Substituted triazinones as thyroid hormone receptor agonists.

Abstract

The present application relates to compounds of formula (I') or (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, that modulate the activity of thyroid hormone receptors, pharmaceutical compositions comprising compounds of formula (I') or (I), and methods of treating or preventing diseases or disorders regulated by thyroid hormone. TIFF2023510835000535.tif24128

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to International Publication No. PCT / CN2020 / 071741, filed January 13, 2020, and International Publication No. PCT / CN2020 / 107757, filed August 7, 2020, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] background Thyroid hormones are important for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms of the hypothalamic-pituitary-thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates the profound influence of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol levels, bone and muscle maintenance, and behavior. Thyroid hormones stimulate cholesterol metabolism in response to bile acids and enhance the lipolytic response of adipocytes to other hormones. Thyroid hormones also affect cardiac function. For example, patients with hyperthyroidism exhibit tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure.

[0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs). THRs form heterodimers with retinoid receptors, which act as ligand-inducible transcription factors. THRs regulate gene expression through interactions with DNA response elements and various nuclear coactivators and corepressors. Thyroid hormone receptors are derived from two separate genes, α and β. The major thyroid receptor isoforms are α1, α2, β1, and β2. Thyroid hormone receptor subtypes may differ in their contribution to specific biological responses. The THRβ isoform is primarily expressed in brain and liver tissues and is responsible for feedback regulation of the HPT axis and lipid-lowering effects. Selective activation of the THRα isoform is associated with adverse effects in the heart and bone. Therefore, selective activation of the THRβ isoform in liver tissue is desirable.

[0004] The therapeutic beneficial effects of thyroid hormone include increased metabolic rate, oxygen consumption, and heat production, which in turn leads to weight loss, lowered LDL, and elevated HDL. Thyroid disorders are commonly treated with hormone replacement therapy by administering either naturally occurring thyroid hormone or thyroid hormone-like analogs that mimic the effects of thyroid hormone.

[0005] The development of thyroid hormone analogs that maintain the beneficial effects of thyroid hormone while avoiding the undesirable effects of hyperthyroidism and hypothyroidism would open new avenues of treatment for patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other disorders and diseases such as fatty liver and NASH, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related disorders and diseases. Thus, there is a need for novel thyroid hormone analog compounds that have the beneficial effects of thyroid hormone while avoiding the undesirable effects. The present application addresses such a need. Summary of the Invention

[0006] overview The present application relates to the treatment of obesity, overweight, hyperlipidemia (e.g., severe hypertriglyceridemia (SHTG), familial partial lipodystrophy (FPLD), familial chylomicronemia syndrome (FCS), xanthomas, familial dysbetalipoproteinemia / hypolipoproteinemia type III, hyperlipidemia, sitosterolemia), sphingolipid metabolism disorders, thyroid disorders (e.g., Hashimoto's disease, thyroiditis, thyroid hypoplasia, congenital hypothyroidism, inherited thyroid hormone binding protein disorders), hypothyroidism, thyroid cancer, and related disorders, such as those described herein. The present invention provides novel thyroid hormone receptor ligands that are useful for the treatment of diseases or disorders controlled by thyroid hormones, including, but not limited to, related disorders and diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, liver fibrosis, hypercholesterolemia, familial hypercholesterolemia (HeFH / HoFH), X-linked adrenoleukodystrophy (X-ALD), diabetes, atherosclerosis, hypertension, coronary heart disease, depression, osteoporosis, cardiac arrhythmias, glaucoma, congestive heart failure, and pancreatitis.

[0007] A first aspect of the present application is a compound of formula (I') or (I): TIFF0007728265000001.tif30128 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, In the formula, R O , R 1 , R 2 , R 3 , R 4 , L, X 1 , X 2 , and X 3 is described in detail below.

[0008] Another aspect of the present application relates to a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0009] Another aspect of the present application relates to a method of treating a disease or disorder controlled by thyroid hormone, such as those described herein, including, but not limited to, liver disease, metabolic disease, thyroid disease, and cardiovascular disease. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0010] Another aspect of the present application relates to a method of treating liver disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0011] Another aspect of the present application relates to a method of treating a metabolic disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0012] Another aspect of the present application relates to a method of treating cardiovascular disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0013] Another aspect of the present application relates to a method of reducing fibrosis (e.g., liver fibrosis), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0014] Another aspect of the present application relates to a method for treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, or liver fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0015] Another aspect of the present application relates to a method of treating atherosclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0016] Another aspect of the present application relates to a method of treating stroke and its complications, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0017] Another aspect of the present application relates to a method of treating myocardial infarction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0018] Another aspect of the present application relates to a method of modulating (e.g., activating) a thyroid hormone receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0019] Another aspect of the present application relates to a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, for use in a method of treating a disease or disorder controlled by thyroid hormone, as described herein.

[0020] Another aspect of the present application relates to the use of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, in the manufacture of a medicament for treating a disease or disorder controlled by thyroid hormone, as described herein.

[0021] The present application further provides a method for treating a disease or disorder associated with the modulation of thyroid hormone receptors, including, but not limited to, liver disease, metabolic disease, cardiovascular disease, fibrosis (e.g., liver fibrosis), NAFLD, NASH, hepatic steatosis, liver fibrosis, atherosclerosis, stroke and its complications, myocardial infarction, and other diseases or disorders described herein, the method comprising administering to a subject suffering from at least one of the diseases or disorders a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0022] The present application provides compounds that are therapeutic agents in the treatment of diseases such as liver diseases (e.g., NAFLD and NASH), metabolic diseases, cardiovascular diseases, and other diseases associated with the modulation of thyroid hormone receptors. [The present invention 1001] Formula (I') or (I): TIFF0007728265000002.tif30128 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, During the ceremony R O is H or (C 1 ~C 4 ) alkyl; X 1 、X 2 , and X 3 are each independently CR X or N, where X 1 、X 2 , and X 3 at most one of is N; Each R X are independently H, (C 1 ~C 4 ) alkyl, CN, F, Cl, or (C 3 ~C 8 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 where X 1 、X 2 , and X 3 One of the groups is N and L is CH 2 If R X (C 3 ~C 8 ) rather than cycloalkyl; L is CH 2 , NH, N((C 1 ~C 4 ) alkyl), S(O) 2 , or O; R 1 is CH 2 F, CHF 2 , C.F. 3 , Cl, NH 2 , or CN, or R 1 is X 1 、X 2 , and X 3 If one of the is N, then H, (C 1 ~C 4 ) alkyl, CH 2 F, CHF 2 , C.F. 3 , Cl, NH 2 , or CN; R 2 and R 3 are each independently H, F, Cl, or CH 3 and; R 4 (CH 2 ) 0~3 S(O) 2 R 4' , S(O) 2 NR 4' R 4'' , C(O)NR 4' R 4'' 、(C 1 ~C 4 ) alkyl, or (C 3 ~C 6 ) cycloalkyl, where X 1 、X 2 , and X 3 One of the groups is N and L is CH 2 If R 4 (C 3~C 6 ) is not cycloalkyl, where R 1 If is CN, then R 4 (C 1 ~C 4 ) not alkyl; R 4' and R 4'' are independently H, (C 1 ~C 4 ) alkyl, (C 3 ~C 15 )cycloalkyl, or a 3- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is selected from one or more (CH 2 ) y R 5 where R 4 is S(O) 2 R 4' If R 4' is not H; or R 4' and R 4'' together with the nitrogen atoms to which they are attached, It may contain 1 to 3 additional heteroatoms selected from N, O and S, and one or more (CH 2 ) y R 5 3- to 10-membered heterocycle optionally substituted with Forming; Each R 5 are independently F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )alkoxy, oxo, CN, (C 3 ~C 6 ) cycloalkyl, heterocyclyl containing one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R7 , or S(O) 2 NR 6 R 6' where each cycloalkyl or heterocyclyl is F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' or If y is 0, then two R 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' a 3- to 6-membered ring optionally substituted with may be formed; Each R 6 and R 6' are independently H, (C 1 ~C 8 ) alkyl, or (C 3 ~C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 or R 6 and R 6' together with the nitrogen atoms to which they are attached, may contain one additional heteroatom selected from N, O, and S, and one or more R 8 3- to 6-membered heterocycle optionally substituted with Forming; Each R 7 are independently H, (C 1 ~C 8 ) alkyl, or (C 3 ~C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 where R 5 is S(O) 2 R 7 or NR 6 S(O) 2 R 7 If R 7 is not H; Each R 8 are independently halogen, NO 2 , N.H. 2 , CN, NH((C 1 ~C 4 ) alkyl), N((C 1 ~C 4 )Alkyl) 2 , OH, oxo, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) alkoxy, where R X 、R 6 , or R 6' is alkyl, R 8 is not oxo; and y is 0, 1, 2, 3, or 4, The compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. [The present invention 1002] X 1 is N and X 2 and X 3 are CR X The compound of the present invention 1001, [The present invention 1003] X 2 is N and X 1 and X 3 are CR X The compound of the present invention 1001, [The present invention 1004] X 3 is N and X 1 and X 2 are CR X The compound of the present invention 1001, [The present invention 1005] X 1 、X 2 , and X 3 are CR X The compound of the present invention 1001, [The present invention 1006] Each R X The compound of any one of 1001 to 1005 of the present invention, wherein is H. [The present invention 1007] At least one R X But (C 1 ~C 4 ) alkyl, CN, F, Cl, or (C 3 ~C 8 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 The compound of any one of 1001 to 1005 of the present invention, which may be substituted with [The present invention 1008] At least one R X but one or more R 8 may be substituted with (C 1 ~C 4 ) A compound of any one of 1001 to 1005 and 1007 of the present invention, wherein the compound is alkyl. [The present invention 1009] At least one R X The compound of any one of 1001 to 1005 and 1007 of the present invention, wherein is CN. [The present invention 1010] At least one R X The compound of any one of claims 1001 to 1005 and 1007 of the present invention, wherein is F or Cl. [The present invention 1011] At least one R X but one or more R 8 may be substituted with (C 3 ~C 8 ) A compound of any one of 1001 to 1005 and 1007 of the present invention, wherein the compound is cycloalkyl. [The present invention 1012] L is S(O) 2 or O. [The present invention 1013] L is S(O) 2 The compound of any one of claims 1001 to 1012 of the present invention, [The present invention 1014] The compound of any one of claims 1001 to 1012, wherein L is O. [The present invention 1015] L is CH 2 , NH, or N((C 1 ~C 4 ) alkyl)). [The present invention 1016] R 1 is CH 2 F, CHF 2 , C.F. 3 , Cl, or NH 2 The compound of any one of claims 1001 to 1015 of the present invention, [The present invention 1017] R 1 is CH 2 F, CF 3 The compound of any one of claims 1001 to 1016, wherein the compound is Cl. [The present invention 1018] R 1 CHF 2 or CF 3 The compound of any one of claims 1001 to 1017 of the present invention, [The present invention 1019] R 1 The compound of any one of claims 1001 to 1015, wherein is CN. [The present invention 1020] X 1 、X 2 , and X 3 If one of the is N, then R 1 is H or (C 1 ~C 4 ) any one of compounds 1001 to 1017 of the present invention, wherein R is alkyl; [The present invention 1021] R 2 and R 3 and each represents H. [The present invention 1022] R 2 and R 3 One of the groups is H and the other is F, Cl, or CH 3 The compound of any one of claims 1001 to 1020 of the present invention, [The present invention 1023] R 2 and R 3 are each independently F, Cl, or CH 3 The compound of any one of claims 1001 to 1020 of the present invention, [The present invention 1024] R 2 and R 3 The compound of any one of 1001 to 1020 and 1023 of the present invention, wherein each independently is F or Cl. [The present invention 1025] R 2 and R 3 The compound of any one of 1001 to 1020, 1023, and 1024 of the present invention, wherein each of [The present invention 1026] R 4 (CH 2 ) 0~3 S(O) 2 R 4' , S(O) 2 NR 4' R 4'' , or C(O)NR 4' R 4'' The compound of any one of 1001 to 1025 of the present invention, [The present invention 1027] R 4 is S(O) 2 NR 4' R 4'' or C(O)NR 4' R 4'' The compound of any one of claims 1001 to 1026 of the present invention, [The present invention 1028] R 4 is S(O) 2 NR 4' R 4'' The compound of any one of claims 1001 to 1027 of the present invention, [The present invention 1029] R 4 But (C 1 ~C 4 ) any one of compounds 1001 to 1025 of the present invention, wherein the aryl group is alkyl; [The present invention 1030] R 4 But (C 3 ~C 6 ) A compound of any one of 1001 to 1025 of the present invention, wherein the compound is cycloalkyl. [The present invention 1031] R 4' and R 4'' and each represents H. [The present invention 1032] R 4' and R 4'' are each independently, (C 1 ~C 4 ) alkyl, (C 3 ~C 15 )cycloalkyl, or a 3- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is selected from one or more (CH 2 ) y R 5 The compound of any one of 1001 to 1028 of the present invention, which may be substituted with [The present invention 1033] R 4' and R 4'' One of the groups is H and the other is (C 1 ~C 4 ) alkyl, (C 3 ~C 15 )cycloalkyl, or a 3- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is selected from one or more (CH 2 ) y R 5 The compound of any one of 1001 to 1028 of the present invention, which may be substituted with [The present invention 1034] R 4' and R 4'' one of which is H and the other is one or more (CH 2 ) y R 5 may be substituted with (C 1 ~C 4 ) A compound of any one of the present inventions 1001 to 1028 and 1033, wherein the compound is alkyl. [This invention 1035] R 4' and R 4'' One of the groups is H and the other is One or more (CH 2 ) y R 5 monocyclic or polycyclic spiro, fused, or bridged (C 3 ~C 15 )Cycloalkyl The compound of any one of 1001 to 1028 and 1033 of the present invention, [The present invention 1036] R 4' and R 4'' One of the groups is H and the other is One or more (CH 2 ) y R 5 3-10 membered monocyclic or polycyclic spiro, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with The compound of any one of 1001 to 1028 and 1033 of the present invention, [This invention 1037] R 4' and R 4'' together with the nitrogen atoms to which they are attached, One or more (CH 2 ) y R5 3-10 membered monocyclic or polycyclic spiro, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with Any one of compounds 1001 to 1028 of the present invention, which forms the formula: [The present invention 1038] At least one R 5 F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) A compound of any one of claims 1001 to 1037, wherein R is alkoxy, oxo, or CN. [This invention 1039] At least one R 5 but, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' (C 3 ~C 6 )Cycloalkyl The compound of any one of claims 1001 to 1037 of the present invention, [The present invention 1040] At least one R 5 but, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, optionally substituted with The compound of any one of claims 1001 to 1037 of the present invention, [This invention 1041] At least one R 5 NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' The compound of any one of claims 1001 to 1037 of the present invention, [The present invention 1042] The Two R's 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' a 3- to 6-membered ring optionally substituted with The compound of any one of claims 1001 to 1037 of the present invention, which forms the formula: [This invention 1043] The Two R's 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' (C 3 ~C 6 )Cycloalkyl Any of compounds 1001 to 1037 and 1042 of the present invention, which form the following: [This invention 1044] The Two R's 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, optionally substituted with Any of compounds 1001 to 1037 and 1042 of the present invention, which form the following: [This invention 1045] R 6 and R 6' and each represents H. [The present invention 1046] R 6 and R 6' One of the groups is H and the other is linear or branched (C 1 ~C 8 ) alkyl or monocyclic or polycyclic spiro, fused, or bridged (C 3 ~C 10 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 The compound of any one of 1001 to 1044 of the present invention, which may be substituted with [This invention 1047] R 6 and R 6' are each independently linear or branched (C 1 ~C 8 ) alkyl or monocyclic or polycyclic spiro, fused, or bridged (C 3 ~C 10 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 The compound of any one of 1001 to 1044 of the present invention, which may be substituted with [This invention 1048] R 6 and R 6' together with the nitrogen atom to which they are attached, form one or more R 8 The compound of any one of 1001 to 1044 of the present invention, which forms a 3- to 6-membered heterocyclic ring optionally substituted by: [This invention 1049] Each R 7 and each represents H. [The present invention 1050] At least one R 7 Is linear or branched (C 1 ~C 8 ) alkyl or monocyclic or polycyclic spiro, fused, or bridged (C 3 ~C 10 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 The compound of any one of 1001 to 1048 of the present invention, which may be substituted with [This invention 1051] Each R 8 are independently halogen NO 2 , N.H. 2 , CN, NH((C 1 ~C 4 ) alkyl), N((C 1 ~C 4 )Alkyl) 2 , OH, oxo, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) The compound of any one of claims 1001 to 1050, wherein R is 1 or 2; [This invention 1052] At least one R 8 The compound of any one of 1001 to 1050 of the present invention, wherein is halogen. [This invention 1053] At least one R 8 NH 2 , CN, NH((C 1 ~C 4 ) alkyl), or N((C 1 ~C 4 )Alkyl) 2 The compound of any one of claims 1001 to 1050 of the present invention, [This invention 1054] At least one R 8 is OH, oxo, or (C 1 ~C 4 ) The compound of any one of claims 1001 to 1050, wherein R is 1 or 2; [This invention 1055] At least one R 8 But (C 1 ~C 4 ) alkyl or (C 1 ~C 4 ) The compound of any one of claims 1001 to 1050, wherein R is 1 or 2; [The present invention 1056] The compound of any one of claims 1001 to 1055, wherein y is 0, 1, or 2. [This invention 1057] The compound of any one of claims 1001 to 1055, wherein y is 1, 2, 3, or 4. [This invention 1058] Any of compounds 1001 to 1057 of the present invention selected from Table 1 and Table 1d. [This invention 1059] The compound of any one of claims 1001 to 1058, wherein one or more hydrogen atoms in said compound are replaced with one or more deuterium atoms. [The present invention 1060] R 1 1059. The compound of any one of claims 1001 to 1059, wherein one or more hydrogen atoms are replaced by one or more deuterium atoms. [The present invention 1061] R 4 1059. The compound of any one of claims 1001 to 1059, wherein one or more hydrogen atoms are replaced by one or more deuterium atoms. [The present invention 1062] R 4' or R 4'' 2. The compound of any one of claims 1001 to 1061, wherein one or more hydrogen atoms are replaced by one or more deuterium atoms. [The present invention 1063] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier. [This invention 1064] A method for modulating a thyroid hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. [This invention 1065] A method for treating a disease or disorder controlled by thyroid hormone, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. [The present invention 1066] Any of the compounds of 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder controlled by thyroid hormone or modulating thyroid hormone receptors. [This invention 1067] Use of any of the compounds of the present invention 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in treating a disease or disorder controlled by thyroid hormone or modulating a thyroid hormone receptor. [The present invention 1068] Any of the compounds of 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease or disorder controlled by thyroid hormone or modulating a thyroid hormone receptor. [The present invention 1069] Use of any of the compounds of the present invention 1001 to 1062, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder controlled by thyroid hormone or modulating a thyroid hormone receptor. [Brief explanation of the drawings]

[0023] [Figure 1]Graph showing in vivo mRNA levels of select THR-responsive genes in liver (DIO1) and heart tissue (α-MHC) measured after 24 hours as a function of dose (mg / kg) for representative compounds. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description Compounds of the present application The present application relates to compounds and compositions thereof that can modulate the activity of thyroid hormone receptors. The present application features methods for treating, preventing, or ameliorating diseases or disorders in which thyroid hormones contribute by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I') or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. The compounds of the present application can be used in the treatment of various diseases and disorders controlled by thyroid hormones, such as those described herein, including, but not limited to, liver diseases (e.g., NAFLD and NASH), metabolic diseases, cardiovascular diseases, and other diseases associated with the modulation of thyroid hormone receptors, by modulating the activity of thyroid hormone receptors.

[0025] In a first aspect of the present application, a compound of formula (I') or (I): TIFF0007728265000003.tif30128 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof is described, During the ceremony R O is H or (C1-C4) alkyl; X 1 , X 2 , and X 3 are each independently CR X or N, where X 1 , X 2 , and X 3 at most one of is N; Each R Xare independently H, (C1-C4) alkyl, CN, F, Cl, or (C3-C8) cycloalkyl, where alkyl or cycloalkyl is selected from one or more R 8 where X 1 , X 2 , and X 3 When one of the groups is N and L is CH, R X is not (C3-C8)cycloalkyl; L is CH2, NH, N((C1-C4) alkyl), S(O)2, or O; R 1 is CH2F, CHF2, CF3, Cl, NH2, or CN, or R 1 is X 1 , X 2 , and X 3 When one of is N, it is H, (C1-C4) alkyl, CH2F, CHF2, CF3, Cl, NH2, or CN; R 2 and R 3 are each independently H, F, Cl, or CH3; R 4 (CH2) 0~3 S(O)2R 4' , S(O)NR 4' R 4'' , C(O)NR 4' R 4'' , (C1-C4) alkyl, or (C3-C6) cycloalkyl, where X 1 , X 2 , and X 3 When one of the groups is N and L is CH, R 4 is not a (C-C)cycloalkyl, where R 1 If is CN, then R 4 is not (C1-C4) alkyl; R 4' and R 4'' are each independently H, (C1-C4) alkyl, (C3-C 15) cycloalkyl, or a 3- to 10-membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is selected from one or more (CH2) y R 5 where R 4 is S(O)2R 4' If R 4' is not H; or R 4' and R 4'' together with the nitrogen atoms to which they are attached, It may contain 1 to 3 additional heteroatoms selected from N, O and S, and one or more (CH2) y R 5 3- to 10-membered heterocycle optionally substituted with Forming; Each R 5 are independently F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, oxo, CN, (C3-C6) cycloalkyl, heterocyclyl containing one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' wherein each cycloalkyl or heterocyclyl is F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6R 6' or If y is 0, then two R 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' a 3- to 6-membered ring optionally substituted with may be formed; Each R 6 and R 6' are independently H, (C1-C8) alkyl, or (C3-C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 or R 6 and R 6' together with the nitrogen atoms to which they are attached, may contain one additional heteroatom selected from N, O, and S, and one or more R 8 3- to 6-membered heterocycle optionally substituted with Forming; Each R 7 are independently H, (C1-C8) alkyl, or (C3-C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 where R 5 is S(O)2R 7 or NR 6 S(O)2R 7 If R 7 is not H; Each R 8are independently halogen, NO2, NH2, CN, NH((C1-C4)alkyl), N((C1-C4)alkyl)2, OH, oxo, (C1-C4)alkyl, or (C1-C4)alkoxy, where R X , R 6 , or R 6' is alkyl, R 8 is not oxo; and y is 0, 1, 2, 3, or 4.

[0026] In some embodiments, the compound of formula (I') or (I) has formula (Ia') or (Ia): TIFF0007728265000004.tif33138, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0027] In some embodiments, the compound of formula (I') or (I) has formula (Ib') or (Ib): TIFF0007728265000005.tif33138, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0028] In some embodiments, the compound of formula (I') or (I) has formula (Ic') or (Ic): TIFF0007728265000006.tif33138, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0029] In one embodiment, for compounds of formula (I'), (I), (Ia'), (Ia), (Ib'), (Ib), (Ic'), or (Ic), where applicable, X 1 , X 2 , X 3 , L, R O , R X , R 1 , R 2 , R 3 , R 4 , R 4' , R4'' , R 5 , R 6 , R 6' , R 7 , R 8 , and y are each as defined below. (1a) In one embodiment, X 1 is N and X 2 and X 3 are CR X In one embodiment, X 2 is N and X 1 and X 3 are CR X In one embodiment, X 3 is N and X 1 and X 2 are CR X is. (1b) In one embodiment, X 1 , X 2 , and X 3 are CR X is. (2a-1) In one embodiment, each R X are independently H, (C1-C4) alkyl, CN, F, or Cl. (2a-2) In one embodiment, each R X is H. (2b) In one embodiment, at least one R X is one or more R 8 (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), F, Cl, CN, or one or more R 8 In one embodiment, one R is a (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl) optionally substituted with X is one or more R 8(C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), F, Cl, CN, or one or more R 8 In one embodiment, two R are optionally substituted (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). X are each independently one or more R 8 (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), F, Cl, CN, or one or more R 8 In one embodiment, three R are optionally substituted (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). X are each independently one or more R 8 (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), F, Cl, CN, or one or more R 8 and optionally substituted (C3-C8)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). (2c) In one embodiment, at least one R X is one or more R 8 In one embodiment, one R is (C1-C4) alkyl optionally substituted with (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). X is one or more R 8 In one embodiment, two R are (C1-C4) alkyl optionally substituted with R (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).X each independently represents one or more R 8 In one embodiment, three R are optionally substituted (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). X each independently represents one or more R 8 and (C1-C4) alkyl optionally substituted with (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). (2d) In one embodiment, at least one R X is CN. In one embodiment, one R X is CN. In one embodiment, two R X is CN. In one embodiment, three R X is CN. (2e) In one embodiment, at least one R X is F or Cl. In one embodiment, one R X is F or Cl. In one embodiment, two R X are each independently F or Cl. In one embodiment, three R X are each independently F or Cl. (2f) In one embodiment, at least one R X is F. In one embodiment, one R X is F. In one embodiment, two R X are each F. In one embodiment, three R X are F respectively. (2g) In one embodiment, at least one R X is Cl. In one embodiment, one R X is Cl. In one embodiment, two R X In one embodiment, three R X are Cl, respectively. (2h) In one embodiment, at least one R X is one or more R 8In one embodiment, one R is a (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl) optionally substituted with X is one or more R 8 In one embodiment, two R are optionally substituted (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). X each independently represents one or more R 8 In one embodiment, three R are optionally substituted (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). X each independently represents one or more R 8 and optionally substituted (C3-C8)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). (2i) In one embodiment, R X None of the is (C3-C8)cycloalkyl. (3a) In one embodiment, L is S(O)2 or O. (3b) In one embodiment, L is S(O)2. (3c) In one embodiment, L is O. (3d) In one embodiment, L is NH. (3e) In one embodiment, L is N((C1-C4) alkyl), where alkyl is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. (3f) In one embodiment, L is a (C1-C4) alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. (3g) In one embodiment, L is NH, N((C1-C4) alkyl), S(O)2, or O. (4a) In one embodiment, R1 is CH2F, CHF2, CF3, Cl, or NH2. (4b) In one embodiment, R 1 is CHF2, CF3, or Cl. (4c) In one embodiment, R 1 is CHF2 or CF3. (4d) In one embodiment, R 1 is CHF2. (4e) In one embodiment, R 1 is CF3. (4f) In one embodiment, R 1 is Cl. (4g) In one embodiment, X 1 , X 2 , and X 3 If one of the is N, then R 1 is H. (4h) In one embodiment, X 1 , X 2 and X 3 If one of the is N, then R 1 is a (C1-C4) alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. (5a) In one embodiment, R 2 and R 3 are H respectively. (5b) In one embodiment, R 2 and R 3 One of them is H and the other is F, Cl, or CH3. (5c) In one embodiment, R 2 and R 3 are each independently F, Cl, or CH3. (5d) In one embodiment, R 2 and R 3 are each independently F or CH3. (5e) In one embodiment, R 2 and R 3 are each independently Cl or CH3. (5f) In one embodiment, R 2 and R3 are each independently F or Cl. (5g) In one embodiment, R 2 and R 3 are F respectively. (5h) In one embodiment, R 2 and R 3 are Cl, respectively. (5i) In one embodiment, R 2 and R 3 are CH3 respectively. (6a) In one embodiment, R 4 (CH2) 0~3 S(O)2R 4' , S(O)NR 4' R 4'' , or C(O)NR 4' R 4'' In one embodiment, R 4 is S(O)2R 4' , S(O)NR 4' R 4'' , or C(O)NR 4' R 4'' is. (6b) In one embodiment, R 4 (CH2) 0~3 S(O)2R 4' In one embodiment, R 4 is S(O)2R 4' is. (6c) In one embodiment, R 4 is S(O)NR 4' R 4'' is. (6d) In one embodiment, R 4 is C(O)NR 4' R 4'' is. (6e) In one embodiment, R 4 is (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). (6f) In one embodiment, R 4 is (C3-C6)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). (7a) In one embodiment, R 4' and R 4'' are H respectively. (7b) In one embodiment, R 4' and R 4'' are each independently (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, or adamantyl), or 3-10 membered monocyclic or polycyclic spiro, fused, or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolidine, linyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl), where alkyl, cycloalkyl, or heterocyclyl is one or more (CH) y R 5 may be substituted with. (7c) In one embodiment, R 4' and R 4'' one of which is H and the other is (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), monocyclic or polycyclic spiro, fused, or bridged (C3-C 15) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, or adamantyl), or 3-10 membered monocyclic or polycyclic spiro, fused, or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolidine, linyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl), where alkyl, cycloalkyl, or heterocyclyl is one or more (CH) y R 5 may be substituted with. (7d) In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 and (C1-C4) alkyl optionally substituted with (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). (7e) In one embodiment, R 4' and R 4'' One of the rings is H and the other is a monocyclic or polycyclic spiro, fused, or bridged (C3-C 15) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, or adamantyl), or 3-10 membered monocyclic or polycyclic spiro, fused, or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl), where cycloalkyl or heterocyclyl is one or more (CH) y R 5 may be substituted with. (7f) In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 Monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) cycloalkyl. In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 Monocyclic (C3-C 15 ) cycloalkyl. In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a monocyclic (C3-C8) cycloalkyl optionally substituted with 4' and R4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a monocyclic (C-C) cycloalkyl optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 Polycyclic spiro (C5-C 15 ) cycloalkyl. In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 Polycyclic fused spiro (C5-C 15 ) cycloalkyl. In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 Polycyclic bridge (C5-C 15 ) cycloalkyl. In one embodiment, R 4' and R 4'' One of the groups is H, and the other group is one or more (CH2) y R 5 and adamantyl, optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, and adamantyl. (7g) In one embodiment, R 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 3-10 membered monocyclic or polycyclic spiro, fused, or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4''One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 3- to 10-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 3- to 6-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 5- to 10-membered polycyclic spiroheterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 5- to 10-membered polycyclic fused heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 In one embodiment, R is a 5- to 10-membered polycyclic bridged heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' One of the groups is H, and the other group is one or more (CH2) y R 5In one embodiment, R is selected from [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and 2,5-diazabicyclo[2.2.1]heptanyl, optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 and R is a 3- to 6-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl), optionally substituted with 4' and R 4'' One of the groups is H and the other is one or more (CH2) y R 5 and 5- to 8-membered polycyclic spiro, fused, or bridged heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with N, O, and S (e.g., 2-oxa-5-azabicyclo[2.2.1]heptanyl or 2,5-diazabicyclo[2.2.1]heptanyl). (7h) In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5In one embodiment, R forms a 3-10 membered monocyclic or polycyclic spiro, fused, or bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, optionally substituted with 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 In one embodiment, R 4' and R 4'' together with the nitrogen atoms to which they are attached, each form one or more (CH2) y R 5In one embodiment, R forms a heterocyclyl selected from [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and 2,5-diazabicyclo[2.2.1]heptanyl, optionally substituted with 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 and R forms a 3-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl), optionally substituted with R. 4' and R 4'' together with the nitrogen atoms to which they are attached form one or more (CH2) y R 5 and forming a 5-8 membered polycyclic spiro, fused, or bridged heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S (e.g., 2-oxa-5-azabicyclo[2.2.1]heptanyl or 2,5-diazabicyclo[2.2.1]heptanyl), optionally substituted with (8a) In one embodiment, at least one R 5is F, Cl, OH, (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), (C1-C4) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), oxo, or CN. (8b) In one embodiment, at least one R 5 is F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' In one embodiment, at least one R is optionally substituted with (C-C)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). 5 is F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, or NR 6 R 6' and optionally substituted (C3-C6)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). (8c) In one embodiment, at least one R 5 is F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6'and heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl), optionally substituted with at least one R 5 is F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, or NR 6 R 6' and heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl). (8d) In one embodiment, at least one R 5 is NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' is. (8e) In one embodiment, two R 5 together with the atom or atoms to which they are attached, represent F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6', N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' In one embodiment, two R 5 together with the atom or atoms to which they are attached, represent F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6' In one embodiment, two R 5 together with the atom or atoms to which they are attached, represent F, Cl, OH, (C1-C4) alkyl, (C1-C4) alkoxy, CN, NR 6 R 6' , N.R. 6 S(O)2R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O)2R 7 , or S(O)NR 6 R 6'and forming a heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl). (9a) In one embodiment, R 6 and R 6' are H respectively. (9b) In one embodiment, R 6 and R 6' one of which is H and the other is a straight-chain or branched (C1-C8) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl, straight-chain or branched heptyl, or straight-chain or branched octyl) or a monocyclic or polycyclic spiro, fused, or bridged (C3-C 10 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 may be substituted with. (9c) In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 In one embodiment, R is a straight-chain or branched (C1-C8) alkyl optionally substituted with (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl, straight-chain or branched heptyl, or straight-chain or branched octyl). 6 and R 6' one of which is H and the other is one or more R 8 and (C1-C4) alkyl optionally substituted with (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or s-butyl). (9d) In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 Monocyclic or polycyclic spiro, fused, or bridged (C3-C 10 ) cycloalkyl. In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 Monocyclic (C3-C 10 ) cycloalkyl. In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 In one embodiment, R is a monocyclic (C3-C8) cycloalkyl optionally substituted with 6 and R 6' one of which is H and the other is one or more R 8 In one embodiment, R is a monocyclic (C-C) cycloalkyl optionally substituted with 6 and R 6' one of which is H and the other is one or more R 8 Polycyclic spiro (C5-C 10 ) cycloalkyl. In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 Polycyclic fused rings (C5-C 10 ) cycloalkyl. In one embodiment, R 6 and R 6' one of which is H and the other is one or more R 8 Polycyclic bridge (C5-C 10 ) cycloalkyl. In one embodiment, R 6 and R 6' is H and the other is one or more R 8and optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, or adamantyl. (9e) In one embodiment, R 6 and R 6' are each independently a straight-chain or branched (C1-C8) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl, straight-chain or branched heptyl, or straight-chain or branched octyl) or (C3-C 10 ) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl), where alkyl or cycloalkyl is selected from one or more R 8 may be substituted with. (9f) In one embodiment, R 6 and R 6' together with the nitrogen atoms to which they are attached, form one or more R 8 and forming an optionally substituted 3- to 6-membered heterocyclyl ring (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, or thiiranyl). (10a) In one embodiment, each R 7 are H respectively. (10b) In one embodiment, at least one R 7is a straight-chain or branched (C1-C8) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl, straight-chain or branched heptyl, or straight-chain or branched octyl) or a monocyclic or polycyclic spiro, fused, or bridged (C3-C 10 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 may be substituted with. (10c) In one embodiment, at least one R 7 is one or more R 8 In one embodiment, at least one R is a straight-chain or branched (C1-C8) alkyl optionally substituted with (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, straight-chain or branched pentyl, straight-chain or branched hexyl, straight-chain or branched heptyl, or straight-chain or branched octyl). 7 is one or more R 8 and (C1-C4) alkyl optionally substituted with (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). (10d) In one embodiment, at least one R 7 is one or more R 8 Monocyclic or polycyclic spiro, fused, or bridged (C3-C 10 ) cycloalkyl. In one embodiment, at least one R 7 is one or more R 8 Monocyclic (C3-C 10 ) cycloalkyl. In one embodiment, at least one R 7 is one or more R 8 In one embodiment, at least one R 7 is one or more R 8 In one embodiment, at least one R7 is one or more R 8 Polycyclic spiro (C5-C 10 ) cycloalkyl. In one embodiment, at least one R 7 is one or more R 8 Polycyclic fused rings (C5-C 10 ) cycloalkyl. In one embodiment, at least one R 7 is one or more R 8 Polycyclic bridge (C5-C 10 ) cycloalkyl. In one embodiment, at least one R 7 are each one or more R 8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, or adamantyl, optionally substituted with (11a) In one embodiment, y is 0, 1, or 2. (11b) In one embodiment, y is 1, 2, 3, or 4. (11c) In one embodiment, y is 0. (11d) In one embodiment, y is 1. (11e) In one embodiment, y is 2. (11f) In one embodiment, y is 3. (11g) In one embodiment, y is 4. (12a) In one embodiment, each R 8are independently halogen (e.g., F, Cl, Br, or I), NO, NH, CN, NH((C-C)alkyl) (wherein the alkyl moiety is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), N((C-C)alkyl) (wherein the alkyl moiety is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), OH, oxo, (C-C)alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), or (C-C)alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy). (12b) In one embodiment, at least one R 8 is a halogen (e.g., F, Cl, Br, or I), NO2, NH2, or CN. (12c) In one embodiment, at least one R 8 is NH2, CN, NH((C1-C4)alkyl) (wherein the alkyl moiety is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), or N((C1-C4)alkyl)2 (wherein the alkyl moiety is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). (12d) In one embodiment, at least one R 8 is OH, oxo, or (C1-C4)alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy). (12e) In one embodiment, at least one R 8 is (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), or (C1-C4) alkoxy (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy). (13a) In one embodiment, R O is H. (13b) In one embodiment, R O is (C1-C4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0030] In some embodiments, X 1 , X 2 , X 3 , L, R O , R X , R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and any group defined herein for any one of y, the remaining X 1 , X 2 , X 3 , L, R O , R X , R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and y may be combined with any group defined herein for one or more of: (A1) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3a). (A2) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3a). (A3) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3b). (A4) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3b). (A5) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3c). (A6) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3c). (A7) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3d). (A8) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3d). (A9) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3e). (A10) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3e). (A11) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3f). (A12) In one embodiment, X 1 , X2 , and X 3 is as defined in (1b) and L is as defined in (3f). (A13) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1a) and L is as defined in (3g). (A14) In one embodiment, X 1 , X 2 , and X 3 is as defined in (1b) and L is as defined in (3g). (B1) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4a). (B2) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4b). (B3) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4c). (B4) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4d). (B5) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4e). (B6) In one embodiment, X 1 , X2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4f). (B7) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4g). (B8) In one embodiment, X 1 , X 2 , X 3 and L is as defined in any one of (A1) to (A14), and R 1 is as defined in (4h). (C1) In one embodiment, R 1 is as defined in (4a) and L is as defined in (3a). (C2) In one embodiment, R 1 is as defined in (4b) and L is as defined in (3a). (C3) In one embodiment, R 1 is as defined in (4c) and L is as defined in (3a). (C4) In one embodiment, R 1 is as defined in (4d) and L is as defined in (3a). (C5) In one embodiment, R 1 is as defined in (4e) and L is as defined in (3a). (C6) In one embodiment, R 1 is as defined in (4f) and L is as defined in (3a). (C7) In one embodiment, R 1 is as defined in (4g) and L is as defined in (3a). (C8) In one embodiment, R 1 is as defined in (4h) and L is as defined in (3a). (C9) In one embodiment, R 1is as defined in (4a) and L is as defined in (3b). (C10) In one embodiment, R 1 is as defined in (4b) and L is as defined in (3b). (C11) In one embodiment, R 1 is as defined in (4c) and L is as defined in (3b). (C12) In one embodiment, R 1 is as defined in (4d) and L is as defined in (3b). (C13) In one embodiment, R 1 is as defined in (4e) and L is as defined in (3b). (C14) In one embodiment, R 1 is as defined in (4f) and L is as defined in (3b). (C15) In one embodiment, R 1 is as defined in (4g) and L is as defined in (3b). (C16) In one embodiment, R 1 is as defined in (4h) and L is as defined in (3b). (C17) In one embodiment, R 1 is as defined in (4a) and L is as defined in (3c). (C18) In one embodiment, R 1 is as defined in (4b) and L is as defined in (3c). (C19) In one embodiment, R 1 is as defined in (4c) and L is as defined in (3c). (C20) In one embodiment, R 1 is as defined in (4d) and L is as defined in (3c). (C21) In one embodiment, R 1 is as defined in (4e) and L is as defined in (3c). (C22) In one embodiment, R 1is as defined in (4f) and L is as defined in (3c). (C23) In one embodiment, R 1 is as defined in (4g) and L is as defined in (3c). (C24) In one embodiment, R 1 is as defined in (4h) and L is as defined in (3c). (C25) In one embodiment, R 1 is as defined in (4a) and L is as defined in (3d). (C26) In one embodiment, R 1 is as defined in (4b) and L is as defined in (3d). (C27) In one embodiment, R 1 is as defined in (4c) and L is as defined in (3d). (C28) In one embodiment, R 1 is as defined in (4d) and L is as defined in (3d). (C29) In one embodiment, R 1 is as defined in (4e) and L is as defined in (3d). (C30) In one embodiment, R 1 is as defined in (4f) and L is as defined in (3d). (C31) In one embodiment, R 1 is as defined in (4g) and L is as defined in (3d). (C32) In one embodiment, R 1 is as defined in (4h) and L is as defined in (3d). (C33) In one embodiment, R 1 is as defined in (4a) and L is as defined in (3e). (C34) In one embodiment, R 1 is as defined in (4b) and L is as defined in (3e). (C35) In one embodiment, R 1is as defined in (4c) and L is as defined in (3e). (C36) In one embodiment, R 1 is as defined in (4d) and L is as defined in (3e). (C37) In one embodiment, R 1 is as defined in (4e) and L is as defined in (3e). (C38) In one embodiment, R 1 is as defined in (4f) and L is as defined in (3e). (C39) In one embodiment, R 1 is as defined in (4g) and L is as defined in (3e). (C40) In one embodiment, R 1 is as defined in (4h) and L is as defined in (3e). (D1) In one embodiment, R 1 is as defined in (4a), and R 4 is as defined in (6a). (D2) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6a). (D3) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6a). (D4) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6a). (D5) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6a). (D6) In one embodiment, R 1 is as defined in (4f), and R 4 is as defined in (6a). (D7) In one embodiment, R 1 is as defined in (4g), and R 4is as defined in (6a). (D8) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6a). (D97) In one embodiment, R 1 is as defined in (4a), and R 4 is as defined in (6b). (D10) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6b). (D11) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6b). (D12) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6b). (D13) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6b). (D14) In one embodiment, R 1 is as defined in (4f), and R 4 is as defined in (6b). (D15) In one embodiment, R 1 is as defined in (4g), and R 4 is as defined in (6b). (D16) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6b). (D17) In one embodiment, R 1 is as defined in (4a), and R 4 is as defined in (6c). (D18) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6c). (D19) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6c). (D20) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6c). (D21) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6c). (D22) In one embodiment, R 1 is as defined in (4f), and R 4 is as defined in (6c). (D23) In one embodiment, R 1 is as defined in (4g), and R 4 is as defined in (6c). (D24) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6c). (D25) In one embodiment, R 1 is as defined in (4a), and R 4 is as defined in (6d). (D26) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6d). (D27) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6d). (D28) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6d). (D29) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6d). (D30) In one embodiment, R 1is as defined in (4f), and R 4 is as defined in (6d). (D31) In one embodiment, R 1 is as defined in (4g), and R 4 is as defined in (6d). (D32) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6d). (D33) In one embodiment, R 1 is as defined in (4a), and R 4 is as defined in (6e). (D34) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6e). (D35) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6e). (D36) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6e). (D37) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6e). (D38) In one embodiment, R 1 is as defined in (4f), and R 4 is as defined in (6e). (D39) In one embodiment, R 1 is as defined in (4g), and R 4 is as defined in (6e). (D40) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6e). (D41) In one embodiment, R 1 is as defined in (4a), and R 4is as defined in (6f). (D42) In one embodiment, R 1 is as defined in (4b), and R 4 is as defined in (6f). (D43) In one embodiment, R 1 is as defined in (4c), and R 4 is as defined in (6f). (D44) In one embodiment, R 1 is as defined in (4d), and R 4 is as defined in (6f). (D45) In one embodiment, R 1 is as defined in (4e), and R 4 is as defined in (6f). (D46) In one embodiment, R 1 is as defined in (4f), and R 4 is as defined in (6f). (D47) In one embodiment, R 1 is as defined in (4g), and R 4 is as defined in (6f). (D48) In one embodiment, R 1 is as defined in (4h), and R 4 is as defined in (6f). (E1) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3a). (E2) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3b). (E3) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3c). (E4) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3d). (E5) In one embodiment, R 4is as defined in (6a) and L is as defined in (3e). (E6) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3f). (E7) In one embodiment, R 4 is as defined in (6a) and L is as defined in (3g). (E8) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3a). (E9) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3b). (E10) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3c). (E11) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3d). (E12) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3e). (E13) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3f). (E14) In one embodiment, R 4 is as defined in (6b) and L is as defined in (3g). (E15) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3a). (E16) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3b). (E17) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3c). (E18) In one embodiment, R 4is as defined in (6c) and L is as defined in (3d). (E19) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3e). (E20) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3f). (E21) In one embodiment, R 4 is as defined in (6c) and L is as defined in (3g). (E22) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3a). (E23) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3b). (E24) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3c). (E25) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3d). (E26) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3e). (E27) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3f). (E28) In one embodiment, R 4 is as defined in (6d) and L is as defined in (3g). (E29) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3a). (E30) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3b). (E31) In one embodiment, R 4is as defined in (6e) and L is as defined in (3c). (E32) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3d). (E33) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3e). (E34) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3f). (E35) In one embodiment, R 4 is as defined in (6e) and L is as defined in (3g). (E36) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3a). (E37) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3b). (E38) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3c). (E39) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3d). (E40) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3e). (E41) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3f). (E42) In one embodiment, R 4 is as defined in (6f) and L is as defined in (3g). (F1) In one embodiment, R 1 and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6a). (F2) In one embodiment, R 1and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6b). (F3) In one embodiment, R 1 and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6c). (F4) In one embodiment, R 1 and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6d). (F5) In one embodiment, R 1 and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6e). (F6) In one embodiment, R 1 and L is as defined in any one of (C1) to (C40), and R 4 is as defined in (6f). (G1) In one embodiment, R 4 and L is as defined in any one of (E1) to (E42), and X 1 , X 2 , and X 3 is as defined in (1a). (G2) In one embodiment, R 4 and L is as defined in any one of (E1) to (E42), and X 1 , X 2 , and X 3 is as defined in (1b). (H1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5a). (H2) In one embodiment, X 1 , X 2, X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5b). (H3) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5c). (H4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5d). (H5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5e). (H6) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5f). (H7) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5g). (H8) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5h). (H9) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , and R 4 is as defined in one of (A1) through (G2), as applicable, and R 2 and R 3 is as defined in (5i). (I1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7a). (I2) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7b). (I3) In one embodiment, X 1 , X 2 , X 3 , L, R1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7c). (I4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7d). (I5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7e). (I6) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7f). (I7) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R4'' is as defined in (7g). (I8) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , and R 4 is as defined in any one of (A1) through (H9), as applicable, and R 4' and R 4'' is as defined in (7h). (J1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , and R 4'' is as defined in any one of (A1) through (I8), as applicable, and R 5 is as defined in (8a). (J2) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , and R 4'' is as defined in any one of (A1) through (I8), as applicable, and R 5 is as defined in (8b). (J3) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , and R 4'' is as defined in any one of (A1) through (I8), as applicable, and R 5 is as defined in (8c). (J4) In one embodiment, X 1 , X2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , and R 4'' is as defined in any one of (A1) through (I8), as applicable, and R 5 is as defined in (8d). (J5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , and R 4'' is as defined in any one of (A1) through (I8), as applicable, and R 5 is as defined in (8e). (K1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6' is as defined in (9a). (K2) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6' is as defined in (9b). (K3) In one embodiment, X 1 , X2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6' is as defined in (9c). (K4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6' is as defined in (9d). (K5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6' is as defined in (9e). (K6) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , and R 5 is as defined in any one of (A1) through (J5), as applicable, and R 6 and R 6'is as defined in (9f). (L1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , and R 6' is as defined in any one of (A1) through (K6), as applicable, and R 7 is as defined in (10a). (L2) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , and R 6' is as defined in any one of (A1) through (K6), as applicable, and R 7 is as defined in (10b). (L3) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , and R 6' is as defined in any one of (A1) through (K6), as applicable, and R 7 is as defined in (10c). (L4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R4' , R 4'' , R 5 , R 6 , and R 6' is as defined in any one of (A1) through (K6), as applicable, and R 7 is as defined in (10d). (M1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , and R 7 is as defined in one of (A1) through (L4), as applicable, and R 8 is as defined in (12a). (M2) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , and R 7 is as defined in one of (A1) through (L4), as applicable, and R 8 is as defined in (12b). (M3) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , and R 7 is as defined in one of (A1) through (L4), as applicable, and R8 is as defined in (12c). (M4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , and R 7 is as defined in one of (A1) through (L4), as applicable, and R 8 is as defined in (12d). (M5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , and R 7 is as defined in one of (A1) through (L4), as applicable, and R 8 is as defined in (12e). (N1) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11a). (N2) In one embodiment, X 1 , X 2 , X 3 , L, R 1, R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11b). (N3) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11c). (N4) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11d). (N5) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11e). (N6) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11f). (N7) In one embodiment, X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 is as defined in any one of (A1) to (M5), if applicable, and y is as defined in (11g).

[0031] In some embodiments, the compound of Formula (I') or (I) has the formula (I1'), (I1), (I2'), (I2), (I3'), (I3), (I4'), (I4), (I5'), (I5), (I6'), (I6), (I7'), (I7), (I8'), or (I8): TIFF0007728265000007.tif136149TIFF0007728265000008.tif136148, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof; In the formula, L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 , and y are each as defined herein; L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and any group defined herein for any one of L, R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and the remaining one or more of y may be combined with any group defined herein, for example, in (A1) to (N7), where applicable.

[0032] In some embodiments, the compound of Formula (I') or (I) has the formula (I1a'), (I1a), (I2a'), (I2a), (I3a'), (I3a), (I4a'), (I4a), (I5a'), (I5a), (I6a'), (I6a), (I7a'), (I7a), (I8a'), or (I8a): TIFF0007728265000009.tif206154TIFF0007728265000010.tif67154, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof; In the formula, L, R 1 , R 2 , R3 , R 4' , R 5 , R 6 , R 6' , R 7 , R 8 , and y are each as defined herein; L, R 1 , R 2 , R 3 , R 4' , R 5 , R 6 , R 6' , R 7 , R 8 and any group defined herein for any one of L, R 1 , R 2 , R 3 , R 4' , R 5 , R 6 , R 6' , R 7 , R 8 and the remaining one or more of y may be combined with any group defined herein, for example, in (A1) to (N7), where applicable.

[0033] In some embodiments, the compound of Formula (I') or (I) has the formula (I1b'), (I1b), (I2b'), (I2b), (I3b'), (I3b), (I4b'), (I4b), (I5b'), (I5b), (I6b'), (I6b), (I7b'), (I7b), (I8b'), or (I8b): TIFF0007728265000011.tif67154TIFF0007728265000012.tif206154, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof; In the formula, L, R 1 , R 2 , R 3 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8, and y are each as defined herein; L, R 1 , R 2 , R 3 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and any group defined herein for any one of L, R 1 , R 2 , R 3 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and the remaining one or more of y may be combined with any group defined herein, for example, in (A1) to (N7), where applicable.

[0034] In some embodiments, the compound of Formula (I') or (I) has the formula (I1c'), (I1c), (I2c'), (I2c), (I3c'), (I3c), (I4c'), (I4c), (I5c'), (I5c), (I6c'), (I6c), (I7c'), (I7c), (I8c'), or (I8c): TIFF0007728265000013.tif171154TIFF0007728265000014.tif101154, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof; In the formula, L, R 1 , R 2 , R 3 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 , and y are each as defined herein; L, R 1 , R 2 , R 3 , R4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and any group defined herein for any one of L, R 1 , R 2 , R 3 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , R 8 and the remaining one or more of y may be combined with any group defined herein, for example, in (A1) to (N7), where applicable.

[0035] Non-limiting exemplary compounds of the present application include those in Table 1.

[0036] (Table 1) TIFF0007728265000015.tif34161TIFF0007728265000016.tif208161TIFF0007728265000017.tif207 161TIFF0007728265000018.tif200161TIFF0007728265000019.tif210161TIFF0007728265000020.ti f212161TIFF0007728265000021.tif214161TIFF0007728265000022.tif218161TIFF000772826500002 3.tif221161TIFF0007728265000024.tif222161TIFF0007728265000025.tif215161TIFF00077282650 00026.tif217161TIFF0007728265000027.tif216161TIFF0007728265000028.tif200161TIFF0007728 265000029.tif210161TIFF0007728265000030.tif201161TIFF0007728265000031.tif220161TIFF000 7728265000032.tif199161TIFF0007728265000033.tif205161TIFF0007728265000034.tif205161TIF F0007728265000035.tif197161TIFF0007728265000036.tif202161TIFF0007728265000037.tif188161

[0037] In one embodiment, the compounds of the present application (e.g., compounds according to any of the formulas disclosed herein or any individual compound) are deuterated, i.e., one or more hydrogen atoms in the compound are replaced with one or more deuterium atoms.

[0038] The compounds of the present application (e.g., compounds according to any of the formulas disclosed herein or any individual compound) may be deuterated at any part of the molecule, e.g., at any position within the group X 1 , X 2 , X3 , L, R X , R 1 , R 2 , R 3 , R 4 , R 4' , R 4'' , R 5 , R 6 , R 6' , R 7 , and R 8 wherein one or more hydrogen atoms are replaced with one or more deuterium atoms.

[0039] In one embodiment, R 1 and / or R 4 At least one hydrogen atom in is replaced with at least one deuterium atom.

[0040] In one embodiment, R 1 In one embodiment, at least one hydrogen atom in R 1 is CHF or CHF, where one or both hydrogen atoms are replaced with a deuterium atom. 1 is CHF, where one or both hydrogen atoms are replaced with a deuterium atom. 1 is CHF2, where the hydrogen atoms are replaced with deuterium atoms.

[0041] In one embodiment, R 4 At least one hydrogen atom in is replaced with at least one deuterium atom.

[0042] In one embodiment, R 4 is S(O)NR 4' R 4'' and R 4' or R 4'' In one embodiment, at least one hydrogen atom in R 4' and R 4''One of the rings is H and the other is a monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) cycloalkyl, where monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) At least one of the hydrogen atoms of the cycloalkyl is replaced with at least one deuterium atom.

[0043] In one embodiment, R 4 is C(O)NR 4' R 4'' and R 4' or R 4'' In one embodiment, at least one hydrogen atom in R 4' and R 4'' One of the rings is H and the other is a monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) cycloalkyl, where monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) At least one of the hydrogen atoms of the cycloalkyl is replaced with at least one deuterium atom.

[0044] In one embodiment, R 4 is S(O)2R 4' and R 4' In one embodiment, at least one hydrogen atom in R 4' is monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) cycloalkyl, where monocyclic or polycyclic spiro, fused, or bridged (C3-C 15 ) At least one of the hydrogen atoms of the cycloalkyl is replaced with at least one deuterium atom.

[0045] In one embodiment, one or more of the three six-membered rings in any of the formulas or any individual compound disclosed herein is deuterated. 2 and R 3The phenyl ring to which is attached is deuterated.

[0046] Non-limiting exemplary deuterated compounds of the present application include those in Table 1d.

[0047] (Table 1d) TIFF0007728265000038.tif187161TIFF0007728265000039.tif213161TIFF0007728265000040.tif51161

[0048] Due to the presence of double bonds, the compounds of the present application may be in the cis or trans or Z or E configuration. Although one configuration may be depicted in the structure of the compounds or formulas of the present application, it is understood that the present application also encompasses the other configuration.

[0049] In one embodiment, the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) are pharmaceutically acceptable salts.In another embodiment, the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) are solvates.In another embodiment, the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) are hydrates.

[0050] Details of the present application are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, exemplary methods and materials are described here. Other features, objects, and advantages of the present application will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0051] definition The articles "a" and "an" are used in this application to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0052] The term "and / or" is used in this application to mean either "and" or "or," unless stated otherwise.

[0053] The present application also includes pharmaceutical compositions comprising an effective amount of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) and a pharmaceutically acceptable carrier.

[0054] The term "alkyl," as used herein, in certain embodiments, refers to a saturated, straight- or branched-chain hydrocarbon radical containing from 1 to 6 carbon atoms. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.

[0055] As used herein, the term "alkenyl" refers, in certain embodiments, to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 carbon atoms and having at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0056] The term "alkoxy" refers to an --O-alkyl radical.

[0057] The terms "hal," "halo," and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0058] The term "aryl," as used herein, refers to a monocyclic or polycyclic carbocyclic ring system having one or more aromatic rings, whether fused or non-fused, and includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

[0059] The term "aralkyl," as used herein, refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0060] As used herein, the term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound (fused, bridged, or spiro ring). As used herein, "cycloalkyl" includes monocyclic cycloalkyl groups and polycyclic (i.e., polycyclic) cycloalkyl groups containing two or more ring groups that can form spiro, fused, or bridged ring systems. These cycloalkyls may have 3 to 15 ring carbon atoms. C3 to C 10 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octyl, and adamantyl. Monovalent groups derived from monocyclic or polycyclic carbocyclic ring compounds having at least one carbon-carbon double bond by the removal of a single hydrogen atom are also contemplated. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

[0061] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic (e.g., bi- or tricyclic or higher), fused or non-fused radical or ring system having at least one aromatic ring and having 5 to 10 ring atoms, of which one ring atom is selected from S, O, and N; 0, 1, or 2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and the like.

[0062] The term "heteroaralkyl," as used herein, refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like.

[0063] The term "heterocyclyl" or "heterocycloalkyl," as used herein, refers to a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (fused, bridged, or spirocyclic), or 11-, 12-, 13-, or 14-membered tricyclic ring system (fused, bridged, or spirocyclic), where (i) each ring contains 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bond and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms are optionally oxidized, and (iv) the nitrogen heteroatom is optionally quaternized. Representative heterocycloalkyl groups include [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4R)-2λ 2 -Azabicyclo[2.2.1]heptanyl, (1R,4S)-2λ 2-Azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-azaspiro[3.3]heptan-5-amine, 1-azaspiro[3.3]heptan-5-amine, 1-oxa-6-azaspiro[3.3]heptan-3-amine, 2-azaspiro[3.3]heptan-6-amine, 1-azaspiro[3.3]heptan-6-amine, 6-azaspiro[3.4 ]octan-2-amine, 5-azaspiro[3.4]octan-2-amine, 6-azaspiro[3.4]octan-1-amine, 5-azaspiro[3.4]octan-1-amine, 5-oxa-2-azaspiro[3.4]octan-7-amine, 7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]octan-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide and the like.

[0064] The term "alkylamino," for example, refers to a group having the structure NH(C1-C6 alkyl), where C1-C6 alkyl is as defined above.

[0065] The term "dialkylamino," for example, refers to a group having the structure N(C1-C6 alkyl)2, where C1-C6 alkyl is as defined above.

[0066] According to the present application, any of the aryls, substituted aryls, heteroaryls, and substituted heteroaryls described herein may be any aromatic group. The aromatic group may be substituted or unsubstituted.

[0067] As described herein, the compounds of the present application may be substituted with one or more substituents as outlined above or exemplified by specific classes, subclasses, and species of the present application. It will be recognized that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," regardless of the presence of the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. "Optionally substituted," "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted cycloalkyl," "optionally substituted cycloalkenyl," "optionally substituted aryl," "optionally substituted heteroaryl," "optionally substituted aralkyl," "optionally substituted heteroaralkyl," "optionally substituted heterocyclyl," and any other optionally substituted group as used herein refer to a group that is substituted or unsubstituted by independent replacement of one, two, or three or more hydrogen atoms thereof with substituents including, but not limited to, the following: -F, -CI, -Br, -I, -OH, protected hydroxy, -NO, -CN, -NH, protected amino, -NH-C1-C1 12 -Alkyl, -NH-C2~C 12 -Alkenyl, -NH-C2-C 12 -Alkenyl, -NH-C3-C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C 12 -Alkyl, -O-C2~C 12 -Alkenyl, -O-C2-C 12 -Alkenyl, -O-C3-C 12-Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -Alkyl, -C(O)-C2-C 12 -Alkenyl, -C(O)-C 12 -Alkenyl, -C(O)-C3-C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -Alkyl, -CONH-C2~C 12 -Alkenyl, -CONH-C2-C 12 -Alkenyl, -CONH-C3-C 12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -Alkyl, -OCO2-C2~C 12 -Alkenyl, -OCO2-C2~C 12 -Alkenyl, -OCO2-C3~C 12 -Cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -Alkyl, -OCONH-C2~C 12 -Alkenyl, -OCONH-C2-C 12 -Alkenyl, -OCONH-C3-C 12 -Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C1-C 12 -Alkyl, -NHC(O)-C2-C 12 -Alkenyl, -NHC(O)-C 12 -Alkenyl, -NHC(O)-C3-C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-C 12 -Alkyl, -NHCO2-C2~C 12 -Alkenyl, -NHCO2-C2~C 12 -Alkenyl, -NHCO2-C3~C12 -Cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C 12 -Alkyl, -NHC(O)NH-C2-C 12 -Alkenyl, -NHC(O)NH-C 12 -Alkenyl, -NHC(O)NH-C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH2, -NHC(S)NH-C1-C 12 -Alkyl, -NHC(S)NH-C2~C 12 -Alkenyl, -NHC(S)NH-C2-C 12 -Alkenyl, -NHC(S)NH-C3-C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -Alkyl, -NHC(NH)NH-C2-C 12 -Alkenyl, -NHC(NH)NH-C 12 -Alkenyl, -NHC(NH)NH-C3-C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NHheterocycloalkyl, -NHC(NH)-C 12 -Alkyl, -NHC(NH)-C2-C 12 -Alkenyl, -NHC(NH)-C2-C 12 -Alkenyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -Alkyl, -C(NH)NH-C2-C 12 -Alkenyl, -C(NH)NH-C 12 -Alkenyl, C(NH)NH-C3-C 12-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C1-C 12 -Alkyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C3-C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl-SO2NH2, -SO2NH-C1-C 12 -Alkyl, -SO2NH-C2~C 12 -Alkenyl, -SO2NH-C2~C 12 -Alkenyl, -SO2NH-C3~C 12 -Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -Alkyl, -NHSO2-C2~C 12 -Alkenyl, -NHSO2-C2~C 12 -Alkenyl, -NHSO2-C3~C 12 -Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C 12 -Alkyl, -S-C2~C 12 -Alkenyl, -S-C2-C 12 -Alkenyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl.

[0068] The term "carrier" as used in this application encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a drug from one organ or part of the body of a subject to another organ or part of the body.

[0069] The compounds of the present application may form salts that are also within the scope of the present application. Reference herein to a compound of a formula is understood to include reference to salts thereof, unless otherwise specified.

[0070] Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothioate, lactate, lactobiolate, and the like. phosphate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0071] For example, the compounds of the present application, including pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers of the compounds, can exist in unsolvated or solvated forms with other solvent molecules.

[0072] "Solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.Some compounds or salts tend to trap a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by the combination of one or more water molecules with one molecule of a substance, where water retains its molecular state as H2O.

[0073] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds, including those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of an asymmetric carbon), rotamer forms, atropisomers, and diastereomeric forms (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), are contemplated within the scope of the present application, as well as positional isomers (e.g., 4-pyridyl, 3-pyridyl, etc.). For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both cis- and trans-forms and mixtures are encompassed within the scope of the present application. Individual stereoisomers of the compounds of the present application may, for example, be substantially free of other isomers or may be, for example, racemic or mixed with all or selected other stereoisomers. The chiral centers of the present application may have the S or R configuration as defined by the 1974 IUPAC Recommendations. Use of the terms "salt," "solvate," "ester," "prodrug," and the like is intended to apply equally to salts, solvates, esters, prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the invention.

[0074] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be due to constitution (geometric isomers) or ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of the present application (e.g., compounds of any formula disclosed herein or any individual compound) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, or as individual enantiomers or diastereomers.

[0075] In this specification, the structural formula of a compound may in some cases conveniently represent a particular isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, and tautomers.

[0076] "Isomers" means compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0077] The compounds of the present application may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, as well as mixtures thereof, including racemic mixtures, are intended to form part of the present application. In addition, the present application encompasses all geometric and positional isomers. For example, if a compound of the present application incorporates a double bond or a fused ring, both cis and trans forms and mixtures are encompassed within the scope of the present application. Each compound disclosed herein includes all enantiomers consistent with the general structure of the compound. The compounds may be racemic or enantiomerically pure, or any other form in terms of stereochemistry. Assay results may reflect data collected for racemic, enantiomerically pure, or any other form in terms of stereochemistry.

[0078] A carbon atom bonded to four nonidentical substituents is called a "chiral center."

[0079] "Chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to a considered chiral center are ranked according to the rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0080] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about double bonds. These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.

[0081] In another embodiment of the present application, the compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound) are enantiomers. In some embodiments, the compounds are (S)-enantiomers. In another embodiment, the compounds are (R)-enantiomers. In yet another embodiment, the compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound) may be (+) or (-) enantiomers. The compounds may contain more than one stereocenter.

[0082] In another embodiment of the present application, the compounds of the present application (e.g., any compound of any of the formulas disclosed herein or any individual compound) are diastereomers. In some embodiments, the compounds are syn diastereomers. In other embodiments, the compounds are anti diastereomers.

[0083] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0084] It is also possible that compounds of the present application may exist in different tautomeric forms, and all such forms are included within the scope of the application. Also included in the application are, for example, all keto-enol and imine-enamine forms of the compounds.

[0085] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that become interconvertible through tautomerization is called tautomerism.

[0086] Of the various possible types of tautomerism, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of an electron and a hydrogen atom occurs; and ring-chain tautomerism, as exemplified by glucose, results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form.

[0087] Common tautomeric pairs are ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomers in heterocycles (e.g., in nucleobases such as guanine, thymine, cytosine), amine-enamine, and enamine-imine.

[0088] The present application relates to compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof that are capable of modulating thyroid hormone receptors, and that are useful for treating diseases and disorders associated with modulation of thyroid hormone receptors. The present application further relates to compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof that are useful for modulating thyroid hormone receptors.

[0089] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that have advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0090] In some aspects, the present application provides compounds of the present application (e.g., any compound of any of the formulas disclosed herein or any individual compound) that are at least as potent as one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, with respect to modulating the activity of thyroid hormone receptors, and that have additional advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0091] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more potent than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, with respect to modulating the activity of thyroid hormone receptors.

[0092] In some aspects, the present application provides compounds of the present application (e.g., any compound of any of the formulas disclosed herein or any individual compound) that are more potent than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, with respect to modulating the activity of thyroid hormone receptors, and that have additional advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0093] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more isoform selective than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0094] In some aspects, the present application provides compounds of the present application (e.g., any compound of any of the formulas disclosed herein or any individual compound) that are more isoform selective with respect to modulating the activity of thyroid hormone receptors than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, and have additional advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0095] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more tissue selective than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0096] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more tissue selective for modulating the activity of thyroid hormone receptors than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, and have additional advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0097] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more liver tissue selective than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0098] In some aspects, the present application provides compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) that are more liver tissue selective for modulating the activity of thyroid hormone receptors than one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141, and have additional advantageous properties compared to one or more known thyroid hormone receptor ligands, including, but not limited to, MGL-3196, VK-2809, eprotirome, sobetirome, and KB-141.

[0099] The potency of an agonist or activator is determined by the EC 50 The EC value can be determined by the EC 50 Compounds with lower EC 50 Compounds with higher values ​​are more potent agonists or activators compared to compounds with higher values.

[0100] The compounds of the present application can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide) to provide other compounds of the present application. Thus, all shown and claimed nitrogen-containing compounds, where permitted by valency and structure, include the shown compounds and their N-oxide derivatives (N→O or N + -O -and N-alkoxy (which may be represented as N-hydroxy or N-alkoxy). Additionally, in other cases, nitrogens in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine with an oxidizing agent such as m-CPBA. All depicted and claimed nitrogen-containing compounds are also deemed to encompass both the depicted compound and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, where R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3- to 14-membered carbocyclic, or 3- to 14-membered heterocyclic) derivatives, where permitted by valency and structure.

[0101] As used in this application, the term "prodrug" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0102] Because prodrugs are known to improve many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturability, etc.), the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers can be delivered in prodrug form. Thus, the present application is intended to encompass prodrugs of the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) or their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, methods of delivering the same, and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present application in which a hydroxyl or amino group is bonded to any group that is cleaved to form a free hydroxyl or free amino group, respectively, when the prodrug of the present application is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the respective formulas described herein, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0103] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate.

[0104] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (such as the replacement of an atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0105] The present application also includes isotopically labeled compounds identical to those represented by each of the formulas described herein, but which differ by the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present application are: 3 H, 11 C. 14 C. 2 H and 18 Includes isotopes of hydrogen, carbon, nitrogen, and fluorine, such as F.

[0106] Compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound) or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof that contain said and / or other isotopes of other atoms are within the scope of the present application. Isotopically labeled compounds of the present application, e.g., 3 H, 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are useful due to their ease of preparation and detectability. 11 C and 18 F isotopes are useful for PET (positron emission tomography). PET is useful for imaging the brain. In addition, deuterium, i.e., 2Substitution with heavier isotopes, such as H, can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced required dosage, and therefore may be preferable in some circumstances; isotopically labeled compounds of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples set forth herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one aspect, a compound of the present application (e.g., compounds of any of the formulas disclosed herein or any individual compound), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, is not isotopically labeled.

[0107] The terms "administer," "administering," or "administration" as used in this application refer to administering to a subject directly a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound, or to administering to a subject a prodrug, derivative, or analog of a compound or a pharmaceutically acceptable salt or composition of a compound that is capable of forming an equivalent amount of the active compound in the subject's body.

[0108] A "patient" or "subject" is a mammal, for example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0109] An "effective amount" or "therapeutically effective amount" when used in reference to a compound or pharmaceutical composition is an amount effective to treat or prevent a disease in a subject, as described herein.

[0110] The term "treating" with respect to a subject refers to ameliorating at least one symptom of a disorder in a subject. Treating includes curing, ameliorating, or at least partially ameliorating a disorder.

[0111] The compounds of the present application, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can also be used to prevent a disease, condition, or disorder. As used herein, "preventing" or "prevent" describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0112] The term "disorder" is used herein to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0113] As used herein, the term disease or disorder controlled by thyroid hormone means any disease or other deleterious condition in which thyroid hormone is known to play a role. Accordingly, another aspect of the present application relates to treating or lessening the severity of one or more diseases in which thyroid hormone is known to play a role. Specifically, the present application relates to a method for treating liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, liver fibrosis, hepatitis, cirrhosis, or hepatocellular carcinoma (HCC) / hepatoma), metabolic diseases (e.g., dyslipidemia, hyperlipidemia, severe hypertriglyceridemia (SHTG), familial partial lipodystrophy (FPLD), familial chylomicronemia syndrome (FCS), xanthomas, familial dysbetalipoproteinemia / hypolipoproteinemia type III), hypercholesterolemia, familial hypercholesterolemia (HeFH / HoFH), metabolic disorders, obesity, or diabetes (e.g., type II diabetes), thyroid diseases (e.g., hypothyroidism, thyroid hormone resistance (RTH) syndrome, thyroid cancer, allergic rheumatoid arthritis, ... the present invention relates to a method for treating or lessening the severity of a disease or condition controlled by thyroid hormones (e.g., Herndon-Dudley syndrome, Graves' disease, Hashimoto's disease, thyroiditis, thyroid hypoplasia, congenital hypothyroidism, or inherited thyroid hormone-binding protein defects), cardiovascular disease (e.g., hypertension, atherosclerosis, heart failure, cardiac arrhythmia, coronary heart disease, or cardiac hypertrophy), rare diseases controlled by thyroid hormones (e.g., X-linked adrenoleukodystrophy (X-ALD), glycogen storage disease (GSD), male pattern baldness (AGA), or multiple sclerosis), pancreatitis, and other diseases controlled by thyroid hormones (e.g., fibrosis, such as pulmonary fibrosis and renal fibrosis, or skin disorders). In one embodiment, the disease or condition regulated by thyroid hormone is selected from liver disease, liver inflammation, fibrosis (e.g., liver fibrosis), NAFLD, NASH, atherosclerosis, stroke and its complications, Alzheimer's disease, cardiovascular disease, metabolic disease, atherosclerosis, and myocardial infarction.In one embodiment, the disease or condition regulated by thyroid hormone is a liver disease selected from NAFLD, NASH, hepatic steatosis, hepatic fibrosis, hepatitis, cirrhosis, and HCC / hepatoma. In one embodiment, the liver disease is selected from NAFLD, NASH, fatty liver, and hepatic fibrosis. In one embodiment, the disease or condition regulated by thyroid hormone is a metabolic disease selected from dyslipidemia, hyperlipidemia, hypercholesterolemia, familial hypercholesterolemia (HeFH / HoFH), metabolic disorders, obesity, and diabetes (e.g., type II diabetes). In one embodiment, the metabolic disease is selected from hyperlipidemia, hypercholesterolemia, and familial hypercholesterolemia (HeFH / HoFH). In one embodiment, the disease or condition regulated by thyroid hormone is a thyroid disease selected from hypothyroidism, RTH syndrome, thyroid cancer, Allan-Herndon-Dudley syndrome, and Graves' disease. In one embodiment, the disease or condition controlled by thyroid hormone is a cardiovascular disease selected from hypertension, atherosclerosis, heart failure, arrhythmia, coronary heart disease, and cardiac hypertrophy. In one embodiment, the disease or condition controlled by thyroid hormone is a rare disease controlled by thyroid hormone selected from X-ALD, GSD, AGA, and multiple sclerosis. In one embodiment, the disease or condition controlled by thyroid hormone is selected from fibrosis, such as pulmonary fibrosis and renal fibrosis, and skin disorders. In one embodiment, the disease or condition controlled by thyroid hormone is selected from NAFLD, NASH, hepatic steatosis, hepatic fibrosis, hyperlipidemia, hypercholesterolemia, familial hypercholesterolemia (HeFH / HoFH), and X-ALD.

[0114] Methods for Preparing Compounds The compounds of the present application may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes below.

[0115] The compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis, using methods readily apparent to those skilled in the art. The selected processes and the reaction conditions and order of their implementation must be consistent with the preparation of the compounds of the present application.

[0116] Those skilled in the art will recognize whether a stereocenter exists in the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound). Accordingly, the present application includes both possible stereoisomers (unless specified in the synthesis), including not only the racemate but also the individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0117] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0118] The compounds of the present application can be prepared in many ways well known to those skilled in the art of organic synthesis. As an example, the compounds of the present application can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthetic chemistry or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present application (i.e., compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound)) can be synthesized according to the steps outlined in the general schemes described in the Examples. Starting materials are commercially available or are made by known procedures in published literature or as illustrated.

[0119] Analytical methods, materials, and equipment Unless otherwise noted, reagents and solvents were used as received from the supplier. Proton and fluorine nuclear magnetic resonance (NMR) spectra were acquired on either a Bruker or Varian spectrometer at 400 MHz and 376 MHz, respectively. Spectra are reported in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Liquid chromatography-mass spectrometry (LC / MS) was collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were determined using an Agilent 1260-6125B LCMS system (equipped with a diode array detector and an Agilent G6125BA mass spectrometer) or a Waters Acquity UPLC system (equipped with a diode array detector and a Waters 3100 mass detector). Purity was characterized by UV wavelengths of 214 nm, 220 nm, and 254 nm and by electrospray spectrometry (ESI). Column: Waters Analytical CORTECS C18 2.7 μm 4.6 x 30 mm; Flow rate: 1.8 mL / min; Solvent A (100 / 0.1% water / formic acid), Solvent B (100% acetonitrile); Gradient: 5% B hold until 0.3 min, 5 to 95% B from 0.3 to 2 min, 95% B hold until 4.8 min, 95 to 5% B from 4.8 to 5.4 min, then 5% B hold until 6.5 min. Alternatively, Column: Acquity UPLC BEH C18 1.7 μm 2.1 x 50 mm; Flow rate: 0.5 mL / min; Solvent A (0.1% formic acid in water), Solvent B (acetonitrile); Gradient: 5% B hold until 0.2 min, 5 to 95% B from 0.2 to 2.0 min, 95% B hold until 3.1 min, then 5% B hold until 3.5 min.

[0120] Abbreviations used in the following examples and elsewhere in this specification are as follows: TIFF0007728265000041.tif182146

[0121] Biological assays The biological activity of the compounds of the present application can be assessed by methods and assays known in the art.

[0122] Methods using compounds The compounds of the present application are useful for modulating (e.g., activating) thyroid hormone receptors. The relative modulating power of a compound can be determined in various ways, for example, by the amount required to modulate the activity of thyroid hormone binding to thyroid hormone receptors in in vitro assays using recombinant human proteins or recombinant non-human enzymes, in cell assays expressing normal enzymes, or in in vivo tests. Thus, the present application relates to methods for modulating (e.g., activating) thyroid hormone receptors for the treatment of diseases or disorders.

[0123] The compounds of the present application are useful for treating diseases or disorders regulated by thyroid hormone, including, but not limited to, thyroid hormone disorders, fibrosis or fibrotic diseases, liver diseases, cardiovascular diseases, and metabolic diseases.

[0124] Inflammation or inflammatory diseases (e.g., inflammation or inflammatory diseases regulated by thyroid hormone) include, but are not limited to, arthritis, synovitis, Crohn's disease, ulcerative colitis, irritable bowel disease, asthma (e.g., eosinophilic asthma, severe asthma, asthma exacerbated by viruses), chronic pain, chronic pain from osteoarthritis, chronic pulmonary obstructive disease, cystic fibrosis, bronchiectasis, autoimmune liver disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, NAFLD, NASH, neuroinflammation, cirrhosis of the liver, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and its complications, myocardial infarction and its complications, post-stroke inflammatory cellular tissue destruction, psoriasis, contact dermatitis, diabetic inflammation, skin inflammation, lung inflammation, liver inflammation, and the like.

[0125] Fibrosis or fibrotic diseases (e.g., fibrotic diseases controlled by thyroid hormone) include, but are not limited to, cystic fibrosis, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), liver cirrhosis, renal fibrosis, pulmonary fibrosis, fibrosis of other organs and tissues, radiation-induced fibrosis, and other diseases in which excessive fibrosis contributes to the disease pathology.

[0126] Liver diseases (e.g., liver diseases controlled by thyroid hormones) include, but are not limited to, liver inflammation, liver fibrosis, fatty liver, NASH, NAFLD, cirrhosis, autoimmune diseases of the liver, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, and hepatocellular carcinoma.

[0127] Respiratory diseases (e.g., respiratory diseases controlled by thyroid hormone) include, but are not limited to, pulmonary fibrosis, lung inflammation, asthma (e.g., eosinophilic asthma, severe asthma, virally exacerbated asthma), chronic pulmonary obstructive disease, cystic fibrosis, and bronchiectasis.

[0128] Metabolic diseases include, but are not limited to, dyslipidemia, hyperlipidemia, hypercholesterolemia, familial hypercholesterolemia (HeFH / HoFH), metabolic disorders, obesity, or diabetes (eg, type II diabetes).

[0129] Thyroid diseases include, but are not limited to, hypothyroidism, thyroid hormone resistance (RTH) syndrome, thyroid cancer, Allan-Herndon-Dudley syndrome, or Graves' disease.

[0130] Cardiovascular diseases include, but are not limited to, hypertension, atherosclerosis, heart failure, cardiac arrhythmia, coronary heart disease, or cardiac hypertrophy.

[0131] Rare diseases controlled by thyroid hormone include, but are not limited to, X-linked adrenoleukodystrophy (X-ALD), glycogen storage disease (GSD), male pattern baldness (AGA), or multiple sclerosis.

[0132] Other diseases regulated by thyroid hormone include, but are not limited to, fibrosis, such as pulmonary fibrosis and renal fibrosis, or skin disorders.

[0133] Another aspect of the present application relates to a method for treating, preventing, inhibiting, or eliminating a disease or disorder controlled by thyroid hormone, comprising the step of administering to a subject in need of treatment for a disease or disorder associated with modulation of thyroid hormone receptors an effective amount of a compound of the present application (e.g., any compound of the formulas disclosed herein or any individual compound), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of the present application (e.g., any compound of the formulas disclosed herein or any individual compound).

[0134] Another aspect of the present application relates to a method of modulating a thyroid hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application (e.g., any compound of the formulas disclosed herein or any individual compound), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of the present application (e.g., any compound of the formulas disclosed herein or any individual compound).

[0135] Another aspect of the present application relates to a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating a disease or disorder controlled by thyroid hormone. In one embodiment, the disease or disorder controlled by thyroid hormone is a disease or disorder described herein.

[0136] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating a disease or disorder controlled by thyroid hormone. In one embodiment, the disease or disorder controlled by thyroid hormone is a disease or disorder described herein.

[0137] Another aspect of the present application relates to a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating thyroid hormone receptors.

[0138] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating thyroid hormone receptors.

[0139] Another aspect of the present application relates to the use of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder controlled by thyroid hormone. In one embodiment, the disease or disorder controlled by thyroid hormone is a disease or disorder described herein.

[0140] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for treating a disease or disorder controlled by thyroid hormone. In one embodiment, the disease or disorder controlled by thyroid hormone is a disease or disorder described herein.

[0141] Another aspect of the present application relates to the use of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for modulating a thyroid hormone receptor.

[0142] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for modulating a thyroid hormone receptor.

[0143] The disclosed compounds of the present application can be administered in an amount effective to treat or prevent a disorder in a subject and / or prevent its onset.

[0144] The compounds of the present application can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations) or methods, e.g., non-drug therapies. For example, synergistic effects can occur with other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory substances. In some embodiments, the compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound) are administered in combination with an additional therapeutic agent selected from anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotropic factors, drugs for treating liver disease, drugs for treating metabolic diseases, drugs for treating thyroid disease, drugs for treating cardiovascular disease, drugs for treating pulmonary disease, drugs for treating kidney disease, drugs for treating eye diseases, drugs for treating skin diseases, antiviral agents, drugs for treating blood disorders, drugs for treating diabetes, and drugs for treating immunodeficiency disorders. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compounds will naturally vary depending on the type of co-medication employed, the specific drug employed, the condition being treated, etc.

[0145] Combination therapy includes the administration of the target compound further in combination with other biologically active ingredients (such as, but not limited to, anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotropic factors, drugs for treating cardiovascular diseases, drugs for treating liver diseases, antiviral agents, drugs for treating blood disorders, drugs for treating diabetes, drugs for treating immunodeficiency disorders, and drugs for treating pain) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatment procedures. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of treatment.

[0146] Pharmaceutical Compositions The present application also provides pharmaceutical compositions comprising a compound of the present application (e.g., a compound of any of the formulas disclosed herein or any individual compound) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof in combination with at least one pharmaceutically acceptable excipient or carrier.

[0147] A "pharmaceutical composition" is a formulation containing a compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof) in a unit dose of composition is an effective amount and will vary depending on the particular treatment involved. Those skilled in the art will recognize that routine variations in dosage may be necessary depending on the age and condition of the patient. Dosage will also vary depending on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0148] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0149] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0150] The pharmaceutical compositions of the present application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate, and an agent for adjusting isotonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid and sodium hydroxide. Parenteral preparations can be packaged in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0151] The compounds or pharmaceutical compositions of the present application can be administered to a subject by many well-known methods currently used for chemotherapeutic treatment. The selected dosage should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects. Preferably, the patient's condition and health status should be carefully monitored during and after treatment for a reasonable period of time.

[0152] The term "therapeutically effective amount," as used herein, refers to the amount of a pharmaceutical agent for treating, ameliorating, or preventing an identified disease or condition, or for exerting a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The exact effective amount for each subject will vary depending on the subject's weight, size, and health; the nature and extent of symptoms; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for each given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician. In one embodiment, the disease or disorder is a disease or disorder described herein.

[0153] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0154] Dosage and administration methods are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0155] Pharmaceutical compositions containing the active compounds of the present application (i.e., a compound of the present application (e.g., any compound of the formulas disclosed herein or any individual compound)) may be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, micronizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or auxiliaries that facilitate processing of the active compound(s) into pharmaceutically usable preparations. Of course, appropriate formulations will depend upon the selected route of administration.

[0156] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy filling and release into a syringe exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0157] Sterile injectable solution can be prepared by incorporating the required amount of active compound into a suitable solvent, which contains one or a combination of the ingredients listed above as needed, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and the other ingredients listed above as needed.For the preparation of sterile powder for sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which can obtain the powder of active ingredient plus any additional desired ingredients from the solution that has been previously sterile-filtered.

[0158] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is orally applied, gargled, and expectorated or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0159] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0160] Systemic administration may also be via transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salve, gel, or cream, as generally known in the art.

[0161] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Methods for preparing such formulations will be clear to those skilled in the art.These materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc.Liposomal suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0162] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.As used herein, dosage unit form refers to a physically discrete unit suitable as a single dose for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier.The specifications for each dosage unit form in this application are determined by and directly vary according to the specific properties of the active compound and the specific therapeutic effect to be achieved.

[0163] For therapeutic applications, the dosage of a pharmaceutical composition used for a given application will vary depending on the drug, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the treating clinician or practitioner, among other factors affecting the selected dosage. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical is an amount that produces an objectively identifiable improvement as noted by a clinician or other qualified observer. As used herein, the term "dosage-effective manner" refers to the amount of active compound to produce the desired biological effect in a subject or cell.

[0164] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0165] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present application where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactate, and the like. These include, but are not limited to, those derived from inorganic and organic acids selected from biotic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, basic acetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and naturally occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0166] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present application also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0167] All references to pharmaceutically acceptable salts should be understood to include the solvent addition forms (solvates) or crystal forms (polymorphs) of the salt as defined herein.

[0168] The compounds of the present application can also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, e.g., methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate, or other ester.

[0169] The compounds of the present application can also be prepared as prodrugs, e.g., pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Because prodrugs are known to improve many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturability, etc.), the compounds of the present application can be delivered in prodrug form. Thus, the present application is intended to encompass prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. "Prodrug" is intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo when such prodrug is administered to a subject. Prodrugs in the present application are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present application having a hydroxy, amino, sulfhydryl, carboxy or carbonyl group bonded to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.

[0170] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds of the present application, esters (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) of amino functional groups, N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups, and the like; see Bundegaard, H., Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

[0171] The compound, or its pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative, is administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound, or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer, is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0172] The administration regimen utilizing the compound is selected depending on various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the particular compound employed, or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0173] Techniques for formulating and administering the compounds disclosed herein can be found in Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound, or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer, will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage, within the ranges described herein.

[0174] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present application will become apparent from the various examples. The examples provided illustrate various elements and methods useful in carrying out the present application. The examples do not limit the claimed application. Based on the present application, one skilled in the art will be able to identify and adopt other elements and methodologies useful for carrying out the present application. [Example]

[0175] The present application is further illustrated by the following examples and synthetic schemes, which are not to be construed as limiting the scope or spirit of the present application to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments, and that no limitation to the scope of the present application is intended thereby. It should be further understood that various other embodiments, modifications, and equivalents, which may themselves suggest themselves to those skilled in the art, may be used without departing from the spirit of the present application and / or the scope of the appended claims.

[0176] Example 1: General Scheme A - Synthesis of Intermediate A TIFF0007728265000042.tif27160

[0177] Process 1:A-2 TIFF0007728265000043.tif311To a solution of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione A-1 (10 g, 52.09 mmol) in DMF (100 mL) at 280 °C, sodium hydride (8.33 g, 208.36 mmol, 60% purity) was added portionwise. The reaction mixture was stirred at 0 °C for 30 min. 1-(Chloromethyl)-4-methoxybenzene (20.39 g, 130.23 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (500 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=5:1) to give 6-bromo-2,4-bis(4-methoxybenzyl)-1,2,4-triazine-3,5(2H,4H)-dione A-2 (12 g, 26.37 mmol, 50% yield) as a pale yellow solid. LCMS: [M+Na] + =454.0.

[0178] Process 2:A-3 A mixture of 6-bromo-2,4-bis(4-methoxybenzyl)-1,2,4-triazine-3,5(2H,4H)-dione A-2 (3.0 g, 6.94 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (5.33 g, 27.76 mmol, 3.51 mL), and copper(I) iodide (2.64 g, 13.88 mmol) in DMF (50 mL) was stirred at 120 °C for 16 h under N2 (g) protection. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=2:1) ​​to give 2,4-bis(4-methoxybenzyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione A-3 (2.8 g, 6.65 mmol, 96% yield) as a pale yellow solid. LCMS: [M+Na] + =444.0.

[0179] Step 3: Intermediate A A mixture of 2,4-bis(4-methoxybenzyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione A-3 (2.1 g, 4.98 mmol) and ceric ammonium nitrate (27.32 g, 49.84 mmol) in MeCN (57 mL) and water (19 mL) was stirred at 85 °C under N2 (g) protection for 3.5 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione intermediate A (880 mg, 4.62 mmol, 93% yield) as a pale yellow solid. LCMS: [M+H] +=182.0.

[0180] Example 2: General Scheme B - Synthesis of Intermediate B TIFF0007728265000046.tif81162

[0181] Process 1:B-3 To a mixture of aminourea hydrochloride B-1 (7.5 g, 67.25 mmol) in 1 N HCl (50 mL) at 280 °C was added 3-bromo-2-oxo-propanoic acid B-2 (7.50 g, 44.92 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was filtered to give a white solid. The white solid was dried under vacuum to give (2Z)-3-bromo-2-(carbamoylhydrazono)propanoic acid B-3 (6.0 g, 38% yield) as a white solid. TIFF0007728265000048.tif5149

[0182] Process 2:B-4 A mixture of (Z)-3-bromo-2-(2-carbamoylhydrazono)propanoic acid B-3 (6.0 g, 26.78 mmol) in SOCl2 (60 mL) was stirred at 80 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give 6-(chloromethyl)-1,2,4-triazine-3,5(2H,4H)-dione B-4 (4.3 g, 94% yield) as a yellow solid. LCMS: [M+H] + =162.0.

[0183] Process 3:B-5 TIFF0007728265000050.tif31128 A mixture of 6-(chloromethyl)-2H-1,2,4-triazine-3,5-dione B-4 (5.5 g, 34.05 mmol) in water (80 mL) was stirred at 100 °C for 4 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give the residue 6-(hydroxymethyl)-2H-1,2,4-triazine-3,5-dione B-5 (4.7 g, 92% yield) as a yellow solid. LCMS: [M+H] + =144.0.

[0184] Process 4:B-6 TIFF0007728265000051.tif30128 To a mixture of 6-(hydroxymethyl)-2H-1,2,4-triazine-3,5-dione B-5 (4.85 g, 33.89 mmol) and imidazole (6.92 g, 101.68 mmol) in DMF (50 mL) at room temperature was added tert-butyldimethylsilyl chloride (7.66 g, 50.84 mmol). The reaction mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=5:1) to give 6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2H-1,2,4-triazine-3,5-dione B-6 (3.2 g, 35% yield) as a pale yellow solid. LCMS: [M+H] + =258.1.

[0185] Process 5:B-7 A mixture of 6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2H-1,2,4-triazine-3,5-dione B-6 (1.0 g, 3.89 mmol), N,N-diisopropylethylamine (3.01 g, 23.31 mmol, 4.06 mL), and 4-methoxybenzyl chloride (1.83 g, 11.66 mmol) in DMF (50 mL) was stirred at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA = 10:1 to 3:1) to give 6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-7 (1.7 g, 35% yield) as a pale yellow solid. LCMS: [M+Na] + =520.2.

[0186] Process 6:B-8 TIFF0007728265000053.tif33128 To a solution of 6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-7 (1.91 g, 3.84 mmol) in THF (20 mL) at room temperature was added tetrabutylammonium fluoride (1 M, 3.84 mL). The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in EtOAc (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 6-(hydroxymethyl)-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-8 (1.2 g, 77% yield) as a pale yellow oil. LCMS: [M+H] + =384.1.

[0187] Process 7:B-9 TIFF0007728265000054.tif331 To a solution of 6-(hydroxymethyl)-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-8 (700 mg, 1.83 mmol) in CHCl (10 mL) at 280 °C was added Dess-Martin (1.55 g, 3.65 mmol). The reaction mixture was stirred at room temperature for 5 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 2,4-bis[(4-methoxyphenyl)methyl]-3,5-dioxo-1,2,4-triazine-6-carbaldehyde B-9 (634 mg, 87% yield) as a pale yellow solid. LCMS: [M+H] + =382.1.

[0188] Process 8:B-10 TIFF0007728265000055.tif30128 To a solution of 2,4-bis[(4-methoxyphenyl)methyl]-3,5-dioxo-1,2,4-triazine-6-carbaldehyde B-9 (814 mg, 2.13 mmol) and ethanol (19.67 mg, 426.87 mmol) in CHCl (5 mL) at room temperature, BAST (802.75 mg, 3.63 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 6-(difluoromethyl)-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-10 (660 mg, 73% yield) as a pale yellow solid. LCMS: [M+Na]+ =426.0.

[0189] Step 9: Intermediate B A mixture of 6-(difluoromethyl)-2,4-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione B-10 (660 mg, 1.64 mmol) and CAN (8.97 g, 16.36 mmol) in CHCN (30 mL) and water (10 mL) was stirred at 85 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to remove most of the CHCN to give a residue. The residue was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (200 mg, yield 67%) as a pale yellow solid. TIFF0007728265000057.tif12132

[0190] Example 3: General Scheme C - Synthesis of Intermediate C TIFF0007728265000058.tif43151

[0191] Process 1:C-3 To a solution of 4-methoxyphenol C-2 (15 g, 120.83 mmol) in DMF (150 mL) was added NaH (7.25 g, 181.25 mmol, 60% purity) at 0 °C and stirred for 10 min. 1,2,3-Trichloro-5-nitrobenzene C-1 (27.36 g, 120.83 mmol) was then added, and the mixture was stirred at 120 °C for 2 h under N2 (g). TLC (PE: EtOAc = 20:1) showed the reaction was complete. The reaction mixture was poured into water (500 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc: DCM = 50:1:1) to give a crude product. The crude product was triturated with PE at room temperature for 16 hours and then filtered. The solid was dried in vacuo to give 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene C-3 (18 g, 57.30 mmol, 47% yield) as a yellow solid.

[0192] Process 2:C-4 TIFF0007728265000060.tif31128 To a solution of 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene C-3 (18 g, 57.30 mmol) in ethanol (100 mL) and water (100 mL) was added iron powder (32.00 g, 573.03 mmol) and NH4Cl (15.33 g, 286.51 mmol). The mixture was stirred at 80 °C under N2(g) for 3 h. LCMS showed the reaction was complete. The reaction mixture was filtered and concentrated. The residue was diluted with water (150 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was titrated with (PE: EtOAc = 20:1) at room temperature for 1 h and then filtered. The solid was dried in vacuo to give 3,5-dichloro-4-(4-methoxyphenoxy)aniline C-4 (14 g, 49.27 mmol, 86% yield) as a yellow solid. LCMS: [M+H]+ =284.0 / 286.0.

[0193] Process 3:C-5 To a suspension of CuBr (6.06 g, 42.23 mmol) in MeCN (80 mL) was added tBuONO (5.81 g, 56.31 mmol) at 0 °C and stirred for 10 min. 3,5-Dichloro-4-(4-methoxyphenoxy)aniline C-4 (8 g, 28.16 mmol) was then added, and the resulting mixture was stirred at 10 °C for 16 h under N2(g). TLC (PE: EtOAc = 5:1) indicated that the reaction was nearly complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (PE: EA = 50:1) to give 5-bromo-1,3-dichloro-2-(4-methoxyphenoxy)benzene C-5 (4 g, 11.49 mmol, 41% yield) as a white solid.

[0194] Process 4:C-6 TIFF0007728265000062.tif20128To a solution of 5-bromo-1,3-dichloro-2-(4-methoxyphenoxy)benzene C-5 (3 g, 8.62 mmol) in TFA (30 mL) was added (CH2)6N4 (3.02 g, 21.55 mmol). The mixture was stirred at 70 °C under N2 (g) for 3 h. TLC showed the reaction was complete. The reaction mixture was concentrated. The residue was poured into saturated aqueous NaHCO3 (100 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude 5-(4-bromo-2,6-dichlorophenoxy)-2-methoxybenzaldehyde C-6 (3 g, 7.98 mmol, 93% yield) as a yellow solid, which was used directly in the next step without further purification.

[0195] Step 5: Intermediate C TIFF0007728265000063.tif23128THF (20mL), tTo a solution of 5-(4-bromo-2,6-dichlorophenoxy)-2-methoxybenzaldehyde C-6 (3 g, 7.98 mmol) in BuOH (60 mL) and 2-methylbut-1-ene (10 mL) was added a solution of NaClO (7.22 g, 79.78 mmol) in NaHPO (0.6 M, 106.37 mL). The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (DCM) to give 5-(4-bromo-2,6-dichlorophenoxy)-2-methoxybenzoic acid intermediate C (2.9 g, 7.40 mmol, 93% yield) as a white solid. LCMS: [M+H] + =390.9 / 392.9 / 394.9.

[0196] Example 4: General Scheme D - Synthesis of Intermediate D TIFF0007728265000064.tif134161

[0197] Process 1:D-3 TIFF0007728265000065.tif25128 DMF (0.5 ml, 0.588 mmol) was slowly added to a solution of 2-cyanoacetic acid D-1 (10 g, 11.76 mmol) and ethyl carbamate D-2 (10.47 g, 11.76 mmol) in dry toluene (50 mL). POCl3 (5.5 ml, 5.88 mmol) was then added dropwise at 0 °C under nitrogen. The reaction mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the solvent and POCl3 were removed under reduced pressure. The residue was poured into ice water (300 mL). The precipitate was filtered to give ethyl (2-cyanoacetyl)carbamate D-3 (10 g, 54%) as a gray solid. TIFF0007728265000066.tif19159

[0198] Process 2: D-6 To a solution of 1,3-dichloro-2-fluoro-5-nitrobenzene D-4 (19.5 g, 0.09 mol) in DMF (800 mL) was added 4-methoxyphenol D-5 (14.0 g, 0.129 mol) and CsCO (60.0 g, 0.184 mol). The reaction mixture was heated to 80 °C and stirred for 5 h. After cooling to 25 °C, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with HO (3 × 200 mL) and brine (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene D-6 (24.8 g, 85%) as a white solid. TIFF0007728265000068.tif5157

[0199] Process 3:D-7 TIFF0007728265000069.tif37128 To a solution of stannous chloride dihydrate (35.6 g, 157.6 mmol) in concentrated hydrogen chloride (15 mL) was added 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene D-6 (10.998 g, 35.02 mmol) in EtOH (100 mL). The mixture was refluxed for 2 h. The resulting mixture was cooled to 25 °C and diluted with ethyl acetate (200 mL). The mixture was made basic with 10% NaOH (aq). The organic phase was washed with water (3 × 20 mL), brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3,5-dichloro-4-(4-methoxyphenoxy)aniline (7.0 g, 70%) as a yellow oil. To a solution of 3,5-dichloro-4-(4-methoxyphenoxy)aniline (7.0 g, 27.45 mmol) in ethyl acetate was added concentrated hydrogen chloride slowly until pH = 1. The suspension was left at 4 °C overnight, and the product was collected by filtration and washed with PE to give 3,5-dichloro-4-(4-methoxyphenoxy)aniline hydrochloride D-7 (7.8 g, 69%) as a white solid, which was used in the next step without further purification. LCMS: [M+H] + =284.0.

[0200] Process 4:D-8 To a solution of 3,5-dichloro-4-(4-methoxyphenoxy)aniline hydrochloride D-7 (5.78 g, 16.22 mmol) in HO (200 mL) and concentrated HCl (724.08 mmol, 33 mL) was added a solution of NaNO (1.25 g, 18.12 mmol) in HO (2.5 mL) dropwise at −5 °C to 0 °C. After 20 min, the yellow solution of 3,5-dichloro-4-(4-methoxyphenoxy)benzenediazonium chloride D-8 was filtered, and the filtrate was used directly in the next step.

[0201] Process 5:D-9 TIFF0007728265000071.tif33128To a solution of ethyl (2-cyanoacetyl)carbamate D-3 (3.10 g, 17.84 mmol) in 100 mL of pyridine and 300 mL of HO was added 3,5-dichloro-4-(4-methoxyphenoxy)benzenediazonium chloride D-8 at 0 °C. After 40 min, the red solid was collected, washed with water, and air-dried to give (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)hydrazono)acetyl)carbamate D-9 (5.5 g, 66%) as a red solid. The material was used in the next step without further purification. LCMS: [M+H] + =451.0.

[0202] Process 6: D-10 A slurry of (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)hydrazono)acetyl)ethylcarbamate D-9 (2.5 g, 5.54 mmol) and anhydrous sodium acetate (2.27 g, 27.7 mmol) in 50 mL of HOAc was stirred at reflux for 2 hours. The resulting yellow solution was then concentrated under reduced pressure. Water was added dropwise to the residue. The resulting solid was filtered and purified by silica gel column chromatography eluting with PE / EA (1:3) to give 2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile D-10 (1.0 g, 44%) as a red solid. TIFF0007728265000073.tif12144

[0203] Process 7:D-11 A slurry of 2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile D-10 (1.0 g, 2.47 mmol) in HOAc (20 mL) and concentrated HCl (5 mL) was refluxed for 18 h. The resulting clear solution was concentrated and titrated with water. The solid was filtered and dried to give crude 2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid D-11 (0.75 g, 71%) as a yellow solid, which was used directly in the next step without further purification. LCMS: [MH] - =422.1.

[0204] Process 8:D-12 To a solution of 2-[3,5-dichloro-4-(4-methoxyphenoxy)phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylic acid D-11 (16.0 g, 37.72 mmol) in 2-methylpropan-2-ol (300 mL) was added N,N-diethylethanamine (5.73 g, 56.58 mmol) and [azido(phenoxy)phosphoryl]oxybenzene (15.57 g, 56.58 mmol). The resulting mixture was stirred at 90 °C for 16 h. The mixture was cooled to 25 °C, and the solvent was removed under vacuum. The residue was then purified by silica gel column chromatography (PE:EA=5:1) to give tert-butyl N-[2-[3,5-dichloro-4-(4-methoxyphenoxy)phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate D-12 (18.0 g, 96%) as a red solid. LCMS: [M+H] + =495.3.

[0205] Process 9:D-13 To a solution of tert-butyl N-[2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate D-12 (18.0 g, 34.26 mmol) in CHCl (200 mL) was added 2,2,2-trifluoroacetic acid (60 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with H0 (100 mL) and extracted with EA (3 × 300 mL). The mixture was then washed with NaHCO (3 × 100 mL) and brine (300 mL). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give 6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione D-13 (13.0 g, 95%). LCMS: [M+H] + =395.2.

[0206] Process 10:D-14 A mixture of 6-amino-2-[3,5-dichloro-4-(4-methoxyphenoxy)phenyl]-1,2,4-triazine-3,5-dione D-13 (1.5 g × 6, 2.53 mmol) in glacial acetic acid (30 mL) and hydrochloric acid (30 mL) was stirred at 0 °C for 10 minutes. Sodium nitrite (261.88 mg, 3.80 mmol) was then added to the solution, and the mixture was stirred at 0 °C for 16 hours. TLC showed the formation of a new spot. Sodium nitrite (261.88 mg, 3.80 mmol) was then added to the mixture, which was further stirred for 4 hours. The mixture was concentrated, and the residue was washed with NaHCO (3 × 50 mL) and brine (50 mL). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA=8:1) to give 6-chloro-2-[3,5-dichloro-4-(4-methoxyphenoxy)phenyl]-1,2,4-triazine-3,5-dione D-14 (2.5 g, 24%) as a yellow solid. LCMS: [M+H] + =414.6.

[0207] Process 11:D-15 A mixture of 6-chloro-2-[3,5-dichloro-4-(4-methoxyphenoxy)phenyl]-1,2,4-triazine-3,5-dione D-14 (2.5 g, 6.03 mmol) in TFA (30 mL) was stirred at 25 °C for 10 minutes. 1,3,5,7-tetraazatricyclo[3.3.1.1]decane (1.27 g, 9.04 mmol) was then added to the solution, and the mixture was stirred at 70 °C for 4 hours. The mixture was concentrated, and the residue was washed with NaHCO (3 × 50 mL) and brine (50 mL). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give 5-[2,6-dichloro-4-(6-chloro-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-2-methoxy-benzaldehyde D-15 (910 mg, 34%) as a yellow solid. LCMS: [M+H] + =442.6.

[0208] Step 12: Intermediate D To a mixture of 5-(2,6-dichloro-4-(6-chloro-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-methoxybenzaldehyde D-15 (410 mg, 926.27 μmol) and 2-methylpropan-2-ol (10 mL) in THF (3 mL) stirred at 25 °C was added potassium dihydrogen phosphate (126.05 mg, 926.27 μmol). The mixture was stirred at 25 °C for 16 h and then concentrated. The residue was washed with NaHCO (3 × 50 mL) and brine (50 mL). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give 5-(2,6-dichloro-4-(6-chloro-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-methoxybenzoic acid intermediate D (210 mg, 49% yield) as a yellow solid. LCMS: [M+H] + =458.6.

[0209] Example 5: General Scheme E - Synthesis of Intermediate E TIFF0007728265000080.tif16137

[0210] Process 1:E-2 TIFF0007728265000081.tif181285-Bromo-1,3-dichloro-2-(4-methoxyphenoxy)benzene E-1 (4.1 g, 11.78 mmol) was slowly added to sulfonic acid chloride (17.50 g, 150.19 mmol, 10 mL) at 0 °C. The mixture was stirred under N2(g) at 0 °C for 0.5 h. TLC (PE: EtOAc = 10:1) showed the reaction was complete. The reaction mixture was poured into ice (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc = 20: 1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (3.8 g, 72% yield) as a white solid. TIFF0007728265000082.tif12156

[0211] Step 2: Intermediate E To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (400 mg, 895.80 mmol) in CHCl (5 mL) was added BBr (4.49 g, 17.92 mmol). The mixture was stirred at 20 °C under N for 4 h. TLC (PE: EtOAc = 5:1) showed the reaction was complete. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to afford 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonyl chloride intermediate E (350 mg, 90% yield) as a yellow oil, which was used directly in the next step without further purification.

[0212] Example 6: General Scheme F - Synthesis of Intermediate F TIFF0007728265000084.tif30137

[0213] Process 1:F-1 A mixture of 5-bromo-1,3-dichloro-2-(4-methoxyphenoxy)benzene C-5 (2.8 g, 8.05 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (801.08 mg, 5.63 mmol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (2.62 g, 16.09 mmol), potassium phosphate (5.12 g, 24.14 mmol), and CuI (3.83 g, 20.11 mmol) in NMP (1.5 mL) was stirred at 130 °C for 16 h. LCMS indicated product formation. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (CHCl:CHOH=20:1) to give 2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione F-1 (1.7 g, 47% yield) as a yellow solid. LCMS: [M+H] + =430.0.

[0214] Step 2: Intermediate F TIFF0007728265000086.tif33128To a solution of 2-(3,5-dichloro-4-(4-methoxyphenoxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione F-1 (1.0 g, 2.32 mmol) in CHCl (10 ml) was added ClSOH (2 ml) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo. The crude product 5-(2,6-dichloro-4-(6-(difluoromethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-methoxybenzenesulfonyl chloride intermediate F (1.0 g, crude) was used in the next step without purification. LCMS: [M+Na] + =550.0.

[0215] Example 7: Synthesis of Compound 1 TIFF0007728265000087.tif49128

[0216] Process 1:1-2 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzoic acid Intermediate C (Example 3) (200 mg, 510.17 μmol) in THF (50 mL) was added HATU (290.97 mg, 765.25 μmol). The reaction mixture was stirred at room temperature for 5 minutes, and then cyclobutanamine 1-1 (72.57 mg, 1.02 mmol, 87.12 μL) was added. The reaction mixture was stirred for 5 minutes, and then N,N-diisopropylethylamine (197.80 mg, 1.53 mmol, 266.58 μL) was added. The reaction mixture was stirred for an additional 6 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in EtOAc (20 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=1:2) to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-benzamide 1-2 (203 mg, 80% yield) as a pale yellow solid. LCMS: [M+H] + =443.9.

[0217] Process 2:1-3 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-benzamide 1-2 (100 mg, 224.65 μmol), 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione intermediate B (Example 2) (73.27 mg, 449.30 μmol), copper(I) iodide (85.57 mg, 449.30 μmol), potassium phosphate (143.06 mg, 673.95 μmol), and (1R,2R)-cyclohexane-1,2-diamine (25.65 mg, 224.65 μmol) in NMP (4 mL) was stirred at 135° C. under microwave irradiation for 2 hours. LCMS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (CHCl:MeOH=1:50) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzamide 1-3 (11 mg, 8% yield) as a pale yellow solid. LCMS: [M+H] + =527.0.

[0218] Step 3: Compound 1 To a solution of N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzamide 1-3 (11 mg, 20.86 μmol) in CHCl (2 mL) was added boron tribromide in CHCl (1 M, 104.3 μL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. LCMS indicated the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, ACN-HO (0.05% NH); gradient: 20–30) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzamide compound 1 (1.2 mg, 11% yield) as a pale yellow solid. TIFF0007728265000091.tif27162

[0219] The compounds of formula (I') or (I) in Table 2 below were made according to Example 7 of Compound 1.

[0220] (Table 2) TIFF0007728265000092.tif29163

[0221] Example 8: Synthesis of Compound 3 TIFF0007728265000093.tif54155

[0222] Process 1:3-2 TIFF0007728265000094.tif31128 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzoic acid Intermediate C (Example 3) (225 mg, 573.94 umol) in DMF (3 mL) was added 3,3-difluorocyclobutanamine 3-1 (61.47 mg, 573.94 umol), HATU (436.46 mg, 1.15 mmol), and DIPEA (222.53 mg, 1.72 mmol). The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 3: 1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-(3,3-difluorocyclobutyl)-2-methoxy-benzamide 3-2 (240 mg, 86% yield) as a white solid. LCMS: [M+H] + =479.9 / 482.0.

[0223] Process 2:3-3 TIFF0007728265000095.tif32128N2(g) 5-(4-bromo-2,6-dichloro-phenoxy)-N-(3,3-difluorocyclobutyl)-2-methoxy-benzamide 3-2 (240 mg, 498.84 umol) and 6-(trifluoromethyl)-2H-1,2,4-triazine-3, in NMP (2 mL) were subjected to 100% COOH / 2 COOH reaction. A solution of 5-dione intermediate A (Example 1) (180.65 mg, 997.68 μmol), (1R,2R)-cyclohexane-1,2-diamine (56.96 mg, 498.84 μmol), CuI (190.01 mg, 997.68 μmol), and KPO (317.26 mg, 1.50 mmol) was microwaved at 135 °C for 1.5 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give a residue. The residue was purified by preparative TLC (CH2Cl2:MeOH=20:1) to give 5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-N-(3,3-difluorocyclobutyl)-2-methoxy-benzamide 3-3 (35 mg, 12% yield) as a yellow oil. LCMS: [M+H] + =581.0 / 583.0.

[0224] Step 3: Compound 3 To a solution of 5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-N-(3,3-difluorocyclobutyl)-2-methoxy-benzamide 3-3 (35 mg, 60.21 μmol) at −30° C. was added BBr3 (75.40 mg, 300.63 μmol). The mixture was stirred at −30° C. for 5 minutes. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by preparative HPLC (Xbridge 5u C18 150 × 19 mm, mobile phase: ACN-HO (0.05% NH3), gradient: 15–25) to give 5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-N-(3,3-difluorocyclobutyl)-2-hydroxy-benzamide compound 3 (6.8 mg, 19% yield) as a white solid. TIFF0007728265000097.tif26162

[0225] The compounds of formula (I') or (I) in Table 3 below were made according to Example 8 of Compound 3.

[0226] (Table 3) TIFF0007728265000098.tif44163

[0227] Example 9: Synthesis of Compound 6 TIFF0007728265000099.tif56163

[0228] Process 1:6-2 A mixture of 3,5-difluoroadamantane-1-carboxylic acid 6-1 (2.0 g, 9.25 mmol), triethylamine (940.65 mg, 9.30 mmol, 1.30 mL), and diphenylphosphoryl azide (2.56 g, 9.30 mmol, 2.01 mL) in toluene (50 mL) was stirred at 85 °C for 1.0 h. The reaction mixture was then cooled to room temperature, and benzyl alcohol (1.01 g, 9.30 mmol, 957.37 μL) was added to the reaction mixture. The reaction mixture was stirred at 85 °C for 72 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 4:1) to give benzyl N-(3,5,7-trifluoro-1-adamantyl)carbamate 6-2 (2.5 g, 80% yield) as a pale yellow solid.

[0229] Process 2:6-3 TIFF0007728265000101.tif28128 To a solution of benzyl N-(3,5,7-trifluoro-1-adamantyl)carbamate 6-2 (2.5 g, 7.37 mmol) in EtOAc (50 mL) at room temperature was added aqueous 10% palladium on carbon (500 mg). The reaction mixture was stirred under H2(g) at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 3,5,7-trifluoroadamantan-1-amine 6-3 (1.2 g, 79% yield) as a gray solid. LCMS: [M+H] + =206.2.

[0230] Step 3:6-4 TIFF0007728265000102.tif35128 To a solution of 5-(4-bromo-2,6-dichlorophenoxy)-2-methoxybenzoic acid Intermediate C (Example 3) (199.94 mg, 510.02 μmol) in CHCl (20 mL) was added HATU (290.89 mg, 765.03 μmol) and 3,5,7-trifluoroadamantan-1-amine 6-3 (157 mg, 765.03 μmol). The reaction mixture was stirred at room temperature for 10 minutes. N,N-Diisopropylethylamine (131.83 mg, 1.02 mmol, 177.67 μL) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 2.0 hours. LC-MS indicated the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-N-(3,5,7-trifluoro-1-adamantyl) benzamide 6-4 (260 mg, 88% yield) as a pale yellow solid. LCMS: [M+H] + =578.0 / 580.0.

[0231] Process 4:6-5 TIFF0007728265000103.tif341285-5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-N-(3,5,7-trifluoro-1-adamantyl)benzamide 6-4 (200 mg, 345.28 umol) in NMP (4 mL) and 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-di A mixture of one intermediate B (Example 2) (84.46 mg, 517.93 μmol), CuI (65.76 mg, 345.28 μmol), N1,N2-dimethylcyclohexane-1,2-diamine (39.29 mg, 276.23 μmol), and potassium phosphate (219.88 mg, 1.04 mmol) was stirred in a microwave at 135° C. for 1.5 hours. LC-MS showed the reaction was successful. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (CH2Cl2:MeOH=50:1) to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-N-(3,5,7-trifluoro-1-adamantyl)benzamide 6-5 (15 mg, 6% yield) as a pale yellow solid. LCMS: [M+H] + =661.1 / 663.1.

[0232] Step 5: Compound 6 To a solution of 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-N-(3,5,7-trifluoro-1-adamantyl)benzamide 6-5 (13 mg, 19.66 μmol) in CHCl (4 mL) at 280 °C was added boron tribromide in CHCl (1 M, 98.28 μL). The reaction mixture was stirred at 0 °C for 30 minutes. LC-MS indicated the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, mobile phase: MeCN-HO (0.05% NH), gradient: 20–30) to give 5-(2,6-dichloro-4-(6-(difluoromethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxy-N-(3,5,7-trifluoroadamantan-1-yl)benzamide 6 (2 mg, 15% yield) as a white solid. TIFF0007728265000105.tif19157

[0233] Example 10: Synthesis of Compounds 7 and 8 TIFF0007728265000106.tif66132

[0234] Process 1:7-2 To a solution of 5-[2,6-dichloro-4-(6-chloro-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-2-methoxybenzoic acid (Intermediate D (Example 4)) (51 mg, 111.20 μmol), 2-azabicyclo[2.2.1]heptane 7-1 (11.88 mg, 122.32 μmol), and HATU (63.76 mg, 166.80 μmol) in DMF (2.6 mL) was added DIPEA (43.12 mg, 333.60 μmol, 58.11 μL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (0-10% MeOH in DCM) to give 2-[4-[3-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl]-6-chloro-1,2,4-triazine-3,5-dione 7-2 (47 mg, 77% yield) as a yellow oil. LCMS: [M+H] + =537.1.

[0235] Step 2: Compounds 7 and 8 To a solution of 2-[4-[3-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-phenoxy]-3,5-dichloro-phenyl]-6-chloro-1,2,4-triazine-3,5-dione 7-2 (47 mg, 87.40 μmol) in DCM (1 mL) was added boron trichloride CHCl solution (1 M, 873.96 μL) dropwise at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with saturated NaHCO (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, and concentrated in vacuo. The residue was separated by SFC (chromatographic column: ChiralPak-OZ; mobile phase: CO₂-MeOH (0.1% DEA)). The separated chiral products (P1 4.697 min and P2 5.320 min) were purified by preparative HPLC (chromatographic column: Kromasil-C18 100 × 21.2 mm). Further purification by HPLC with 5 μm elution; mobile phase: ACN-HO (0.05% NH); gradient: 25-35 μm afforded 2-[4-[3-[(1R,4S)-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-hydroxy-phenoxy]-3,5-dichloro-phenyl]-6-chloro-1,2,4-triazine-3,5-dione compound 7 (5.6 mg, 12% yield) as a white solid and 2-[4-[3-[(1S,4R)-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-hydroxy-phenoxy]-3,5-dichloro-phenyl]-6-chloro-1,2,4-triazine-3,5-dione compound 8 (1.6 mg, 4% yield) as a white solid. LCMS: [M+H] + =523.1. TIFF0007728265000109.tif41160

[0236] Example 11: Synthesis of Compound 9 TIFF0007728265000110.tif88149

[0237] Process 1:9-2 A solution of 1-bromo-2-methoxy-benzene 9-1 (3.0 g, 16.04 mmol, 2.00 mL) in THF (20 mL) was cooled in a dry ice-acetone bath. After the mixture was stirred for 10 minutes, n-BuLi (2.5 M in hexane) (12 mL) was added dropwise via syringe. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 0.5 hours. LCMS showed that no starting material remained. Then, cyclobutanone (1.24 g, 17.64 mmol, 1.32 mL) was added to the mixture via syringe under a dry ice-acetone bath. The reaction mixture was then stirred at 25 °C for 14 hours. TLC (PE: EtOAc = 20:1) showed the reaction was complete. The reaction was quenched by the addition of 100 mL of saturated ammonium chloride. The aqueous layer was extracted with 50 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to give 1-(2-methoxyphenyl)cyclobutanol (2.8 g, crude). The crude product was dissolved in CHCl2 (20 mL), and TFA (1.79 g, 15.71 mmol, 1.21 mL) and triethylsilane (5.48 g, 47.13 mmol, 7.53 mL) were added to the mixture. The mixture was stirred at 25 °C for 16 h. TLC (PE = 100%) showed the reaction was complete. The volatiles were removed in vacuo to give a residue. The residue was purified by silica gel chromatography (PE = 100%) to give 1-cyclobutyl-2-methoxy-benzene 9-2 (1.6 g, 62% yield) as a pale yellow solid.

[0238] Process 2:9-3 To a solution of 1-cyclobutyl-2-methoxy-benzene 9-2 (1 g, 6.16 mmol) in CHCl (10 mL) was slowly added ClSOH (1.44 g, 12.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (PE: EtOAc = 10:1) showed the reaction was complete. The reaction mixture was poured onto ice and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1) to give 3-cyclobutyl-4-methoxy-benzenesulfonyl chloride 9-3 (1.2 g, 74% yield) as a yellow solid.

[0239] Step 3:9-4 A solution of 3-cyclobutyl-4-methoxy-benzenesulfonyl chloride 9-3 (700 mg, 2.68 mmol) and Zn (175.55 mg, 2.68 mmol) in 5 mL of 25% HSO was stirred at 110 °C for 4 h. TLC (PE = 100%) showed the reaction was complete. The reaction mixture was extracted with EtOAc (3 × 200 mL) and washed with brine (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE = 100%) to give 3-cyclobutyl-4-methoxy-benzenethiol 9-4 (300 mg, 57% yield) as a yellow solid.

[0240] Step 4:9-6 To a solution of 1,3-dichloro-2-fluoro-5-nitro-benzene 9-5 (324.24 mg, 1.54 mmol) and CsCO (1.00 g, 3.09 mmol) in CHCN (5 mL) was added 3-cyclobutyl-4-methoxy-benzenethiol 9-4 (300 mg, 1.54 mmol). The mixture was stirred at room temperature for 3 h. TLC (PE = 100%) indicated the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE=100%) to give 1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-5-nitro-benzene 9-6 (450 mg, 75% yield) as a yellow oil.

[0241] Process 5:9-7 A solution of 1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-5-nitro-benzene 9-6 (500 mg, 1.30 mmol), Fe (726.63 mg, 13.01 mmol), and NH₄Cl (351.31 mg, 6.51 mmol) in EtOH (3 mL) and HO (3 mL) was stirred at 70 °C for 4 h. TLC (PE:EA = 5:1) showed the reaction was complete. The reaction mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 ml) and dried over anhydrous Na₂SO₄. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA=5:1) to give 3,5-dichloro-4-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-aniline 9-7 (250 mg, 54% yield) as a yellow solid. LCMS: [M+H] + =354.1 / 356.0.

[0242] Process 6:9-8 TIFF0007728265000116.tif31128 in CH3CN (5 mL) t A mixture of BuONO (145.50 mg, 1.41 mmol) and CuBr (151.83 mg, 1.06 mmol) was stirred at 25 °C for 15 minutes. Then, 3,5-dichloro-4-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-aniline 9-7 (250 mg, 705.63 mmol) in CH CN (1 mL) was added to the mixture. The mixture was stirred at 25 °C for 20 hours. LCMS showed the reaction was complete, and TLC (PE: EtOAc = 20:1) showed a new spot. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous Na SO . The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 20: 1) to give 5-bromo-1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-benzene 9-8 (150 mg, 50% yield) as a yellow oil.

[0243] Process 7:9-9 To a solution of 5-bromo-1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl)sulfanyl-benzene 9-8 (150 mg, 370.66 μmol) in CHCl (3 mL) was slowly added m-CPBA (159.38 mg, 926.65 μmol) at 25 °C. The mixture was then stirred at 25 °C for 16 h. TLC (PE: EtOAc = 8:1) showed that the starting material was consumed and one new spot was detected. The mixture was quenched with NaHSO (20 mL saturated solution) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 8: 1) to give 5-bromo-1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl) sulfonyl-benzene 9-9 (90 mg, 53% yield) as a yellow solid. LCMS: [M+H] +=448.9 / 450.9.

[0244] Process 8:9-10 A solution of 5-bromo-1,3-dichloro-2-(3-cyclobutyl-4-methoxy-phenyl)sulfonyl-benzene 9-9 (55 mg, 122.18 μmol), 6-(trifluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate A (Example 1) (44.25 mg, 244.35 μmol), (1R,2R)-cyclohexane-1,2-diamine (13.95 mg, 122.18 μmol), CuI (46.54 mg, 244.35 μmol), and KPO (77.70 mg, 366.53 μmol) in NMP (1.5 mL) under TIFF0007728265000118.tif34128N2(g) was microwaved at 135 °C for 1.5 hours. LCMS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (CHCl:MeOH = 20:1) to give 2-[3,5-dichloro-4-(3-cyclobutyl-4-methoxy-phenyl)sulfonyl-phenyl]-6-(trifluoromethyl)-1,2,4-triazine-3,5-dione 9-10 (15 mg, 22% yield) as a yellow oil. LCMS: [M+H] + =550.0 / 551.9.

[0245] Step 9: Compound 9 To a solution of 2-[3,5-dichloro-4-(3-cyclobutyl-4-methoxy-phenyl)sulfonyl-phenyl]-6-(trifluoromethyl)-1,2,4-triazine-3,5-dione 9-10 (15 mg, 27.26 μmol) in CHCl (1 mL) at 0° C. was added BBr (0.5 mL). The mixture was stirred at 0° C. for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u C18 150 × 19 mm, mobile phase: ACN-HO (0.05% NH3), gradient: 20–30) to give 2-[3,5-dichloro-4-(3-cyclobutyl-4-hydroxyphenyl)sulfonyl-phenyl]-6-(trifluoromethyl)-1,2,4-triazine-3,5-dione compound 9 (4.5 mg, 30% yield) as a white solid. TIFF0007728265000120.tif26159

[0246] Example 12: Synthesis of Compound 10 TIFF0007728265000121.tif83170

[0247] Process 1:10-3 To a solution of 2-fluoro-4-methoxy-phenol 10-1 (2.0 g, 14.07 mmol) in DMF (20 mL) was added NaH (539.19 mg, 14.07 mmol, 60%) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 1,3-dichloro-2-fluoro-5-nitro-benzene 10-2 (2.95 g, 14.07 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 1.5 h. TLC showed that the starting material was consumed and a new spot was detected. The mixture was cooled to 0 °C, quenched with HO (100 mL), and extracted with EtOAc (2 × 100 mL). The organic layers were combined, dried over NaSO, filtered, and the solvent was removed in vacuo to give a residue. The residue was purified by silica gel column chromatography (eluent: PE: EtOAc = 10:1) to give 1,3-dichloro-2-(2-fluoro-4-methoxy-phenoxy)-5-nitro-benzene 10-3 (3.1 g, yield 63%) as a yellow solid.

[0248] Process 2:10-4 A mixture of 1,3-dichloro-2-(2-fluoro-4-methoxy-phenoxy)-5-nitro-benzene 10-3 (2.0 g, 6.02 mmol), ammonium chloride (1.61 g, 30.11 mmol, 1.05 mL), and Fe (3.36 g, 60.22 mmol, 427.87 μL) in EtOH (15 mL) and water (15 mL) was stirred at 80 °C for 3 h. TLC showed the reaction was complete. The mixture was filtered, and the filtrate was extracted with EtOAc (3 × 13 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give 3,5-dichloro-4-(2-fluoro-4-methoxy-phenoxy)aniline 10-4 (1.7 g, 84% yield) as a yellow oil. LCMS [M+H] + =302.0.

[0249] Process 3:10-5 To a mixture of tert-butyl nitrite (1.16 g, 11.25 mmol, 1.34 mL) and cuprous bromide (1.21 g, 8.44 mmol) in MeCN (20 mL) was added 3,5-dichloro-4-(2-fluoro-4-methoxyphenoxy)aniline 10-4 (1.70 g, 5.62 mmol). The reaction was stirred at 25 °C for 16 h. TLC showed the reaction was complete. Water (13 mL) was added, and the mixture was extracted with EtOAc (3 × 13 mL). The combined organic layers were washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified by flash chromatography (PE: EtOAc = 3: 1) to give 5-bromo-1,3-dichloro-2-(2-fluoro-4-methoxy-phenoxy)benzene 10-5 (1 g, 46% yield) as a white solid. LCMS [M+H] + =365.0.

[0250] Process 4:10-6 To a solution of 5-bromo-1,3-dichloro-2-(2-fluoro-4-methoxy-phenoxy)benzene 10-5 (1.0 g, 2.73 mmol) in TFA (10 mL) was added (CH2)6N4 (574.52 mg, 4.10 mmol) at 0 °C. The mixture was stirred at 70 °C for 18 h. TLC showed that the starting material was consumed and a new spot was detected. The mixture was cooled to 0 °C, quenched with H2O (20 mL), and extracted with EtOAc (2 × 20 mL). The organic solutions were combined, dried over Na2SO4, filtered, and the solvent was removed by vacuum to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-4-fluoro-2-methoxy-benzaldehyde 10-6 (900 mg, 75% yield) as a yellow solid.

[0251] Process 5:10-7 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-4-fluoro-2-methoxy-benzaldehyde 10-6 (900 mg, 2.28 mmol) in 2-methylbut-1-ene (6 mL), t-BuOH (36 mL), and THF (12 mL) was added sodium chlorite (2.07 g, 22.84 mmol) in monopotassium phosphate (0.6 M, 30.46 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. TLC indicated that the starting material was consumed and a new spot was detected. The mixture was cooled to 0 °C, quenched with HO (20 mL), and extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over NaSO, filtered, and the solvent removed in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 2:1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-4-fluoro-2-methoxy-benzoic acid 10-7 (920 mg, 88% yield) as a yellow solid.

[0252] Process 6:10-9 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-4-fluoro-2-methoxy-benzoic acid 10-7 (480 mg, 1.17 mmol) in DMF (5 mL) was added DIPEA (302.60 mg, 2.34 mmol, 407.81 μL) and HATU (667.69 mg, 1.76 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, and then cyclobutanamine 10-8 (124.89 mg, 1.76 mmol, 149.93 μL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed that the starting material was consumed and the target product was detected. The mixture was cooled to 0 °C, quenched with HO (20 mL), and extracted with EtOAc (2 x 20 mL). The organic solutions were combined, dried over NaSO, filtered, and the solvent was removed in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-4-fluoro-2-methoxy-benzamide 10-9 (400 mg, 59% yield) as a yellow solid. LCMS [M+H] + =462.0.

[0253] Process 7:10-10 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-4-fluoro-2-methoxy-benzamide 10-9 (27 mg, 58.30 μmol), 6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione A (31.67 mg, 174.90 μmol), cuprous iodide (22.21 mg, 116.60 μmol), potassium phosphate (37.13 mg, 174.90 μmol), and (1R,2R)-cyclohexane-1,2-diamine (5.33 mg, 46.64 μmol) in NMP (2 mL) was stirred at 140° C. under MW for 1.5 hours. LCMS showed that the starting material was consumed and the target product was detected. The mixture was cooled to 0 °C, quenched with HO (20 mL), and extracted with EtOAc (2 x 20 mL). The organic solutions were combined, dried over NaSO, filtered, and the solvent was removed in vacuo to give a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give N-cyclobutyl-5-(2,6-dichloro-4-(3,5-dioxo-6-(trifluoromethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-4-fluoro-2-methoxybenzamide 10-10 (2 mg, 6.1% yield) as a white solid. LCMS [M+H] + =563.0.

[0254] Step 8: Compound 10 To a solution of N-cyclobutyl-5-(2,6-dichloro-4-(3,5-dioxo-6-(trifluoromethyl)-2,5-dihydro-1,2,4-triazin-4(3H)-yl)phenoxy)-4-fluoro-2-methoxybenzamide 10-10 (2.0 mg, 3.55 μmol) in DCM (1 mL) was added boron tribromide (1 M, 7.1 μL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. LCMS showed that the starting material was consumed and the target product was detected. The mixture was cooled to 0 °C and quenched with H2O (0.5 mL). The mixture was filtered. The solvent was removed in vacuo to give a residue. The residue was purified by preparative HPLC (column: Gemini-C18; 100 × 21.2 mm, 5 μm; mobile phase: MeCN-HO (0.05% NH); gradient: 45–55) to give N-cyclobutyl-5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-4-fluoro-2-hydroxy-benzamide compound 10 (0.5 mg, 4.9% yield) as a white solid. TIFF0007728265000130.tif19160

[0255] Example 13: Synthesis of Compound 11 TIFF0007728265000131.tif30153

[0256] Process 1:11-1 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-4-fluoro-2-methoxy-benzamide 10-9 (see synthesis of compound 10) (50 mg, 107.96 μmol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (35.21 mg, 215.92 μmol), (1R,2R)-cyclohexane-1,2-diamine (7.40 mg, 64.78 μmol), potassium phosphate (68.75 mg, 323.89 μmol), and CuI (41.12 mg, 215.92 μmol) in NMP (1.5 mL) was stirred at 150° C. under microwave irradiation for 3 hours. LCMS showed the reaction was complete. Water (15 mL) was added, and the mixture was extracted with EtOAc (3 × 13 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: DCM:MeOH = 10:1) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-4-fluoro-2-methoxy-benzamide 11-1 (10 mg, 14% yield) as a yellow solid. LCMS: [M+H] + =545.0.

[0257] Step 2: Compound 11 To a solution of N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-4-fluoro-2-methoxy-benzamide 11-1 (10 mg, 18.34 μmol) in DCM (1 mL) was added boron tribromide in CHCl (1 M, 183.39 μL) at 0° C. The mixture was stirred at 0° C. for 0.5 h. LCMS indicated that the starting material had been consumed and the target product had been detected. The reaction was quenched with water, and the residue was taken up in DCM (3 × 5 mL). The organic layer was washed with water (3 × 5 mL), dried over MgSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, mobile phase: MeCN-HO (0.05% NH) gradient: 16–26) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-4-fluoro-2-hydroxy-benzamide compound 11 (1.3 mg, 13% yield) as a white solid. TIFF0007728265000134.tif19155

[0258] Example 14: Synthesis of Compound 12 TIFF0007728265000135.tif60156

[0259] Process 1:12-2 TIFF0007728265000136.tif40128 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (100 mg, 223.95 μmol) in dichloromethane (10 mL) was added triethylamine (45.32 mg, 447.90 μmol, 62.43 μL) and cyclobutanamine 12-1 (31.85 mg, 447.90 μmol, 38.24 μL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with CHCl (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-benzenesulfonamide 12-2 (93 mg, 86% yield) as a white solid. LCMS: [M+H] + =482.0 / 483.9.

[0260] Process 2:12-3 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-benzenesulfonamide 12-2 (30 mg, 62.35 μmol), 6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione intermediate B (Example 2) (20.33 mg, 124.69 μmol), copper(I) iodide (23.75 mg, 124.69 μmol), potassium phosphate (39.70 mg, 187.04 μmol), and (1R,2R)-cyclohexane-1,2-diamine (7.12 mg, 62.35 μmol) in NMP (2 mL) was stirred at 150° C. under microwave irradiation for 3 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by TLC (CHCl:MeOH=10:1) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonamide 12-3 (7 mg, 20% yield) as a pale yellow solid. LCMS: [M+H] + =563.1.

[0261] Step 3: Compound 12 To a solution of N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonamide 12-3 (7 mg, 12.43 μmol) in CHCl (2 mL) was added boron tribromide (1 M, 124.25 μL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1.0 h. LC-MS indicated the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, mobile phase: MeCN-HO (0.05% NH) gradient: 15–25) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 12 (2.7 mg, 39% yield) as a white solid. TIFF0007728265000139.tif26157

[0262] The compounds of formula (I') or (I) in Table 4 below were made according to Example 14 of Compound 12.

[0263] (Table 4) TIFF0007728265000140.tif92163

[0264] Example 15: Synthesis of Compound 18 TIFF0007728265000141.tif83162

[0265] Process 1:18-2 TIFF0007728265000142.tif33128To a solution of 3-aminocyclobutanecarboxylic acid hydrochloride 18-1 (0.3 g, 1.98 mmol) in MeOH (5 mL) was added thionyl chloride (1.18 g, 9.90 mmol) slowly at 0 °C. The mixture was stirred at 50 °C for 2 h. LCMS showed that the product was formed. The mixture was concentrated to give methyl 3-aminocyclobutanecarboxylate 18-2 (200 mg, 78% yield) as a white solid. LCMS: [M+H] + =130.2

[0266] Process 2:18-3 A solution of methyl 3-aminocyclobutanecarboxylate 18-2 (36.64 mg, 283.72 μmol), 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonyl chloride F (50 mg, 94.57 μmol), and TEA (28.71 mg, 283.72 μmol) in CHCl (2 mL) was stirred at 25° C. for 16 h. LCMS indicated product formation. To the mixture was added water (20 mL). The aqueous solution was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2:CH3OH=15:1) to give methyl 3-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-phenyl]sulfonylamino]cyclobutenecarboxylate 18-3 (30 mg, 51% yield) as a yellow solid. LCMS: [M+H] + =621.1.

[0267] Process 3:18-5 A mixture of methyl 3-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylamino]cyclobutanecarboxylate 18-3 (30 mg, 41.24 μmol), 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (5.74 mg, 41.24 μmol), and cyclopropanamine 18-4 (1 mL) in a sealed tube was stirred at 60 °C for 16 h. LCMS indicated the reaction was complete. The solution was concentrated in vacuo. The residue was purified by preparative TLC (eluent: EtOAc:PE=1:1) to give N-cyclopropyl-3-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylamino]cyclobutanecarboxamide 18-5 (10 mg, 32% yield) as a yellow oil. LCMS: [M+H] + =646.1.

[0268] Step 4: Compound 18 To a solution of N-[3-(cyclopropanecarbonyl)cyclobutyl]-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonamide 18-5 (10.29 mg, 16.30 μmol) in CHCl (2 mL) was added BBr (886.29 mg, 3.55 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Kromasil 100-5 C18 5um 100 × 21.5mm, mobile phase: MeCN-HO (0.1% FA), gradient: 50–60) to give N-[3-(cyclopropanecarbonyl)cyclobutyl]-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 18 (2.1 mg, 20% yield) as a white solid. TIFF0007728265000146.tif33157

[0269] Example 16: Synthesis of Compound 19 TIFF0007728265000147.tif63156

[0270] Process 1:19-2 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (250 mg, 559.88 μmol) in CHCl (10 mL) was added triethylamine (113.31 mg, 1.12 mmol, 156.07 μL) and cyclopropanamine 19-1 (63.93 mg, 1.12 mmol, 77.59 μL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with CHCl (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclopropyl-2-methoxy-benzenesulfonamide 19-2 (244 mg, 93% yield) as a white solid. LCMS: [M+H] + =467.9 / 469.9.

[0271] Process 2:19-3 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclopropyl-2-methoxy-benzenesulfonamide 19-2 (50 mg, 107.03 μmol), 6-(trifluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate A (Example 1) (38.76 mg, 214.06 μmol), (1R,2R)-cyclohexane-1,2-diamine (12.22 mg, 107.03 μmol), tripotassium phosphate (68.16 mg, 321.09 μmol), and copper iodide (40.77 mg, 214.06 μmol) in NMP (1 mL) was stirred at 150° C. for 2 hours under microwave irradiation. LC-MS indicated the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl:MeOH=10:1) to give N-cyclopropyl-5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonamide 19-3 (8 mg, 13% yield) as a pale yellow solid. LCMS: [M+H] + =567.0.

[0272] Step 3: Compound 19 To a solution of N-cyclopropyl-5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonamide 19-3 (8 mg, 14.10 μmol) in CHCl (1 mL) was added boron tribromide (1 M, 141.01 μL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. LC-MS indicated the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Viridis Silica OBD, mobile phase: MeCN-HO (0.05% NH)) to give N-cyclopropyl-5-[2,6-dichloro-4-[3,5-dioxo-6-(trifluoromethyl)-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 19 (1.8 mg, 23% yield) as a white solid. TIFF0007728265000151.tif19155

[0273] The compounds of formula (I') or (I) in Table 5 below were made according to Example 16 for Compound 19.

[0274] (Table 5) TIFF0007728265000152.tif44163

[0275] Example 17: Synthesis of Compound 22 TIFF0007728265000153.tif80148

[0276] Process 1:22-2 TIFF0007728265000154.tif25128To a solution of 1-aminocyclopropanecarboxylic acid 22-1 (1.0 g, 9.89 mmol) in MeOH was added 1 M NaOH (9.89 mmol, 8 mL), followed by di-tert-butyl dicarboxylate (2.7 g, 12.36 mmol). The reaction was stirred at 25 °C for 15 h. LCMS showed the reaction was complete. The reaction mixture was acidified with dilute aqueous hydrogen chloride and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid 22-2 (1.6 g, 80%) as a residue. The residue was used in the next step without further purification. LCMS: [M+Na] + =224.0.

[0277] Process 2:22-3 TIFF0007728265000155.tif19128To a solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid 22-2 (1.1 g, 5.47 mmol), methylamine hydrochloride (1.85 g, 27.33 mmol), and TEA (4.43 g, 43.73 mmol, 6.10 mL) in DMF (5 mL) was added HATU (3.12 g, 8.20 mmol) at 0 °C. The reaction was stirred at 25 °C for 15 h. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO (10 mL), 5% aqueous lithium chloride solution (10 mL), and water (10 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo to give tert-butyl (1-(methylcarbamoyl)cyclopropyl)carbamate 22-3 (2.0 g, 100%). The residue was used in the next step without further purification. LCMS: [M+Na] + =237.1.

[0278] Step 3:22-4 A solution of tert-butyl N-[1-(methylcarbamoyl)cyclopropyl]carbamate 22-3 (2.0 g, 9.33 mmol) in 4M HCl in dioxane (5 mL) was stirred at 90 °C for 1.5 h. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was azeotroped twice with toluene to remove HCl, and the residue was dried under high vacuum to give 1-amino-N-methylcyclopropane-1-carboxamide hydrochloride 22-4 (2.0 g, 100%). The residue was used in the next step without further purification. LCMS: [M+H] + =115.1.

[0279] Step 4:22-5 A solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (500 mg, 1.12 mmol), 1-amino-N-methyl-cyclopropanecarboxamide hydrochloride 22-4 (337.28 mg, 2.24 mmol), and DIPEA (3.36 mmol, 0.5 ml) in DMF (5 mL) was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2:MeOH=20:1) to give 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]-N-methyl-cyclopropanecarboxamide 22-5 (280 mg, 47% yield) as a yellow solid. LCMS: [M+H] + =522.9 / 525.0.

[0280] Process 5:22-6 A mixture of 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]-N-methyl-cyclopropanecarboxamide 22-5 (100 mg, 190.76 μmol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (62.22 mg, 381.52 μmol), CuI (90.83 mg, 476.91 μmol), and KPO (121.32 mg, 572.29 μmol) in NMP (2 mL) was stirred at 130 °C for 15 h in a sealed tube. LCMS indicated the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl:MeOH=20:1) to give 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-phenyl]sulfonylamino]-N-methyl-cyclopropanecarboxamide 22-6 (20 mg, 17% yield) as a yellow solid. LCMS: [M+H] + =606.1 / 608.1.

[0281] Step 6: Compound 22 To a solution of 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-phenyl]sulfonylamino]-N-methyl-cyclopropanecarboxamide 22-6 (60 mg, 99 mmol) in CHCl (2 mL) was added BBr (247.37 mg) slowly at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u C18 150 × 19 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 30–40) to give 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-phenyl]sulfonylamino]-N-methyl-cyclopropanecarboxamide compound 22 (4.1 mg, 7% yield) as a white solid. TIFF0007728265000160.tif26161

[0282] Example 18: Synthesis of Compound 23 TIFF0007728265000161.tif67150

[0283] Process 1:23-2 TIFF0007728265000162.tif25128 To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate 23-1 (500 mg, 2.67 mmol) in methanol (5 mL) was added HCl (4 M in MeOH, 2.00 mL). The mixture was stirred under N2(g) at 20 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was crude 3-aminocyclobutanol 23-2 (230 mg, 98% yield). This was a yellow oil, which was used directly in the next step without further purification. LCMS: [M+H] +=88.2.

[0284] Process 2:23-3 To a solution of 3-aminocyclobutanol 23-2 (230 mg, 2.64 mmol) and DIPEA (1.02 g, 7.92 mmol, 1.38 mL) in CHCl (10 mL) was added tert-butyl-chloro-dimethyl-silane (795.82 mg, 5.28 mmol). The mixture was stirred at 20 °C under N for 12 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was crude 3-[tert-butyl(dimethyl)silyl]oxycyclobutanamine 23-3 (500 mg, 94% yield). This is a yellow oil that is used directly in the next step without further purification. LCMS: [M+H] + =202.1.

[0285] Step 3:23-4 To a solution of 3-[tert-butyl(dimethyl)silyl]oxycyclobutanamine 23-3 (405.89 mg, 2.02 mmol) in CHCl (10 mL) was added 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (300 mg, 671.85 mmol). The mixture was stirred at 20° C. under N (g) for 1 h. TLC (PE: EtOAc = 5:1) indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-2-methoxy-benzenesulfonamide 23-4 (348 mg, 84% yield) as a white solid.

[0286] Step 4:23-5 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-2-methoxy-benzenesulfonamide 23-4 (50 mg, 81.77 μmol) and 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (26.67 mg, 163.55 μmol) in NMP (1 mL) was added (1R,2R)-cyclohexane-1,2-diamine (6.54 mg, 57.24 μmol), CuI (38.93 mg, 204.43 μmol), and KPO (52.07 mg, 245.32 μmol). The mixture was microwaved at 130 °C for 4 h. LC-MS showed that the product was formed. The reaction mixture was poured into water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl:MeOH=20:1) to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-N-(3-hydroxycyclobutyl)-2-methoxy-benzenesulfonamide 23-5 (15 mg, 31% yield) as a yellow solid. LCMS: [M+Na] + =693.1.

[0287] Step 5: Compound 23 TIFF0007728265000166.tif36128 To a solution of 5-(2,6-dichloro-4-(6-(difluoromethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-N-((1r,3r)-3-hydroxycyclobutyl)-2-methoxybenzenesulfonamide 23-5 (15 mg, 25.89 umol) in CHCl (1 mL) was added BBr (64.86 mg, 258.91 umol). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Kromasil 100-5 C18 5 μm 100 × 21.5 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 40–50) to give 5-(2,6-dichloro-4-(6-(difluoromethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxy-N-((1r,3r)-3-hydroxycyclobutyl)benzenesulfonamide Compound 23 (2.9 mg, 19% yield) as a white solid. TIFF0007728265000167.tif26158

[0288] Example 19: Synthesis of Compound 24 TIFF0007728265000168.tif60160

[0289] Process 1:24-2 A solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (600 mg, 1.34 mmol), methyl 1-aminocyclopropanecarboxylate 24-1 (309.40 mg, 2.69 mmol), and DIPEA (347.32 mg, 2.69 mmol) in CHCl (10 mL) was stirred at 25° C. for 15 h. LCMS showed that the product had formed. The mixture was filtered and concentrated in vacuo. The aqueous solution was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (PE: EtOAc = 2: 1) to give methyl 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxylate 24-2 (680 mg, 96% yield) as a yellow solid. LCMS: [M+H] + =524.0 / 525.9

[0290] Process 2:24-3 A mixture of methyl 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxylate 24-2 (680 mg, 1.29 mmol) in 7M ammonia in methanol (2 ml, 14 mmol) was stirred in a sealed tube under N at 50 °C for 15 h. LCMS showed the desired product was formed. The mixture was concentrated in vacuo. The aqueous solution was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH=10:1) to give 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxamide 24-3 (360 mg, 54% yield) as a white solid. LCMS: [M+H] + =509.0 / 510.9

[0291] Step 3:24-4 A solution of 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxamide 24-3 (250 mg, 490.02 μmol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (159.83 mg, 980.04 μmol), N1,N2-dimethylcyclohexane-1,2-diamine (55.76 mg, 392.01 μmol), CuI (233.31 mg, 1.23 mmol), and K3PO4 (311.65 mg, 1.47 mmol) in NMP (2 mL) was stirred at 130 °C for 15 h in a sealed tube. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl2:MeOH=10:1) to give 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxamide 24-4 (70 mg, 24% yield) as a yellow solid. LCMS: [M+H] + =592.0 / 594.0

[0292] Step 4: Compound 24 To a solution of 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxamide 24-4 (70 mg, 118.17 μmol) in CHCl (2 mL) was added BBr (886.29 mg, 3.55 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Kromasil 100-5 C18 5um 100 × 21.5mm, mobile phase: MeCN-HO (0.1% TFA), gradient: 32-42) to give 1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-phenyl]sulfonylamino]cyclopropanecarboxamide compound 24 (5.8 mg, 8% yield) as a white solid. TIFF0007728265000173.tif26160

[0293] The compounds of formula (I') or (I) in Table 6 below were made according to Example 19 for Compound 24.

[0294] (Table 6) TIFF0007728265000174.tif25163

[0295] Example 20: Synthesis of Compound 26 TIFF0007728265000175.tif110148

[0296] Process 1:26-2 To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate 26-1 (3.0 g, 16.02 mmol) and triethylamine (4.86 g, 48.07 mmol, 6.70 mL) in CHCl (30 mL) at 280 °C was added methanesulfonyl chloride (2.20 g, 19.23 mmol, 1.49 mL) dropwise. The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate 26-2 (4.1 g, 96% yield) as a yellow oil. The yellow oil was used directly in the next step without further purification. LCMS: [M+Na] + =288.2.

[0297] Process 2:26-3 TIFF0007728265000177.tif21128To a solution of (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate 26-2 (2.0 g, 7.54 mmol) in DMF (10 mL) was added sodium cyanide (567 mg, 11.57 mmol). The reaction mixture was stirred at 85 °C for 16 h. Then, another batch of sodium cyanide (779 mg, 15.90 mmol) was added to the reaction mixture. The reaction mixture was stirred at 85 °C for 7 days. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 2:1) to give tert-butyl ((1r,3r)-3-cyanocyclobutyl)carbamate 26-3 (0.96 g, 64% yield) as a pale yellow solid. LCMS: [M+H] + =197.2.

[0298] Step 3:26-4 TIFF0007728265000178.tif20128 To a solution of tert-butyl ((1r,3r)-3-cyanocyclobutyl)carbamate 26-3 (100 mg, 509.57 umol) in CHCl (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give the residue (1r,3r)-3-((2,2,2-trifluoroacetyl)-14-azanyl)cyclobutane-1-carbonitrile 26-4 (48 mg, 97% yield) as a yellow oil. The residue was used directly in the next step without purification. LCMS: [M+H] + =97.2.

[0299] Step 4:26-5 To a solution of (1r,3r)-3-((2,2,2-trifluoroacetyl)-14-azanyl)cyclobutane-1-carbonitrile 26-4 (102.9 mg, 535.55 μmol) and N,N-diisopropylethylamine (346.37 mg, 2.68 mmol, 466.81 μL) in CHCl (10 mL) at 280 °C was added 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (239.34 mg, 536.00 μmol). The reaction mixture was stirred at room temperature for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 2:1) to give 5-(4-bromo-2,6-dichlorophenoxy)-N-((1r,3r)-3-cyanocyclobutyl)-2-methoxybenzenesulfonamide 26-5 (240 mg, 88% yield) as a pale yellow solid. LCMS: [M+H] + =505.0 / 507.0.

[0300] Process 5:26-6 To a solution of 5-(4-bromo-2,6-dichlorophenoxy)-N-((1r,3r)-3-cyanocyclobutyl)-2-methoxybenzenesulfonamide 26-5 (506.2 mg, 1.00 mmol) in CHCl (10 mL) at 280 °C was added boron tribromide (2.51 g, 10.00 mmol). The reaction mixture was stirred at 0 °C for 30 min. LC-MS showed the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 5-(4-bromo-2,6-dichlorophenoxy)-N-((1r,3r)-3-cyanocyclobutyl)-2-hydroxybenzenesulfonamide 26-6 (460 mg, 93% yield) as a pale yellow solid. The residue was used directly in the next step without purification. LCMS: [M+H] + =491.0 / 493.0.

[0301] Step 6: Compound 26 TIFF0007728265000181.tif401285-5-(4-bromo-2,6-dichlorophenoxy)-N-((1r,3r)-3-cyanocyclobutyl)-2-hydroxybenzenesulfonamide 26-6 (340 mg, 690.82 umol) in NMP (4 mL) and 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-diol. A mixture of one intermediate B (Example 2) (225.32 mg, 1.38 mmol), cuprous iodide (328.92 mg, 1.73 mmol), potassium phosphate (439.91 mg, 2.07 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (78.61 mg, 552.65 mmol) was stirred at 130 °C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl:MeOH = 10:1) to give the crude product. The crude product was further purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, mobile phase: MeCN-HO (0.1% FA), gradient: 45–55) to give N-(3-cyanocyclobutyl)-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 26 (19.8 mg, 5% yield) as a white solid. TIFF0007728265000182.tif26160

[0302] Example 21: Synthesis of Compound 27 TIFF0007728265000183.tif56154

[0303] Process 1:27-2 TIFF0007728265000184.tif23128 To a solution of 4,4-difluoropiperidine 27-1 (98.02 mg, 809.25 μmol) and pyridine (192.03 mg, 2.43 mmol) in CHCl (10 mL) was added 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonyl chloride intermediate E (Example 5) (350 mg, 809.25 μmol). The mixture was stirred under N at 20 °C for 16 h. TLC (PE: EtOAc = 5:1) showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give 4-(4-bromo-2,6-dichloro-phenoxy)-2-[(4,4-difluoro-1-piperidyl)sulfonyl]phenol 27-2 (380 mg, yield 90%) as a white solid.

[0304] Step 2:27-3 To a solution of 4-(4-bromo-2,6-dichloro-phenoxy)-2-[(4,4-difluoro-1-piperidyl)sulfonyl]phenol 27-2 (150 mg, 290.04 μmol) in DMF (2 mL) was added K2CO3 (120.26 mg, 870.12 μmol) and 1-(chloromethyl)-4-methoxy-benzene (90.85 mg, 580.08 μmol). The mixture was stirred under N2 at 20 °C for 16 h. TLC (PE: EtOAc = 5:1) showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 5: 1) to give 1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonyl-4,4-difluoro-piperidine 27-3 (130 mg, yield 70%) as a white solid.

[0305] Step 3:27-4 To a solution of 1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-4,4-difluoro-piperidine 27-3 (50 mg, 78.45 umol) and 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (25.59 mg, 156.91 umol) in NMP (1 mL) was added (1R,2R)-cyclohexane-1,2-diamine (6.27 mg, 54.92 umol), CuI (37.35 mg, 196.13 umol), and KPO (49.96 mg, 235.36 umol). The mixture was irradiated in a microwave oven at 130° C. for 3.5 hours. LC-MS showed that the product had formed. The reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (3×20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl:MeOH=20:1) to give 2-[3,5-dichloro-4-[3-[(4,4-difluoro-1-piperidyl)sulfonyl]-4-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione 27-4 (15 mg, 26% yield) as a yellow solid. LCMS: [M+Na] + =740.9.

[0306] Step 4: Compound 27 To a solution of 2-[3,5-dichloro-4-[3-[(4,4-difluoro-1-piperidyl)sulfonyl]-4-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione 27-4 (15 mg, 20.85 μmol) in CHCl (1 mL) was added TFA (0.1 mL). The mixture was stirred at 25 °C for 1 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Xtimate 10 μL C18 250 × 30 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 52–62). The resulting solution was cooled to 0°C, and 1 M HCl (0.5 mL) was added. The mixture was lyophilized to give 2-[3,5-dichloro-4-[3-[(4,4-difluoro-1-piperidyl)sulfonyl]-4-hydroxy-phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione Compound 27. TIFF0007728265000188.tif27162

[0307] The compounds of formula (I') or (I) in Table 7 below were made according to Example 21 for Compound 27.

[0308] (Table 7) TIFF0007728265000189.tif235163

[0309] Example 22: Synthesis of Compound 40 TIFF0007728265000190.tif67168

[0310] Process 1:40-2 TIFF0007728265000191.tif27128 To a solution of azetidin-3-ol 40-1 (500 mg, 6.84 mmol) and imidazole (931.41 mg, 13.68 mmol) in CHCl (20 mL) was added tert-butyl-chloro-dimethyl-silane (1.34 g, 8.89 mmol, 1.65 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was added to water (50 mL) and extracted with EtOAc (2 × 50 mL). The organic solutions were combined, dried over NaSO, filtered, and the solvent was removed in vacuo to give azetidin-3-yloxy-tert-butyl-dimethyl-silane 40-2 (616 mg, 48% yield) as a yellow oil. LCMS: [M+H] + =188.2.

[0311] Process 2:40-3 TIFF0007728265000192.tif40128To a solution of azetidin-3-yloxy-tert-butyl-dimethyl-silane 40-2 (616 mg, 3.29 mmol) in CHCl (10 mL), 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonyl chloride intermediate E (Example 5) (355.51 mg, 821.97 μmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with 30 mL of water and extracted with EtOAc (3×20 ml). The organic layer was dried over NaSO and concentrated. The residue was purified by flash chromatography (PE: EtOAc = 5: 1) to give 4-(4-bromo-2,6-dichloro-phenoxy)-2-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]sulfonyl-phenol 40-3 (395 mg, 21% yield) as a yellow solid. LCMS: [M+Na] + =582.0.

[0312] Process 3:40-4 A mixture of 4-(4-bromo-2,6-dichloro-phenoxy)-2-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]sulfonyl-phenol 40-3 (395 mg, 677.07 μmol), K2CO3 (280.73 mg, 2.03 mmol), and 1-(chloromethyl)-4-methoxy-benzene (212.07 mg, 1.35 mmol) in DMF (12 mL) was stirred at room temperature for 16 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (eluent: PE: EtOAc = 5: 1) to give [1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonylazetidin-3-yl] oxy-tert-butyl-dimethyl-silane 40-4 (386 mg, 81%) as a yellow oil. LCMS: [M+Na] + =724.2 / 726.2.

[0313] Process 4:40-5 TIFF0007728265000194.tif34128N2 [1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylazetidin-3-yl]oxy-tert-butyl-dimethyl-silane 40-4 (100 mg, 142.14 umol) and 6-(difluoromethyl)-2H-1,2 A mixture of 4-triazine-3,5-dione intermediate B (Example 2) (46.36 mg, 284.28 umol), tripotassium phosphate (90.51 mg, 426.41 umol), (1R,2R)-cyclohexane-1,2-diamine (12.98 mg, 113.71 umol), and copper iodide (67.68 mg, 355.34 umol) was stirred in a microwave at 130° C. for 3.5 hours. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl:MeOH=10:1) to give 2-[3,5-dichloro-4-[3-(3-hydroxyazetidin-1-yl)sulfonyl-4-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione 40-5 (6 mg, 6% yield) as a yellow solid. LCMS: [M+Na] + =693.0 / 695.1.

[0314] Step 5: Compound 40 To a solution of 2-[3,5-dichloro-4-[3-(3-hydroxyazetidin-1-yl)sulfonyl-4-[(4-methoxyphenyl)methoxy]phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione 40-5 (25 mg, 37.23 μmol) in CHCl (1 mL) was added TFA (148.00 mg, 1.30 mmol, 0.1 mL). The resulting mixture was stirred at room temperature for 1 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (chromatography column: Kromasil 100-5 C18 5 um 100 × 21.5 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 37–47) to give 2-[3,5-dichloro-4-[4-hydroxy-3-(3-hydroxyazetidin-1-yl)sulfonyl-phenoxy]phenyl]-6-(difluoromethyl)-1,2,4-triazine-3,5-dione compound 40 (11.3 mg, 55% yield) as a white solid. TIFF0007728265000196.tif19159

[0315] The compounds of formula (I') or (I) in Table 8 below were made according to Example 22 for Compound 40.

[0316] (Table 8) TIFF0007728265000197.tif106163

[0317] Example 23: Synthesis of Compound 46 TIFF0007728265000198.tif91143

[0318] Process 1:46-2 To a solution of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate 46-1 (2.0 g, 10.74 mmol, 1.87 mL) and EtN (3.26 g, 32.21 mmol, 4.49 mL) in CHCl (20 mL) was added methanesulfonyl chloride (1.85 g, 16.11 mmol, 1.25 mL) with stirring at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO to give (S)-tert-butyl 3-(methylsulfonamido)pyrrolidine-1-carboxylate 46-2 (2.5 g, 79% yield) as a pink solid. LCMS: [M+Na] + =287.1.

[0319] Process 2:46-3 TIFF0007728265000200.tif23128 A solution of (S)-tert-butyl 3-(methylsulfonamido)pyrrolidine-1-carboxylate 46-2 (2.8 g, 10.59 mmol) and TFA (2 mL) in CH2Cl2 (10 mL) was stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated to give N-[(3S)-pyrrolidin-3-yl]methanesulfonamide 46-3 (1.5 g, 78% yield) as a pink solid. LCMS: [M+H] + =165.1.

[0320] Step 3:46-5 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonyl chloride intermediate E (Example 5) (101 mg, 233.53 umol), N-[(3S)-pyrrolidin-3-yl]methanesulfonamide 46-4 (76.70 mg, 467.05 umol), and DIPEA (0.4 mL) in DMF (2 mL) was stirred at 60 °C for 1 h. LCMS showed the reaction was complete. Water (15 mL) was added, and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified by flash chromatography (PE: EtOAc = 1: 1) to give N-[(3S)-1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide 46-5 (100 mg, 73% yield) as a yellow solid. LCMS: [M+H] + =560.9.

[0321] Step 4:46-6 A mixture of 1-(chloromethyl)-4-methoxy-benzene (69.88 mg, 446.22 μmol), N-[(3S)-1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide 46-5 (100 mg, 178.49 μmol), and potassium carbonate (74.00 mg, 535.46 μmol) in DMF (2 mL) was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. Water (15 mL) was added, and the mixture was extracted with EtOAc (3 × 13 mL). The combined organic layers were washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified by flash chromatography (PE: EtOAc = 1: 1) to give N-[(3S)-1-[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonylpyrrolidin-3-yl] methanesulfonamide 46-6 (100 mg, 74% yield) as a yellow solid. LCMS: [M+Na] + =702.0.

[0322] Process 5:46-7 TIFF0007728265000203.tif36128 (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (14.63 mg, 102.88 umol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione Intermediate B (Example 2) (47.94 mg, 293.94 umol), and N-[(3S)-1- A mixture of [5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide 46-6 (100 mg, 146.97 μmol), CuI (69.98 mg, 367.42 μmol), and potassium phosphate (93.59 mg, 440.91 μmol) was stirred at 130° C. for 16 hours. LCMS showed the reaction was complete. Water (15 mL) was added, and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2:MeOH=10:1) to give N-[(3S)-1-[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide 46-7 (32 mg, 25% yield) as a yellow solid. LCMS: [M+Na] + =784.1.

[0323] Step 6: Compound 46 To a solution of N-[(3S)-1-[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide 46-7 (32 mg, 41.96 μmol) in CHCl (3 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL). The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water, extracted with EtOAc (3 × 50 mL), and washed with NaHCO. The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u C18 150 × 19 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 40–50) to give N-[(3S)-1-[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-phenyl]sulfonylpyrrolidin-3-yl]methanesulfonamide compound 46 (2.5 mg, 9% yield) as a white solid. TIFF0007728265000205.tif34160

[0324] The compounds of formula (I') or (I) in Table 9 below were made according to Example 23 for Compound 46.

[0325] (Table 9) TIFF0007728265000206.tif34161TIFF0007728265000207.tif230161

[0326] Example 24: Synthesis of Compound 58 TIFF0007728265000208.tif86139

[0327] Process 1:58-2 To a solution of methyl glycinate hydrochloride 58-1 (1.02 g, 8.09 mmol) and TEA (818.88 mg, 8.09 mmol) in CHCl (20 mL), 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonyl chloride intermediate E (Example 5) (1 g, 2.31 mmol) was added. The mixture was stirred at 25 °C for 1 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 2: 1) to give methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylamino]acetate 58-2 (700 mg, 62% yield) as a white solid. LCMS: [M+Na] + =507.9.

[0328] Process 2:58-3 To a solution of methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylamino]acetate 58-2 (700 mg, 1.44 mmol) in DMF (7 mL) was added K2CO3 (398.83 mg, 2.89 mmol) and 1-(chloromethyl)-4-methoxy-benzene (316.36 mg, 2.02 mmol). The mixture was stirred at 25 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with CHCl2 (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonyl-[(4-methoxyphenyl) methyl] amino] acetate 58-3 (160 mg, 15% yield) as a white solid. LCMS: [M+Na] + =748.0.

[0329] Process 3:58-4 To a solution of methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetate 58-3 (160 mg, 220.56 μmol) in THF (2 mL) was added NH3 (6 M in MeOH, 5.83 mL). The mixture was sealed and stirred at 25 °C for 48 h. LC-MS indicated that the product had formed. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 1:1) to give 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonyl-[(4-methoxyphenyl) methyl] amino] acetamide 58-4 (65 mg, 41% yield) as a white solid. LCMS: [M+Na] + =734.0.

[0330] Process 4:58-5 To a solution of 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetamide 58-4 (65 mg, 91.50 μmol) and 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (29.84 mg, 182.99 μmol) in NMP (2 mL) was added N1,N2-dimethylcyclohexane-1,2-diamine (9.11 mg, 64.05 μmol), CuI (34.85 mg, 182.99 μmol), and K3PO4 (58.26 mg, 274.49 μmol). The mixture was stirred in a sealed tube under N2(g) at 130 °C for 16 h. LC-MS showed that the product was formed. The reaction mixture was diluted with EtOAc (80 mL), washed with aqueous NH4Cl (3 × 50 mL) and brine (3 × 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl2:MeOH = 10:1) to give 2-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetamide 58-5 (25 mg, 34% yield) as a yellow solid. LCMS: [M+Na] + =814.0.

[0331] Step 5: Compound 58 To a solution of 2-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetamide 58-5 (24 mg, 30.28 μmol) in CHCl (2 mL) was added TFA (0.5 mL). The mixture was stirred at 80° C. under N (g) for 2 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (chromatography column: Kromasil 100-5 C18 5 μm 100 × 21.5 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 30–40, flow rate: 25 ml / min) to give 2-((5-(2,6-dichloro-4-(6-(difluoromethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-2-hydroxyphenyl)sulfonamido)acetamide compound 58 (3.9 mg, 23% yield) as a white solid. TIFF0007728265000214.tif19157

[0332] The compounds of formula (I') or (I) in Table 10 below were made according to Example 24 for Compound 58.

[0333] (Table 10) TIFF0007728265000215.tif87161

[0334] Example 25: Synthesis of Compound 63 TIFF0007728265000216.tif82166

[0335] Process 1:63-1 TIFF0007728265000217.tif38128 To a mixture of methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylamino]acetate 58-2 (2.0 g, 4.12 mmol) and potassium carbonate (1.71 g, 12.37 mmol) in DMF (20 mL) at room temperature, 1-(chloromethyl)-4-methoxy-benzene (1.29 g, 8.25 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was successful. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 3: 1) to give methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonyl-[(4-methoxyphenyl) methyl] amino] acetate 63-1 (2.0 g, 66% yield) as a pale yellow solid. LCMS: [M+Na] + =745.9.

[0336] Process 2:63-2 A mixture of methyl 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetate 63-1 (1.5 g, 2.07 mmol) and LiOH-HO (260.54 mg, 6.20 mmol) in water (5 mL), MeOH (5 mL), and THF (5 mL) was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was added to water (50 mL), and the pH was adjusted to 2–3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetic acid 63-2 (1.45 g, 98% yield) as a pale yellow oil. LCMS: [M+Na] + =732.2.

[0337] Step 3:63-4 TIFF0007728265000219.tif38128 To a solution of 2-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonyl-[(4-methoxyphenyl)methyl]amino]acetic acid 63-2 (500 mg, 702.84 μmol) in DMF (10 mL) at room temperature, HATU (400.86 mg, 1.05 mmol) and azetidine hydrochloride 63-3 (197.26 mg, 2.11 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. N,N-Diisopropylethylamine (272.51 mg, 2.11 mmol, 367.26 μL) was then added to the reaction mixture. The reaction mixture was stirred for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 2:1) to give N-[2-(azetidin-1-yl)-2-oxo-ethyl]-5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]-N-[(4-methoxyphenyl)methyl]benzenesulfonamide 63-4 (400 mg, 75% yield) as a pale yellow oil. LCMS: [M+Na] + =771.2.

[0338] Process 4:63-5 TIFF0007728265000220.tif48128 N-[2-(azetidin-1-yl)-2-oxo-ethyl]-5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]-N-[(4-methoxyphenyl)methyl]benzenesulfonamide 63-4 (200 mg, 266.50 umol) in NMP (4 mL) and 6-(difluoromethyl)-2H-1,2,4 A mixture of -triazine-3,5-dione intermediate B (Example 2) (86.92 mg, 532.99 μmol), cuprous iodide (126.89 mg, 666.24 μmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (30.33 mg, 213.20 μmol), and potassium phosphate (169.70 mg, 799.49 μmol) was stirred in a sealed tube under N2(g) at 130 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CH2Cl2:MeOH=20:1) to give N-[2-(azetidin-1-yl)-2-oxo-ethyl]-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]benzenesulfonamide 63-5 (30 mg, 15%) as a pale yellow solid. LCMS: [M+Na] + =854.1.

[0339] Step 5: Compound 63 A mixture of N-[2-(azetidin-1-yl)-2-oxo-ethyl]-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]-N-[(4-methoxyphenyl)methyl]benzenesulfonamide 63-5 (30 mg, 36.03 μmol) in TFA (4 mL) was stirred at room temperature for 2 hours. LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was dissolved in CHCl (5 mL), and NH in MeOH (7 M / L, 1 mL) was added to the mixture. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm, 5 μm, mobile phase: MeCN-HO 0.1% FA), gradient: 35–45) to give N-[2-(azetidin-1-yl)-2-oxo-ethyl]-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 63 (9.5 mg, 44% yield) as a white solid. TIFF0007728265000222.tif33161

[0340] Example 26: Synthesis of Compound 64 TIFF0007728265000223.tif106157

[0341] Process 1:64-2 TIFF0007728265000224.tif19128To a solution of 5-bromo-6-methoxy-pyridin-3-amine 64-1 (10 g, 49.25 mmol) in diiodomethane (263.83 g, 985.05 mmol, 79.23 mL) tBuONO (11.16 g, 108.36 mmol) was added slowly. The mixture was stirred at 60° C. for 1 h. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography PE (100%) to give 3-bromo-5-iodo-2-methoxy-pyridine 64-2 (5.0 g, 32% yield) as a yellow solid. LCMS: [M+H] + =314.0 / 315.9.

[0342] Process 2:64-4 A solution of 3-bromo-5-iodo-2-methoxy-pyridine 64-2 (3.8 g, 12.11 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 64-3 (2.46 g, 9.68 mmol), Pd(dppf)Cl (4.94 g, 6.76 mmol), and KOAc (3.56 g, 36.32 mmol) in dioxane (5 mL) under TIFF0007728265000225.tif36128N2 was stirred at 100 °C for 1 h under microwave irradiation. LCMS indicated the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 50:1) to give 3-bromo-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 64-4 (2.0 g, 52% yield) as a yellow solid. LCMS: [M+H] + =314.1 / 316.1.

[0343] Process 3:64-5 To a solution of 3-bromo-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 64-4 (1.5 g, 4.78 mmol) in THF (20 mL) was added 2N NaOH (5 mL) and 30% H2O2 (3 mL). The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was complete and the desired product was detected. The reaction was used in the next step without further workup. LCMS: [M+H] + =204.0 / 206.0.

[0344] Step 4:64-7 TIFF0007728265000227.tif23128 To a solution of 5-bromo-6-methoxy-pyridin-3-ol 64-5 (966 mg, 4.73 mmol) from the previous step was added 1,3-dichloro-2-fluoro-5-nitro-benzene 64-6 (994.26 mg, 4.73 mmol) and K2CO3 (1.31 g, 9.47 mmol). The reaction was stirred at 25 °C for 15 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 50: 1) to give 3-bromo-5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine 64-7 (1.08 g, 57% yield) as a yellow solid. LCMS: [M+H] + =392.9 / 394.9.

[0345] Process 5:64-9 A mixture of 3-bromo-5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine 64-7 (1.2 g, 3.05 mmol), (4-methoxyphenyl)methanethiol 64-8 (469.73 mg, 3.05 mmol), Pd(dba) (139.34 mg, 152.28 mmol), Xantphos (44.0 mg, 76.1 mmol), and DIPEA (785.78 mg, 6.09 mmol) in dioxane (10 mL) was stirred at 90 °C for 15 h under a N atmosphere. LCMS indicated the reaction was complete. The residue was added to water (50 mL) and extracted with EtOAc (3 × 20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography (PE: EtOAc = 30:1) to give 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-3-(4-methoxyphenyl)pyridine 64-9 (1.2 g, 93% yield) as a yellow oil. LCMS: [M+H] + =467.0 / 469.1.

[0346] Process 6:64-10 TIFF0007728265000229.tif28128To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-3-[(4-methoxyphenyl)methylsulfanyl]pyridine 64-9 (1.2 g, 2.57 mmol) in AcOH (3 mL) and HO (1 mL) was added NCS (1.37 g, 10.27 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed that the product was formed. The residue was added to water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 30:1) to give 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine-3-sulfonyl chloride 64-10 (1 g, 94% yield) as a yellow solid.

[0347] Process 7:64-12 To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine-3-sulfonyl chloride 64-10 (700 mg, 1.69 mmol) and cyclobutanamine 64-11 (180.55 mg, 2.54 mmol) in DCM (3 mL) was added TEA (342.50 mg, 3.38 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed that the product was formed. The residue was added to water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give N-cyclobutyl-5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine-3-sulfonamide 64-12 (500 mg, 65% yield) as a yellow solid. LCMS: [M+H] + =448.0 / 450.0

[0348] Process 8:64-13 A solution of N-cyclobutyl-5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-pyridine-3-sulfonamide 64-12 (500 mg, 1.12 mmol), Fe (622.88 mg, 11.15 mmol), and NH4Cl (301.15 mg, 5.58 mmol) in HO (5 mL) and EtOH (5 mL) was stirred at 70 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was used in the next step without further purification. LCMS: [M+H] + =418.1 / 420.0.

[0349] Process 9:64-14 TIFF0007728265000232.tif28128 in CH3CN (3 mL) tTo a mixture of BuONO (162.52 mg, 1.58 mmol) and CuBr (169.76 mg, 1.18 mmol) was added 5-(4-amino-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-pyridine-3-sulfonamide 64-13 (330 mg, 788.92 mmol). The reaction was stirred at 25 °C for 15 h. LCMS showed the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 5:1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-pyridine-3-sulfonamide 64-14 (245 mg, 64% yield) as a yellow solid. LCMS: [M+H] + =481.0 / 483.0.

[0350] Process 10:64-15 A mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-N-cyclobutyl-2-methoxy-pyridine-3-sulfonamide 64-14 (100 mg, 207.39 μmol), 6-(difluoromethyl)-2H-1,2,4-triazine-3,5-dione intermediate B (Example 2) (67.64 mg, 414.79 μmol), (1S,2S)-cyclohexane-1,2-diamine (18.95 mg, 165.91 μmol), CuI (98.75 mg, 518.48 μmol), and KPO (131.90 mg, 622.18 μmol) in NMP (2 mL) under TIFF0007728265000233.tif33128N2 was stirred at 130° C. for 3.5 hours under microwave irradiation. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (CHCl:MeOH=20:1) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-pyridine-3-sulfonamide 64-15 (6 mg, 5% yield) as a yellow solid. LCMS: [M+H] + =564.0 / 566.0.

[0351] Step 11: Compound 64 A solution of N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-pyridine-3-sulfonamide 64-15 (6 mg, 10.63 μmol) and BBr3 (79.74 mg, 318.95 μmol) in CHCl3 (2 mL) was stirred at 0° C. for 1 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (Xbridge 5u C18 150 × 19 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 44–54) to give N-cyclobutyl-5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-pyridine-3-sulfonamide compound 64 (6 mg, 17% yield) as a white solid. TIFF0007728265000235.tif26157

[0352] Example 27: Synthesis of Compound 65 TIFF0007728265000236.tif29150

[0353] Process 1:65-1 To a mixture of 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-methoxy-benzenesulfonyl chloride Intermediate F (Example 6) (10 mg, crude) in CHCl (1 mL) at 280° C. was added boron tribromide in CHCl (1 M, 378.29 μL). The reaction mixture was stirred at 0° C. for 1.0 h. LC-MS indicated the reaction was successful. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonyl chloride 65-1 (9 mg, crude) as a pale yellow oil. The crude product was used directly in the next step without purification. LCMS: [M+H] + =514.0 / 516.0.

[0354] Step 2: Compound 65 A mixture of 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonyl chloride 65-1 (9 mg, crude) and 2-methoxyethan-1-amine 65-2 (6.13 mg, 81.61 μmol, 7.09 μL) in CHCl (5 mL) was stirred at room temperature for 16 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm, mobile phase: MeCN-HO (0.1% TFA), gradient: 39–49). The resulting solution was cooled to 0°C, and 1 M HCl (0.5 mL) was added. The mixture was lyophilized to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-N-(2-methoxyethyl)benzenesulfonamide Compound 65 (1.3 mg, HCl salt, 8% yield over three steps) as a pale yellow solid. TIFF0007728265000239.tif26158

[0355] The compounds of formula (I') or (I) in Table 11 below were made according to Example 27 for Compound 65.

[0356] (Table 11) TIFF0007728265000240.tif49161

[0357] Example 28: Synthesis of Compound 68 TIFF0007728265000241.tif51154

[0358] Process 1:68-1 TIFF0007728265000242.tif24128To a mixture of ammonium chloride (479.18 mg, 8.96 mmol) and triethylamine (1.36 g, 13.44 mmol, 1.87 mL) in CHCl (20 mL) was added 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (1.0 g, 2.24 mmol) in CHCl (20 mL). The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was titrated with hexane (20 mL) to give 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonamide 68-1 (860 mg, 89% yield) as a white solid. LCMS: [M+H] + =425.9 / 427.9.

[0359] Process 2:68-2 To a solution of 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonamide 68-1 (200 mg, 468.28 μmol) in CHCl (10 mL) at 280 °C was added a solution of boron tribromide (1.17 g, 4.68 mmol) in CHCl (2 mL) dropwise. The reaction mixture was stirred at 0 °C for 1 h. TLC (CHCl:MeOH = 10:1) showed the reaction was complete. The reaction mixture was poured into saturated NaHCO (50 mL) solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 5-(4-bromo-2,6-dichlorophenoxy)-2-hydroxybenzenesulfonamide 68-2 (150 mg, 77% yield) as crude material, which was used directly in the next step without purification.

[0360] Process 3:68-3 TIFF0007728265000244.tif21128To a mixture of 5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-benzenesulfonamide 68-2 (600 mg, 1.45 mmol) and potassium carbonate (602.25 mg, 4.36 mmol) in DMF (50 mL) was added 1-(chloromethyl)-4-methoxybenzene (227.48 mg, 1.45 mmol). The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EtOAc = 5: 1) to give 5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] benzenesulfonamide 68-3 (500 mg, 64% yield) as a pale yellow solid. LCMS: [M+Na] + =554.0 / 556.0.

[0361] Process 4:68-4 TIFF0007728265000245.tif33128 5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]benzenesulfonamide 68-3 (300 mg, 562.62 μmol) in NMP (4 mL) and 6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione intermediate B (experimental) A mixture of Example 2 (183.51 mg, 1.13 mmol), cuprous iodide (267.88 mg, 1.41 mmol), potassium phosphate (358.28 mg, 1.69 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (64.02 mg, 450.10 mmol) was stirred in a sealed tube under N2 (g) at 130 °C for 14 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2:MeOH=10:1) to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]benzenesulfonamide 68-4 (44 mg, 12% yield) as a pale yellow solid. LCMS: [M+Na] + =637.0

[0362] Step 5: Compound 68 TIFF0007728265000246.tif31128 To a solution of 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]benzenesulfonamide 68-4 (54 mg, 87.75 μmol) in CHCl (10 mL) at room temperature was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO solution (4 mL). The organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl:MeOH=10:1) to give the crude product as a pale yellow solid. The crude product was titrated with a solvent mixture (hexane:CHCl=1:1) to give 5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-hydroxy-benzenesulfonamide compound 68 (5.4 mg, 12% yield) as a white solid. TIFF0007728265000247.tif19155

[0363] The compounds of formula (I') or (I) in Table 12 below were made according to Example 28 of Compound 68.

[0364] (Table 12) TIFF0007728265000248.tif63163

[0365] Example 29: Synthesis of Compound 71 TIFF0007728265000249.tif91152

[0366] Process 1:71-2 TIFF0007728265000250.tif29128 To a solution of methyl 1-aminocyclopropanecarboxylate 71-1 (2.58 g, 22.40 mmol) and DIPEA (4.34 g, 33.59 mmol) in CHCl (50 mL) was added 5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-benzenesulfonyl chloride E-2 (Example 5) (5 g, 11.20 mmol). The reaction mixture was stirred at 25 °C for 15 h. LCMS showed that the product had formed. The mixture was poured into H0 (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (PE: EtOAc = 2: 1) to give methyl 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxylate 71-2 (3.7 g, 62% yield) as a yellow solid. LCMS: [M+H] + =523.9 / 525.9.

[0367] Process 2:71-4 A solution of methyl 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]cyclopropanecarboxylate 71-2 (600 mg, 1.14 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (159.02 mg, 1.14 mmol) in cyclopropanamine 71-3 (14.13 g, 247.41 mmol, 17.14 mL) was stirred at 60 °C for 15 h. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:CH3OH=20:1) to give 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-4 (600 mg, 95% yield) as a yellow solid. LCMS: [M+H] + =549.0 / 551.0.

[0368] Process 3:71-5 TIFF0007728265000252.tif21128To a solution of 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-methoxy-phenyl]sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-4 (400 mg, 726.94 μmol) in CHCl (5 ml) was added BBr (5.45 g, 21.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed that the product was formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. The reaction mixture was filtered and concentrated in vacuo to give a residue. The crude product 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-5 (430 mg, crude material) was used in the next step without purification. LCMS: [M+H] +=534.9 / 536.9.

[0369] Step 4:71-6 A solution of 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-hydroxy-phenyl]sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-5 (430 mg, 801.91 μmol), PMBCl (182.86 mg, 1.20 mmol), and K2CO3 (221.33 mg, 1.60 mmol) in DMF (5 mL) was stirred at 25 °C for 16 h. LCMS showed that the product had formed. The reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EtOAc = 1: 1) to give 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl) methoxy] phenyl] sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-6 (110 mg, 20% yield) as a white solid. LCMS: [M+Na] + =677.0 / 678.9.

[0370] Process 5:71-7 TIFF0007728265000254.tif411281-6 (110 mg, 167.59 umol) in NMP (2 mL) with 1-[[5-(4-bromo-2,6-dichloro-phenoxy)-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylamino]-N-cyclopropyl-cyclopropanecarboxamide 71-6 (110 mg, 167.59 umol) and 6-(difluoromethyl)-2H-1 A mixture of 2,4-triazine-3,5-dione intermediate B (Example 2) (54.66 mg, 335.18 μmol), N1,N2-dimethylcyclohexane-1,2-diamine (19.07 mg, 134.07 μmol), CuI (79.79 mg, 418.97 μmol), and K3PO4 (106.59 mg, 502.76 μmol) was stirred at 130 °C for 15 h. LCMS showed that the product had formed. The mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The mixture was washed with brine (50 mL) and water (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (CHCl:CHOH=10:1) to give N-cyclopropyl-1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylamino]cyclopropanecarboxamide 71-7 (55 mg, 44% yield) as a yellow solid. LCMS: [M+Na] + =760.1 / 762.0.

[0371] Step 6: Compound 71 To a solution of N-cyclopropyl-1-[[5-[2,6-dichloro-4-[6-(difluoromethyl)-3,5-dioxo-1,2,4-triazin-2-yl]phenoxy]-2-[(4-methoxyphenyl)methoxy]phenyl]sulfonylamino]cyclopropanecarboxamide 71-7 (55 mg, 74.47 μmol) in CHCl...

Claims

1. Formula (I') or (I): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, During the ceremony R 〇 is H or (C 1 ~C 4 ) alkyl; X 1 , X 2 , and X 3 are each independently CR X or X 2 is N and X 1 and X 3 are each independently CR X and Each R X are independently H, (C 1 ~C 4 ) alkyl, CN, F, Cl, or (C 3 ~C 8 ) cycloalkyl, where alkyl or cycloalkyl is one or more R 8 where X 2 is N and L is CH 2 If R X (C 3 ~C 8 ) not cycloalkyl; L is CH 2 , S(O) 2 or O; R 1 is CH 2 F, CHF 2 , C.F. 3 , Cl, NH 2 , or CN, or R 1 is X 2 If N, then H, (C 1 ~C 4 ) alkyl, CH 2 F, CHF 2 , C.F. 3 , Cl, NH 2 , or CN; R 2 and R 3 are each independently H, F, Cl, or CH 3 and R 4 (CH 2 ) 0～3 S(O) 2 R 4' , S(O) 2 NR 4' R 4'' , C(O)NR 4' R 4'' , (C 1 ~C 4 ) alkyl, or (C 3 ~C 6 ) cycloalkyl, where X 2 is N and L is CH 2 If R 4 (C 3 ~C 6 ) is not cycloalkyl, where R 1 If is CN, then R 4 (C 1 ~C 4 ) not alkyl; R 4' and R 4'' are independently H, (C 1 ~C 4 ) alkyl, (C 3 ~C 15 )cycloalkyl, or a 3- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is selected from one or more (CH 2 ) y R 5 where R 4 is S(O) 2 R 4' If R 4' is not H; or R 4' and R 4'' together with the nitrogen atoms to which they are attached, It may contain 1 to 3 additional heteroatoms selected from N, O and S, and one or more (CH 2 ) y R 5 3- to 10-membered heterocycle optionally substituted with Forming; Each R 5 are independently F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )alkoxy, oxo, CN, (C 3 ~C 6 ) cycloalkyl, heterocyclyl containing one 3- to 6-membered ring and 1 to 3 heteroatoms selected from N, O and S, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' where each cycloalkyl or heterocyclyl is F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' or If y is 0, then two R 5 together with the atom or atoms to which they are attached, F, Cl, OH, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) Alkoxy, CN, NR 6 R 6' , N.R. 6 S(O) 2 R 7 , N.R. 6 C(O)R 7 , C(O)R 7 , C(O)NR 6 R 6' , S(O) 2 R 7 , or S(O) 2 NR 6 R 6' a 3- to 6-membered ring optionally substituted with may form Each R 6 and R 6' are independently H, (C 1 ~C 8 ) alkyl, or (C 3 ~C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 or R 6 and R 6' together with the nitrogen atoms to which they are attached, may contain one additional heteroatom selected from N, O, and S, and one or more R 8 3- to 6-membered heterocycle optionally substituted with Forming; Each R 7 are independently H, (C 1 ~C 8 ) alkyl, or (C 3 ~C 10 ) cycloalkyl, where each alkyl or cycloalkyl is selected from one or more R 8 where R 5 is S(O) 2 R 7 or NR 6 S(O) 2 R 7 If R 7 is not H; Each R 8 are independently halogen, NO 2 , N.H. 2 , CN, NH((C 1 ~C 4 ) alkyl), N((C 1 ~C 4 )Alkyl) 2 , OH, oxo, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) alkoxy, where R X , R 6 , or R 6' is alkyl, R 8 is not oxo; and y is 0, 1, 2, 3, or 4, The compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

2. X 2 is N and X 1 and X 3 are each independently CR X 2. The compound of claim 1, wherein:

3. X 1 , X 2 , and X 3 are each independently CR X 2. The compound of claim 1, wherein:

4. Each R X The compound of any one of claims 1 to 3, wherein is H.

5. L is S(O) 2 or O.

6. L is S(O) 2 The compound of any one of claims 1 to 3, wherein

7. 4. The compound of claim 1, wherein L is O.

8. L is CH 2 The compound of any one of claims 1 to 3, wherein

9. R 1 is CH 2 F, CHF 2 , C.F. 3 , Cl, or NH 2 The compound of any one of claims 1 to 3, wherein

10. R 1 CHF 2 , C.F. 3 4. The compound of claim 1, wherein the compound is:

11. R 1 CHF 2 , or CF 3 The compound of any one of claims 1 to 3, wherein

12. R 1 The compound of any one of claims 1 to 3, wherein is CN.

13. X 2 If N, then R 1 is H or (C 1 ~C 4 4. The compound of claim 1, wherein R is 1 or 2.

5. The compound of claim 1, wherein R is 1 or 2.

14. R 2 and R 3 4. The compound of claim 1, wherein each is H.

15. R 2 and R 3 One of the groups is H and the other is F, Cl, or CH 3 The compound of any one of claims 1 to 3, wherein

16. R 2 and R 3 are each independently F, Cl, or CH 3 The compound of any one of claims 1 to 3, wherein

17. R 2 and R 3 The compound of any one of claims 1 to 3, wherein each is independently F or Cl.

18. R 2 and R 3 The compound of any one of claims 1 to 3, wherein each is Cl.

19. R 4 (CH 2 ) 0～3 S(O) 2 R 4' , S(O) 2 NR 4' R 4'' , or C(O)NR 4' R 4'' The compound of any one of claims 1 to 3, wherein

20. R 4 (S(O) 2 NR 4' R 4'' , or C(O)NR 4' R 4'' The compound of any one of claims 1 to 3, wherein

21. R 4 is S(O) 2 NR 4' R 4'' The compound of any one of claims 1 to 3, wherein

22. R 4 But (C 1 ~C 4 ) alkyl or (C 3 ~C 6 4. The compound of claim 1, wherein R is cycloalkyl.

23. A compound selected from the table below, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof: 。

24. A compound selected from the table below, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof: 。

25. 4. The compound of any one of claims 1 to 3, wherein one or more hydrogen atoms in said compound are replaced with one or more deuterium atoms.

26. 25. The compound of claim 23 or 24, wherein one or more hydrogen atoms in said compound are replaced with one or more deuterium atoms.

27. 27. A pharmaceutical composition comprising the compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

28. 27. A pharmaceutical composition for modulating thyroid hormone receptors, comprising a therapeutically effective amount of a compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

29. 27. A pharmaceutical composition for treating a disease or disorder controlled by thyroid hormone, comprising a therapeutically effective amount of a compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

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