Alkyl), -CON(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl or optionally substituted heterocyclyl, wherein each C 1-6 Alkyl groups are independently selected and optionally substituted; A is O, CH2, S, SO or SO2, R 100 and R 102 is independently at each occurrence fluorine, chlorine, bromine, iodine, C optionally substituted with 1-3 fluorine 1-4 alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy or cyclobutyloxy, n is 1, 2, 3 or 4, Where valence permits, p is 0, 1, 2, 3 or 4, R 4 is hydrogen, -CN, -COOH, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Carbocyclic group.

7. A compound selected from Compound No. 1-99 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

9. A method for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, wherein the disease or condition is obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis, fatty liver, nonalcoholic fatty liver disease, bone disease, thyroid axis changes, atherosclerosis, cardiovascular disease, tachycardia, hyperkinesia, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disabilities, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disease, thyroid cancer, or a combination thereof.

10. A method of treating a liver disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8.

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