THR beta analogs and uses thereof

Abstract

Described herein are compounds of formula I: JPEG2025505746000059.jpg6174, and pharma- ceutically acceptable salts, solvates, and stereoisomers thereof, and their use as thyroid hormone receptor (THR) beta activators.

Description

[Technical field]

[0001] Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 308,709, filed February 10, 2022, and U.S. Provisional Patent Application No. 63 / 419,790, filed October 27, 2022, the contents of which are incorporated by reference herein.

[0002] Incorporation by reference of sequence number

[0002] The contents of the file named "MDRI-028_001WO_SeqList_ST26.txt", created on February 7, 2023, and having a size of 1.87KB, are incorporated herein by reference in their entirety. [Background technology]

[0003]

[0003] Thyroid hormones are important for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological reviews, vol. 81(3): pp. 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamic / pituitary / thyroid (HPT) axis. Thyroid dysfunction leading to hypo- or hyperthyroidism clearly demonstrates the profound effects of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0004]

[0004] The biological activity of thyroid hormones is mediated by the thyroid hormone receptor (TR or THR) (MA Lazar, Endocrine Reviews, vol. 14:348-399 (1993)). TRs belong to a superfamily known as nuclear receptors. TRs form heterodimers with retinoid receptors that act as ligand-inducible transcription factors. TRs have ligand-binding, DNA-binding, and amino-terminal domains and 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. These different gene products generate multiple forms of each receptor through differential RNA processing. The major thyroid receptor isoforms are α1, α2, β1, and β2. Thyroid hormone receptors α1, β1, and β2 bind thyroid hormones. It has been shown that subtypes of thyroid hormone receptors may differ in their contribution to specific biological responses. Recent studies suggest that TRβ1 plays an important role in regulating TRH (thyrotropin releasing hormone) and thyroid hormone action in the liver. TRβ2 plays an important role in regulating TSH (thyroid stimulating hormone) (Abel et al., J. Clin. Invest., vol. 104: pp. 291-300 (1999)). TRβ1 plays an important role in regulating heart rate (B. Gloss et al., Endocrinology, vol. 142: pp. 544-550 (2001); C. Johansson et al., Am. J. Physiol., vol. 275: pp. R640-R646 (1998)).

[0005] Efforts are being made to synthesize thyroid hormone analogues that exhibit increased selectivity of thyroid hormone receptor beta and / or tissue selective action. Such thyroid hormone mimetics can obtain desirable reductions in body weight, lipids, cholesterol, and lipoproteins while minimizing the impact on cardiovascular function or the normal function of the hypothalamus / pituitary / thyroid axis (see, for example, Joharapurkar et al., J.Med.Chem., 2012, 55(12), pp. 5649-5675). The development of thyroid hormone analogues that avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones opens new avenues of treatment for patients with metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other disorders and diseases, such as hepatic steatosis and NASH, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, who are resistant to thyroid hormones and related disorders and diseases. Summary of the Invention [Means for solving the problem]

[0006] In some aspects, the present disclosure provides a compound according to formula I:

[0007] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [In the formula, Each R 1 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 3~10 Carbocyclyl, or C 6~14 is aryl, Each R 2 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 is alkynyl, R 3 is halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R dand the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with Existing R 4 and R 6 each independently represents hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R 5 are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR cS(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with m is an integer selected from 0 to 4; n is an integer selected from 0 to 2, X is -C(R 7 )2-, -O-, -NR 8 -, and -S-; Each R 7 are independently hydrogen, halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b, -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with R 8 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R u are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d, -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; The Two R's u together to form oxo, or The Two R's u is, together with one or more intervening atoms, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R a is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; Each R b are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl or C 1~6 may be substituted with haloalkyl, Or, R c , R d may be, together with the nitrogen atom to which they are attached, one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 forming a 3- to 10-membered heterocyclyl optionally substituted with haloalkyl.

[0007] In some aspects, the disclosure provides methods of preparing the compounds described herein.

[0008]

[0008] In some aspects, the disclosure features a pharmaceutical composition including any compound described herein and a pharma- ceutically acceptable excipient.

[0009] In some aspects, the disclosure features a method of treating a disease, disorder, or condition, the method including administering to a subject in need thereof any of the compounds described herein in a pharmaceutical composition.

[0009]

[0010] In some aspects, the disclosure features any of the compounds described herein in a pharmaceutical composition for use to treat a disease, disorder, or condition, including administration to a subject in need thereof.

[0010]

[0011] In some aspects, the disclosure features the use of any of the compounds described herein in a pharmaceutical composition in the manufacture of a medicament for treating a disease, disorder, or condition, including administration to a subject in need thereof.

[0011]

[0012] In some aspects, the disclosure features a method of activating thyroid hormone receptor (THR) β in a patient or biological sample, the method including contacting the patient or biological sample with a compound described herein in a pharmaceutical composition.

[0012]

[0013] In some aspects, the disclosure features any of the compounds described herein in a pharmaceutical composition for use in activating thyroid hormone receptor (THR) β in a patient or biological sample.

[0013]

[0014] In some aspects, the disclosure features the use of any of the compounds described herein in a pharmaceutical composition in the manufacture of a medicament for activating thyroid hormone receptor (THR) β in a patient or biological sample.

[0014]

[0015] In some aspects, the disclosure features a method of treating a liver disease or disorder, or a lipid disease or disorder, comprising administering to a subject in need thereof any of the compounds described herein in a pharmaceutical composition.

[0015]

[0016] In some aspects, the disclosure features any of the compounds described herein in a pharmaceutical composition for use in treating a disease or disorder of the liver, or a lipid disease or disorder.

[0016]

[0017] In some aspects, the disclosure features the use of any of the compounds described herein in a pharmaceutical composition in the manufacture of a medicament for treating a disease or disorder of the liver or a lipid disease or disorder.

[0017]

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In this specification, the singular form also includes the plural form unless otherwise clearly indicated by the context. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of this disclosure, and suitable methods and materials are described below. All publications, patent applications, patents and other references described herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In case of conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will prevail.

[0018]

[0019] Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Compounds of the Disclosure

[0020] In some aspects, the present disclosure provides a compound represented by formula I:

[0020] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [In the formula, Each R 1 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 3~10 Carbocyclyl, or C 6~14 is aryl, Each R 2 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 is alkynyl, R 3 is halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR bC(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with Existing R 4 and R 6 each independently represents hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R 5 are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with m is an integer selected from 0 to 4; n is an integer selected from 0 to 2, X is -C(R7 )2-, -O-, -NR 8 -, and -S-; Each R 7 are independently hydrogen, halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R dand the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with R 8 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R u are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c Rd , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; The Two R's u together to form oxo, or The Two R's u is, together with one or more intervening atoms, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R a is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; Each R b are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl or C 1~6 may be substituted with haloalkyl, Or, R c , R d may be, together with the nitrogen atom to which they are attached, one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 forming a 3- to 10-membered heterocyclyl optionally substituted with haloalkyl.

[0021] In some aspects, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [In the formula, Each R 1 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, or C 6~14 is aryl, Each R 2 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 is alkynyl, R 3 is halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with Existing R 4 and R 6 Each of the above may be independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R 5 are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)Ra , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with m is an integer selected from 0 to 4; n is an integer selected from 0 to 2, X is -C(R 7 )2-, -O-, -NR 8 -, and -S-; Each R 7 are independently hydrogen, halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with R 8 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with Each R u are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; The Two R's utogether to form oxo, or The Two R's u is, together with one or more intervening atoms, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R a is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 may be substituted with haloalkyl; Each R b are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6may be substituted with haloalkyl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~14 aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl or C 1~6 may be substituted with haloalkyl, Or, R c , R d may be, together with the nitrogen atom to which they are attached, one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 forming a 3- to 10-membered heterocyclyl optionally substituted with haloalkyl.

[0022] In some aspects, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [In the formula, Each R 1 are independently halogen, C 1~6 Alkyl, or C 1~6 is an alkoxy; Each R 2 are independently halogen; R 3 -CN, -C(=O)OR b or -C(=O)NR c R d and Existing R 4 and R 6 each is independently hydrogen; m is an integer selected from 0, 1, or 2; n is 0, X is -O-; Each R b are independently hydrogen; Each R c and R d are independently hydrogen.

[0023] In certain embodiments, each R 1 are independently halogen, C 1~6 Alkyl, C 1~6 Alkoxy, or C 6~14 It is aryl.

[0021]

[0024] In certain embodiments, at least one R 1 is a halogen (e.g., F, Cl, or Br).

[0025] In certain embodiments, at least one R 1 is F or Cl.

[0022]

[0026] In certain embodiments, at least one R 1 is F.

[0027] In certain embodiments, at least one R 1 is Cl.

[0028] In certain embodiments, at least one R 1 is C 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0023]

[0029] In certain embodiments, at least one R 1 is methyl.

[0030] In certain embodiments, at least one R 1 is C 1~6Alkoxy (eg, methoxy, ethoxy, or propoxy).

[0024]

[0031] In certain embodiments, at least one R 1 is methoxy.

[0032] In certain embodiments, at least one R 1 is C 6~14 Aryl (eg, phenyl).

[0025]

[0033] In certain embodiments, m is 0, 1, or 2.

[0034] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0026]

[0035] In certain embodiments, each R 2 are independently halogen, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 It is alkynyl.

[0036] In certain embodiments, each R 2 is independently a halogen (e.g., F, Cl, or Br).

[0027]

[0037] In certain embodiments, each R 2 is the chloride.

[0038] In certain embodiments, each R 2 is independently 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0028]

[0039] In certain embodiments, each R 2 is methyl.

[0040] In certain embodiments, each R 2 is independently 2~6 alkenyl (eg, ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0029]

[0041] In certain embodiments, each R 2 is independently 2~6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0042] In certain embodiments, R 3 is halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0030]

[0043] In certain embodiments, R 3 is a halogen (e.g., F, Cl, or Br).

[0044] In certain embodiments, R 3 is C 1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0031]

[0045] In certain embodiments, R 3 is C 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0032]

[0046] In certain embodiments, R 3 is C 2~6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0033]

[0047] In certain embodiments, R 3 is C 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0034]

[0048] In certain embodiments, R 3 is C 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0035]

[0049] In certain embodiments, R 3 is C 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R u may be substituted.

[0036]

[0050] In certain embodiments, R 3 is C 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0051] In certain embodiments, R 3 is a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), the heteroaryl being selected from one or more R umay be substituted.

[0037]

[0052] In certain embodiments, R 3 is C 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more R u may be substituted.

[0038]

[0053] In certain embodiments, R 3 is a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being one or more R u may be substituted.

[0039]

[0054] In certain embodiments, R 3 -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c Rd , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d (For example, R a is methyl or ethyl, R b is H and R c is H and R d is H).

[0040]

[0055] In certain embodiments, R 3 -CN, -C(=O)OR b or -C(=O)NR c R d It is.

[0056] In certain embodiments, R 3 is -CN.

[0041]

[0057] In certain embodiments, each R c and R c is H.

[0058] In certain embodiments, R 3 is -C(=O)NH2.

[0059] In certain embodiments, R b is H.

[0042]

[0060] In certain embodiments, R 3 is -C(=O)OH.

[0061] In certain embodiments, R 4 is hydrogen.

[0062] In certain embodiments, n is 0, 1, or 2.

[0043]

[0063] In certain embodiments, n is 0.

[0064] In certain embodiments, R 6 is hydrogen.

[0065] In certain embodiments, R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0044]

[0066] In certain embodiments, R 4 is C 1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0067] In certain embodiments, R 4 is C 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0045]

[0068] In certain embodiments, R 4 is C 2~6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0046]

[0069] In certain embodiments, R 4is C 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0047]

[0070] In certain embodiments, R 4 is C 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0048]

[0071] In certain embodiments, R 4 is C 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R u may be substituted.

[0049]

[0072] In certain embodiments, R 4 is C 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0073] In certain embodiments, R 4 is a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), the heteroaryl being selected from one or more R u may be substituted.

[0050]

[0074] In certain embodiments, R 4 is C 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more Ru may be substituted.

[0051]

[0075] In certain embodiments, R 4 is a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being one or more R u may be substituted.

[0052]

[0076] In certain embodiments, R 6 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0053]

[0077] In certain embodiments, R 6 is C 1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0078] In certain embodiments, R 6 is C 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0054]

[0079] In certain embodiments, R6 is C 2~6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0055]

[0080] In certain embodiments, R 6 is C 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0056]

[0081] In certain embodiments, R 6 is C 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0057]

[0082] In certain embodiments, R 6 is C 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R u may be substituted.

[0058]

[0083] In certain embodiments, R 6 is C 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0084] In certain embodiments, R 6 is a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), the heteroaryl being selected from one or more R u may be substituted.

[0059]

[0085] In certain embodiments, R 6 is C 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more R u may be substituted.

[0060]

[0086] In certain embodiments, R 6 is a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being one or more R u may be substituted.

[0061]

[0087] In certain embodiments, each R 5 are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0062]

[0088] In certain embodiments, each R 5 is independently a halogen (e.g., F, Cl, or Br).

[0089] In certain embodiments, each R 5 is independently1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0063]

[0090] In certain embodiments, each R 5 is independently 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0064]

[0091] In certain embodiments, each R 5 is independently 2~6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0065]

[0092] In certain embodiments, each R 5 is independently 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0066]

[0093] In certain embodiments, each R 5 is independently 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0067]

[0094] In certain embodiments, each R 5 is independently 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R umay be substituted.

[0068]

[0095] In certain embodiments, each R 5 is independently 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0069]

[0096] In certain embodiments, each R 5 is independently 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), heteroaryl being selected from one or more R u may be substituted.

[0070]

[0097] In certain embodiments, each R 5 is independently 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more R u may be substituted.

[0071]

[0098] In certain embodiments, each R 5 is independently 3-10 membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being selected from one or more R u may be substituted.

[0072]

[0099] In certain embodiments, R 3 -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR cS(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d (For example, R a is methyl or ethyl, R b is H and R c is H and R d is H).

[0073]

[0100] In certain embodiments, X is -C(R 7 )2-, -O-, -NR 8 -, and -S- (e.g., R 7 is H, halogen, or C 1~6 is alkyl, R 8 is H or C 1~6 (It is alkyl).

[0074]

[0101] In certain embodiments, X is selected from -CH2-, -CH(CH3)-, -CHCl-, -CHBr-, -NH-, or -NCH3-.

[0102] In certain embodiments, X is O.

[0075]

[0103] In certain embodiments, R 7 are hydrogen, halogens, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0076]

[0104] In certain embodiments, R 7 is a halogen (e.g., F, Cl, or Br).

[0105] In certain embodiments, R 7 is C 1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0077]

[0106] In certain embodiments, R 7 is C 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0078]

[0107] In certain embodiments, R 7 is C 2~6alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0079]

[0108] In certain embodiments, R 7 is C 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0080]

[0109] In certain embodiments, R 7 is C 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0081]

[0110] In certain embodiments, R 7 is C 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R u may be substituted.

[0082]

[0111] In certain embodiments, R 7 is C 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0112] In certain embodiments, R 7 is a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), the heteroaryl being selected from one or more R u may be substituted.

[0083]

[0113] In certain embodiments, R 7 is C 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more R u may be substituted.

[0084]

[0114] In certain embodiments, R 7 is a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being one or more R u may be substituted.

[0085]

[0115] In certain embodiments, R 7 -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b, -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d (For example, R a is methyl or ethyl, R b is H and R c is H and R d is H).

[0086]

[0116] In certain embodiments, R 8 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3- to 10-membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with (e.g., R u is F, Cl, Br, I, -CN, -NO2, methyl, or ethyl).

[0087]

[0117] In certain embodiments, R 8 is C 1~6 alkyl (e.g., methyl, ethyl, or propyl), which is represented by one or more R u may be substituted.

[0118] In certain embodiments, R 8 is C 2~6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl), where the alkenyl is one or more R u may be substituted.

[0088]

[0119] In certain embodiments, R 8 is C 2~6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl), where the alkynyl is one or more R u may be substituted.

[0089]

[0120] In certain embodiments, R 8 is C 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group), haloalkyl is one or more R u may be substituted.

[0090]

[0121] In certain embodiments, R 8 is C 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group), and hydroxyalkyl is one or more R u may be substituted.

[0091]

[0122] In certain embodiments, R 8 is C 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group), and the aminoalkyl is one or more R u may be substituted.

[0092]

[0123] In certain embodiments, R 8 is C 6~14 aryl (e.g., phenyl or naphthyl), the aryl being one or more R u may be substituted.

[0124] In certain embodiments, R 8 is a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl), the heteroaryl being selected from one or more R umay be substituted.

[0093]

[0125] In certain embodiments, R 8 is C 3~10 carbocyclyl (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), which is a carbocyclyl selected from one or more R u may be substituted.

[0094]

[0126] In certain embodiments, R 8 is a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), the heterocyclyl being one or more R u may be substituted.

[0095]

[0127] In certain embodiments, each R u are independently halogen, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3-10 membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 It may be substituted with haloalkyl.

[0096]

[0128] In certain embodiments, each R u is independently a halogen (e.g., F, Cl, or Br).

[0129] In certain embodiments, each R u C may be independently substituted with one or more of the aforementioned substitutents. 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0097]

[0130] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 alkenyl (eg, ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0098]

[0131] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0099]

[0132] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group).

[0100]

[0133] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group).

[0101]

[0134] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group).

[0102]

[0135] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 6~14 It is aryl (eg, phenyl or naphthyl).

[0136] In certain embodiments, each R u is independently 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl) optionally substituted with one or more of the above-mentioned substituents.

[0103]

[0137] In certain embodiments, each R u C, which may be independently substituted with one or more of the above-mentioned substituents. 3~10 Carbocyclyl (eg, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0104]

[0138] In certain embodiments, each R u is independently a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl) optionally substituted with one or more of the aforementioned substituents.

[0105]

[0139] In certain embodiments, each R u is independently -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR cS(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d (For example, R a is methyl or ethyl, R b is H and R c is H and R d is H).

[0106]

[0140] In certain embodiments, two R u together form an oxo, or two R u is, together with one or more intervening atoms, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 It forms a carbocyclyl or a 3- to 10-membered heterocyclyl.

[0107]

[0141] In certain embodiments, two R u may be taken together with one or more intervening atoms (e.g., C) to form C 6~14 Forms an aryl (eg, phenyl or naphthyl).

[0108]

[0142] In certain embodiments, two R utogether with one or more intervening atoms (e.g., N, O, or S) form a 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl).

[0109]

[0143] In certain embodiments, two R u may be taken together with one or more intervening atoms (e.g., C) to form C 3~10 Forms a carbocyclyl (eg, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0110]

[0144] In certain embodiments, two R u together with one or more intervening atoms (eg, N, O, or S) form a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl).

[0111]

[0145] In certain embodiments, each R a is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3-10 membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 It may be substituted with haloalkyl.

[0112]

[0146] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0113]

[0147] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 alkenyl (eg, ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0114]

[0148] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0115]

[0149] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group).

[0116]

[0150] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group).

[0117]

[0151] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group).

[0118]

[0152] In certain embodiments, each R a is independently 6~14 It is aryl (eg, phenyl or naphthyl).

[0153] In certain embodiments, each R a is independently 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl) optionally substituted with one or more of the above-mentioned substituents.

[0119]

[0154] In certain embodiments, each R a C, which may be independently substituted with one or more of the above-mentioned substituents. 3~10 Carbocyclyl (eg, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0120]

[0155] In certain embodiments, each R a is independently 3-10 membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl) optionally substituted with one or more of the aforementioned substituents.

[0121]

[0156] In certain embodiments, each R b are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10carbocyclyl, or 3-10 membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 It may be substituted with haloalkyl.

[0122]

[0157] In certain embodiments, each R b are independently hydrogen.

[0158] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0123]

[0159] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 alkenyl (eg, ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0124]

[0160] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0125]

[0161] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group).

[0126]

[0162] In certain embodiments, each R bC, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group).

[0127]

[0163] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group).

[0128]

[0164] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 6~14 It is aryl (eg, phenyl or naphthyl).

[0165] In certain embodiments, each R b is independently 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl) optionally substituted with one or more of the above-mentioned substituents.

[0129]

[0166] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 3~10 Carbocyclyl (eg, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0130]

[0167] In certain embodiments, each R b is independently 3-10 membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl) optionally substituted with one or more of the aforementioned substituents.

[0131]

[0168] In certain embodiments, each Rc and R d are independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 carbocyclyl, or 3-10 membered heterocyclyl, and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 It may be substituted with haloalkyl.

[0132]

[0169] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Alkyl (eg, methyl, ethyl, or propyl).

[0133]

[0170] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 2~6 alkenyl (eg, ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0134]

[0171] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents, 2~6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0135]

[0172] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Haloalkyl (e.g., C substituted with one or more halogen atoms) 1~6 alkyl group).

[0136]

[0173] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Hydroxyalkyl (e.g., C substituted with one or more hydroxyl groups) 1~6 alkyl group).

[0137]

[0174] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 1~6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1~6 alkyl group).

[0138]

[0175] In certain embodiments, each R c and R d C, which may be independently substituted with one or more of the above-mentioned substituents. 6~14 It is aryl (eg, phenyl or naphthyl).

[0139]

[0176] In certain embodiments, each R c and R d is independently 5-14 membered heteroaryl (e.g., pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl) optionally substituted with one or more of the above-mentioned substituents.

[0140]

[0177] In certain embodiments, each R b C, which may be independently substituted with one or more of the above-mentioned substituents. 3~10Carbocyclyl (eg, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0141]

[0178] In certain embodiments, each R c and R d is independently 3-10 membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl) optionally substituted with one or more of the aforementioned substituents.

[0142]

[0179] In certain embodiments, R c , R d may be, together with the nitrogen atom to which they are attached, one or more of oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1~6 Alkyl, or C 1~6 In certain embodiments, R c , R d together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl (e.g., tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl), which may be substituted with one or more of the aforementioned substituents.

[0143]

[0180] In certain embodiments, the compound has formula Ia

[0144] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0145]

[0181] In certain embodiments, the compound is selected from the compounds set forth in Table I, and pharma- ceutically acceptable salts, stereoisomers, and solvates thereof.

[0182] In certain embodiments, the compound is selected from the compounds set forth in Table I.

[0146] [Table 1-1]

[0147] [Table 1-2] Further forms of the compounds disclosed herein Pharmaceutically acceptable salts

[0183] In some embodiments, the compounds disclosed herein are present as their pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include the methods of treating disease by administering such pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include the methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0148]

[0184] In some embodiments, the compounds described herein have acidic or basic groups and therefore can be reacted with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0149]

[0185] Examples of pharma- ceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, dicruconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, or the like. salt, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0150]

[0186] Additionally, the compounds described herein can be used to react the free base form of the compounds with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; as well as organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoylbenzoic acid, ... They can be prepared as pharma- ceutically acceptable salts formed by reaction with pharma-ceutically acceptable inorganic or organic acids, including, but not limited to, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0151]

[0187] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as a suitable base of a pharma- ceutically acceptable metal cation, such as hydroxide, carbonate, bicarbonate, or sulfate, ammonia, or a pharma- ceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 Alkyl)4 and the like.

[0152]

[0188] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or insoluble products are obtained by such quaternization.

[0153] solvate

[0189] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Solvates are within the scope of the present invention.

[0154]

[0190] It will also be appreciated by those skilled in the art of organic chemistry that many organic compounds can exist in more than one crystal form. For example, a crystal form may vary from solvate to solvate. Thus, all crystal forms or pharma-ceutically acceptable solvates thereof are contemplated and are within the scope of the present invention.

[0155]

[0191] In some embodiments, the compounds described herein exist as solvates.The present disclosure provides a method for treating disease by administering such solvates.The present disclosure further provides a method for treating disease by administering such solvates as pharmaceutical compositions.

[0156]

[0192] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0157] Isomers / stereoisomers It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0158] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are considered and are within the scope of the present invention.

[0159] In some embodiments, the compounds disclosed herein have one or more chiral centers, and each center is present in the R or S configuration.The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms and corresponding mixtures thereof.All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are considered and are within the scope of the present invention.

[0160] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or transformation are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered with the resolution agent.

[0161] Tautomers In some embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein.

[0162] Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, which involves the interchange of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, there is a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are considered and are within the scope of the present invention. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0163] Preparation of compounds

[0193] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercial Chemicals" means Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0164]

[0194] Suitable reference and technical books detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., Wiley-Interscience, New York, 1992. Further suitable reference and technical books that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd ed., revised and expanded (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th edition (1992) John Wiley&Sons, ISBN: 0-471-60180-2; Otera, J. (ed.) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry, 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, Vol. 8; Organic Reactions (1942-2000) John Wiley & Sons, Vol. 55+; and Chemistry of Functional Groups, John Wiley & Sons, Vol. 73.

[0165]

[0195] Specific similar reactants are optionally identified through indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis companies, where many of the standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0166]

[0196] The coactivator recruitment assay of thyroid receptor beta and thyroid receptor alpha was performed using LanthaScreen™ TR-FRET TR alpha or beta coactivator assay kit (ThermoFIsher). The assay was validated using the control agonist 3,3',5-triiodo-L-thyronine sodium salt, T3 (SIGMA). Test compounds and / or vehicle were incubated with TR alpha LBD-GST or TR beta LBD-GST and coactivator peptide (fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO: 1)) for 30 minutes at room temperature. Measurement of the amount of complex formed was read spectrofluorimetrically (excitation: 337 nm, emission: 520 / 490 nm) on a PHERAstar FS instrument (BMG). The increase in fluorescence induced by test compounds of more than 50 percent compared to the T3 response was used to calculate the EC50 value. Compounds were screened at 30, 10, 3, 1, 0.3, 0.1, and 0.03 μM.

[0167] Pharmaceutical Compositions

[0197] In certain embodiments, the compounds described herein are administered as pure chemicals.In some embodiments, the compounds described herein are combined with pharma- ceutically suitable or acceptable carriers (also referred to herein as pharma- ceutically suitable (or acceptable) excipients, physiologically suitable (or acceptable) excipients, or physiologically suitable (or acceptable) carriers) that are selected based on selected route of administration and standard pharmaceutical practice, for example as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub.Co., Easton, PA (2005)).

[0168]

[0198] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0169]

[0199] In certain embodiments, the compounds provided herein are substantially pure, in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as unreacted intermediates or synthetic by-products created, e.g., in one or more of the steps of the synthetic method.

[0170]

[0200] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the suitable duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dose and treatment regimen provides therapeutic and / or prophylactic benefits (e.g., the composition in an amount sufficient to provide improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's size, weight, or blood volume.

[0171]

[0201] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and epidural, and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0172]

[0202] Suitable doses and dosage regimens are determined by conventional range finding techniques known to those skilled in the art. Generally, treatment is initiated with smaller dosages that are less than the optimal dose of the compounds disclosed herein. The dosage is then increased in small increments until the optimal effect under the circumstances is reached. In some embodiments, the method includes administering at least one compound described herein at about 0.1 μg to about 50 mg per kg of subject body weight. For a 70 kg patient, a dosage of about 10 μg to about 200 mg of the compounds disclosed herein is more commonly used, depending on the physiological response of the subject.

[0173] Treatment Method

[0203] In one aspect, the disclosure provides a method of activating thyroid hormone receptor (THR) β in a patient or biological sample, comprising contacting the patient or biological sample with a compound described herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0174]

[0204] In one aspect, the disclosure provides a method of treating a liver disease or disorder, or a lipid disease or disorder, comprising administering to a patient in need thereof a compound described herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0175]

[0205] In certain embodiments, the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), or fatty liver disease.

[0206] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL), or high low density lipoprotein (LDL).

[0176]

[0207] In certain embodiments, the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

[0177]

[0208] In another aspect, the disclosure provides the use of a compound described herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, in the manufacture of a medicament for treating a disease or disorder of the liver, or a lipid disease or disorder.

[0178]

[0209] In certain embodiments, the liver disease or disorder is NAFLD, NASH, or fatty liver disease.

[0210] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.

[0179]

[0211] In certain embodiments, the hypercholesterolemia is HeFH or HoFH.

[0212] In yet another aspect, the disclosure provides a compound described herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, for use in treating a disease or disorder of the liver, or a lipid disease or disorder.

[0180]

[0213] In certain embodiments, the liver disease or disorder is NAFLD, NASH, or fatty liver disease.

[0214] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.

[0181]

[0215] In certain embodiments, the hypercholesterolemia is HeFH or HoFH. Compound synthesis

[0216] In some aspects, the disclosure provides methods of preparing the compounds disclosed herein.

[0182]

[0217] In some aspects, the disclosure provides a method of preparing a compound, the method comprising one or more steps described herein.

[0218] In some aspects, the disclosure provides compounds obtainable by, obtained by, or directly obtained by the methods for preparing the compounds described herein.

[0183]

[0219] In some aspects, the disclosure provides intermediates that are suitable for use in the methods for preparing the compounds described herein.

[0220] In embodiments, the compounds described herein are prepared according to Scheme 1, Scheme 2, or Scheme 3 below.

[0184] [ka]

[0185] [ka]

[0221] The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further illustrated in the accompanying Examples.

[0186]

[0222] In describing the synthetic methods described herein, and any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0187]

[0223] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0224] It will be understood that during the synthesis of the compounds of the present disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is necessary and how such protecting groups are incorporated and subsequently removed. For examples of protecting groups, see one of the many general books on the subject, for example "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any conventional method described in the literature or known to the skilled chemist as suitable for removing the protecting group in question, such a method being chosen to result in the removal of the protecting group with minimal disturbance of other groups of the molecule. Thus, when reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0188]

[0225] The resulting compounds of the disclosure may be isolated and purified using techniques well known in the art.

[0226] Moreover, by utilizing the procedures described herein, together with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0189]

[0227] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure can be easily obtained by various synthetic routes, some of which are shown in the accompanying examples. Those skilled in the art will easily recognize what kind of reagents and reaction conditions should be used, and how they should be applied and adapted in any particular example, as long as they are necessary or useful, to obtain the compounds of the present disclosure. In addition, some of the compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions to convert one specific functional group present in the compounds of the present disclosure, or a suitable precursor molecule thereof, into another, which methods are well known to those skilled in the art. Similarly, those skilled in the art will easily recognize that, as long as they are necessary or useful, synthetic protecting groups (protecting groups or protective groups) should be applied, and suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, and are described in detail, for example, by PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th Edition (2006) (John Wiley & Sons).

[0190] Biological assays

[0228] Once compounds designed, selected and / or optimized by the methods described above are produced, they can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have the expected activity, binding activity and / or binding specificity.

[0191]

[0229] Moreover, such assays can be used to speed up analysis using high-throughput screening.As a result, it is possible to rapidly screen the molecules described herein for activity using techniques known in the art.The general methodology for carrying out high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263.High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0192]

[0230] In some embodiments, the biological assay is a thyroid receptor beta and / or thyroid receptor alpha coactivator recruitment assay.

[0231] In some embodiments, the assay was validated using 3,3',5-triiodo-L-thyronine sodium salt, T3, as a control agonist.

[0193]

[0232] In some embodiments, test compounds and / or vehicle were incubated with TR alpha LBD-GST or TR beta LBD-GST and coactivator peptides for 30 minutes at room temperature.

[0194]

[0233] In some embodiments, the coactivator peptide is fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO:1).

[0234] In some embodiments, measurement of the amount of complex formed is read spectrofluorometrically (eg, excitation: 337 nm, emission: 520 / 490 nm).

[0195]

[0235] In some embodiments, a test compound-induced increase in fluorescence of greater than 10, 20, 30, 40, 50, 60, 70, 80, or 90 percent compared to the T3 response.

[0236] In some embodiments, a test compound-induced increase in fluorescence of more than 50 percent compared to a T3 response is used to determine EC 50 The value was calculated.

[0196]

[0237] In some embodiments, compounds were screened at 30, 10, 3, 1, 0.3, 0.1, or 0.03 μM. definition

[0238] As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated below.

[0197] chemical definition

[0239] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0198]

[0240] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.F. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, 1972).

[0199]

[0241] The present invention additionally encompasses the compounds depicted herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0242] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0200]

[0243] The following terms are intended to have the meanings present below and are useful in understanding the description and intended scope of the present invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" should be defined as described below. It should further be understood that the terms "group" and "radical" can be considered interchangeably when used herein. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0201]

[0244] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkyl"), or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 It is alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0202]

[0245] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), pentylene (-CHCHCHCHCH-), hexylene (-CHCHCHCHCHCH-), and the like. For example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0203]

[0246] "Alkenyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or external (e.g., 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups are the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0204]

[0247] "Alkenylene" refers to an alkenyl group that removes two hydrogens to provide a divalent radical, which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0205]

[0248] "Alkynyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The carbon-carbon triple bond or bonds can be internal (e.g., 2-butynyl) or external (e.g., 1-butynyl). 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups are the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0206]

[0249] "Alkynylene" refers to a straight-chain alkynyl group, which may be substituted or unsubstituted, in which two hydrogens are removed to provide a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0207]

[0250] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where the heteroatom or heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is an alkyl.

[0208]

[0251] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, that further comprises one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where the heteroatom or heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0209]

[0252] The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, that further comprises one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where the heteroatom or heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl groups"). 2~10In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2~3 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0210]

[0253] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" refer to the divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" groups may be unsubstituted or substituted with one or more substituents described herein.

[0211]

[0254] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracyl).

[0212]

[0255] "Aryl" also includes ring systems, where the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups as defined above, and the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group may be independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0213]

[0256] In certain embodiments, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyano, hydroxy, C 1~6 an aryl group substituted with one or more groups selected from alkoxy, and amino;

[0214]

[0257] "Fused aryl" refers to an aryl having two of its ring carbons shared with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0258] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0215]

[0259] "Heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic arrangement) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings.

[0216]

[0260] "Heteroaryl" also includes ring systems, where the heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, and the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems, where the heteroaryl ring is fused with one or more aryl groups, as defined above, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances, the number of ring members continues to indicate the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0217]

[0261] In some embodiments, the heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl is a 5-9 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-9 membered heteroaryl"). In some embodiments, the heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group may be independently substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0218]

[0262] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridazinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0219]

[0263] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

[0220]

[0264] "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3~8 Carbocyclyl is the aforementioned C 3~6 Exemplary C include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 Carbocyclyl is the aforementioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), but are not limited to these.

[0221]

[0265] As the preceding examples show, in certain embodiments, the carbocyclyl group may be either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems, where the carbocyclyl ring is fused with one or more aryl or heteroaryl groups as defined above, and the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group may be independently substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0222]

[0266] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6 Examples of cycloalkyl include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl are the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl are the aforementioned C 3~6Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0223]

[0267] "Heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting.

[0224]

[0268] Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, e.g. bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above, and the point of attachment is on either the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above, and the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl may independently be substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0225]

[0269] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 14 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0226]

[0270] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0227]

[0271] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group are replaced, where valence permits, with heteroatoms of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5, especially 1 to 3, heteroatoms.

[0228]

[0272] "Acyl" refers to a -C(O)R radical, where R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), and benzylcarbonyl (-C(=O)CH2Ph).

[0229]

[0273] "Acylamino" refers to the radical -NRC(=O)R, where each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino.

[0230]

[0274] "Acyloxy" refers to the radical -OC(=O)R, where R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl.

[0231]

[0275] "Alkoxy" refers to the group -OR, where R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy groups, for example, containing 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

[0232]

[0276] "Azide" refers to the -N3 radical.

[0277] "Carbamoyl" or "amide" refers to the -C(=O)NH2 radical.

[0278] "Amino" refers to the -NH2 radical.

[0233]

[0279] "Oxo" refers to =O.

[0280] "Thioketo" refers to the =S group.

[0281] "Carboxy" refers to the -C(=O)OH radical.

[0234]

[0282] "Cyano" refers to the -CN radical.

[0283] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0235]

[0284] "Hydroxy" refers to the -OH radical.

[0285] "Nitro" refers to the -NO2 radical.

[0286] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims, and the invention is not intended to be limited in any way by the recitation of exemplary substituents above.

[0236] Other definitions

[0287] "Pharmaceutically acceptable" means approved or capable of being approved by a regulatory authority of a federal or state government or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias, for use in animals, or more specifically, in humans.

[0237]

[0288] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylsulfonic acid, ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0238]

[0289] "Solvate" refers to a form of a compound associated with a solvent or water (also called a "hydrate"), usually by a solvolysis reaction. This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharma- ceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, the solvates allow for isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0239]

[0290] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0240]

[0291] Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0241]

[0292] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, differing in the substitution position of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the transfer of electrons and atoms (usually H). For example, enols and ketones are tautomers because they interact rapidly upon treatment with either acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are similarly formed upon treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0242]

[0293] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess over the "R" form. The term "enantiomerically pure" or "pure enantiomer" refers to a compound that contains more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0243]

[0294] As used herein and unless otherwise indicated, the term "enantiomerically pure (R) compound" refers to at least about 95% by weight of the (R) compound and at most about 5% by weight of the (S) compound, at least about 99% by weight of the (R) compound and at most about 1% by weight of the (S) compound, or at least about 99.9% by weight of the (R) compound and at most about 0.1% by weight of the (S) compound. In certain embodiments, the weights are based on the total weight of the compound.

[0244]

[0295] As used herein, unless otherwise indicated, the term "enantiomerically pure (S) compound" or "(S) compound" refers to at least about 95% by weight of the (S) compound and at most about 5% by weight of the (R) compound, at least about 99% by weight of the (S) compound and at most about 1% by weight of the (R) compound, or at least about 99.9% by weight of the (S) compound and at most about 0.1% by weight of the (R) compound. In certain embodiments, the weights are based on the total weight of the compound.

[0245]

[0296] In the compositions provided herein, the enantiomerically pure compound or its pharma- ceutically acceptable salt, solvate, or hydrate may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R) compound may comprise, for example, about 90% by weight of excipients and about 10% by weight of the enantiomerically pure (R) compound. In certain embodiments, the enantiomerically pure (R) compound in such a composition may comprise, for example, at least about 95% by weight of the (R) compound and at most about 5% by weight of the (S) compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S) compound may comprise, for example, about 90% by weight of excipients and about 10% by weight of the enantiomerically pure (S) compound. In certain embodiments, the enantiomerically pure (S) compound in such a composition may comprise, for example, at least about 95% by weight of the (S) compound and at most about 5% by weight of the (R) compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with few or no excipients or carriers.

[0246]

[0297] The compounds of the present invention may possess one or more asymmetric centers and therefore such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof.

[0247]

[0298] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise. The methods for the determination of stereochemistry and separation of stereoisomers are well-known in the art.

[0248]

[0299] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., adolescents, middle-aged adults, or elderly adults), and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0249]

[0300] "Effective amount" means an amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. "Effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. "Therapeutically effective amount" refers to an amount effective for therapeutic treatment. "Prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0250]

[0301] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., keeping at least one clinical symptom of the disease from developing in a subject who has not yet been exposed to a disease-causing pathogen or who is predisposed to the disease prior to the onset of the disease).

[0251]

[0302] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to alleviating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0252]

[0303] The term "about," when referring to a numerical value or numerical range, means that the referenced numerical value or numerical range is plus or minus a certain percentage of the stated value, e.g., 5%, 10%, or 15% of the stated value. For example, about 100 includes 95-105, 90-110, or 85-115.

[0253]

[0304] The term "comprising" (and related terms, e.g., "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any composition of matter, composition of matter, method or process described herein, that "consist of" or "consist essentially of" the described features.

[0254]

[0305] The phrase "and / or" as used herein and in the claims should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified in the "and / or" clause, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used with open-ended language such as "comprising", can refer in one embodiment to only A (optionally including elements other than B); in another embodiment to only B (optionally including elements other than A); in yet another embodiment to both A and B (optionally including other elements), etc.

[0255]

[0306] When used in the present specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., at least one, but also more than one, of a number or list of elements, including any additional unlisted items. Only terms that clearly indicate otherwise, such as "only one of" or "only one of" or "consisting of" when used in the claims, refer to the inclusion of only one element of a number or list of elements. In general, the term "or" as used herein will only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by a term that is exclusive, such as "either," "one of," "only one of," or "only one of." "Consisting essentially of," when used in the claims, has its ordinary meaning as used in the field of patent law.

[0256]

[0307] As used in this specification and the claims, the phrase "at least one" should be understood to mean at least one element selected from any one or more of the elements in the list of elements, which does not necessarily include at least one of every element specifically recited in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for elements to be optionally present other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to the specifically identified elements. Thus, as non-limiting examples, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") refers to, in one embodiment, at least one A, optionally including two or more (optionally including elements other than B), with no B present; in another embodiment, at least one B, optionally including two or more (optionally including elements other than A); in yet another embodiment, at least one A, optionally including two or more (optionally including other elements), and at least one B, optionally including two or more, etc.

[0257]

[0308] While the present teachings will be described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples, but on the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0258]

[0309] Although various inventive embodiments are described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications are considered to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications in which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. Thus, it should be understood that the foregoing embodiments are presented by way of example only, and that within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced other than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the inventive scope of the present disclosure, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0259]

[0310] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and details may be made by those skilled in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. EXAMPLES

[0260]

[0311] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any manner.

[0261] Example 1 Synthesis procedure 4-(2,6-dichloro-4-nitrophenoxy)phthalazin-1(2H)-one (compound 7g)

[0262] [ka]

[0312] Potassium carbonate (2.60 g, 18.50 mmol) was added to a solution of phthalic acid hydrazide (compound 4g, 2.00 g, 12.33 mmol) and compound 5 (1.81 g, 8.63 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 3 h, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 3 (2.98 g), which was further purified by slurry in ethyl acetate to give compound 7g as an off-white solid (2.20 g, yield: 50%). 7g of compound: 1 H NMR (600 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.55 (s, 2H), 8.32 (d, J = 7.5 Hz, 1H), 8.23 ​​(d, J = 7.8 Hz, 1H), 8.12 - 8.07 (m, 1H), 8.06 - 8.00 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 158.89, 150.39, 147.70, 145.43, 134.33, 133.40, 129.40, 129.09, 126.70, 124.63, 123.34, 122.77.LRMS:C 14 H8Cl2N3O4[M+H + ]m / z=352.

[0263] 4-(4-amino-2,6-dichlorophenoxy)phthalazin-1(2H)-one (INT Fg)

[0264] [ka]

[0313] Palladium on carbon (5%, 0.01 g) was added to a solution of compound 7g (0.10 g, 0.28 mmol) in THF (10 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 5 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give INT Fg as a light brown solid (0.098 g, 107%). ITN Fg: 1 H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.05 - 8.01 (m, 1H), 8.00 - 7.95 (m, 1H), 6.71 (s, 2H), 5.64 (s, 2H, NH2). 13 C NMR (151 MHz, DMSO-d6) δ 158.88, 148.48, 148.03, 134.00, 133.90, 132.85, 128.88, 127.90, 126.46, 123.40, 123.37, 112.92.LRMS:C 14 H 10 Cl2N3O2[M+H + ]m / z=322.

[0265] (E,Z)-Ethyl (2-cyano-3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)acryloyl)carbamate (INT Gg)

[0266] [ka]

[0314] Compound 9 (0.97 g, 4.57 mmol) was added to a solution of INT Fg (0.50 g, 20 1.55 mmol) in ACN (10 mL). The mixture was warmed to 80° C. for 5 h. The mixture was cooled and the resulting suspension was filtered. The filter cake was washed with ACN (10 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Gg as an off-white solid (0.52 g, yield: 69%). INT Gg: 1 H NMR (600 MHz, DMSO-d6, main isomer) δ 12.01 (s, 1H), 10.60 (d, J = 13.5 Hz, 1H), 10.46 (s, 1H), 8.49 (d, J = 13.5 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.08 (t, J = 7.0 Hz, 1H), 8.01 (t, J = 7.1 Hz, 1H), 7.80 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 162.26, 158.91, 151.27, 151.20, 148.06, 141.21, 138.93, 134.21, 133.17, 128.98, 128.70, 128.70, 126.61, 123.39, 123.07, 118.31, 118.31, 115.58, 81.74, 60.95, 14.21.LRMS:C 21 H 15 Cl2N5O5[M+H + ]m / z=488.

[0267] 1-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound g)

[0268] [ka]

[0315] INT Gg (0.20 g, 0.42 mmol) was added to a solution containing potassium acetate (0.09 g, 0.92 mmol), THF (4.0 mL), and ACN (2.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 90 °C for 6 days. The resulting suspension was cooled and filtered. The filter cake was purified by column chromatography (2->20% DCM:MeOH). The pure fractions were then concentrated to give compound g as an off-white solid (0.040 g, yield: 22%) containing traces of acetic acid.

[0269]

[0316] Compound g (0.014 g, 0.032 mmol) containing traces of acetic acid was then suspended in water (20 mL), heated to 80° C. for 30 min, cooled to room temperature, and stirred for 2 days. The suspension was filtered to give purified compound g as an off-white solid (0.0077 g, 55% yield). Compound g: 1 H NMR (600 MHz, DMSO-d6) δ 12.31 (s, 1H), 12.05 (s, 1H), 8.92 (s, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.09 (t, J = 7.2 Hz, 1H), 8.03 (t, J = 7.2 Hz, 1H), 7.92 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 158.84, 151.24, 147.96, 144.13, 134.26, 133.23, 129.04, 127.87, 127.87, 127.69, 126.66, 123.43, 123.02, 89.14.LRMS:C 21 H 13 Cl2N6O4[M+ACN+H + ]m / z=483.

[0270] Synthesis of 1-(3,5-dichloro-4-((5-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound a)

[0271] [ka] a. Synthesis of hydrazine reaction

[0272] [ka]

[0317] Sodium acetate (2.70 g, 33.0 mmol) was added to a solution of 3-chlorophthalic anhydride (5.02 g, 27.4 mmol) in acetic acid (25 mL) and stirred. Hydrazine hydrate (1.56 mL, 33.0 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered and washed with water. The solid was then subjected to aqueous KOH solution to dissolve the desired product and the impurities were filtered off as solids. HCl was added dropwise to the aqueous mother liquor until the pH was about 3.5 and then the solid was filtered. The solid was isolated and dried under vacuum for 24 h to give compound 4a as a white solid (4.53 g, yield: 84%). Compound 4a: 1 H NMR (600 MHz, DMSO-d6) δ 11.66 (s, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.5 Hz, 1H), 7.82 (dd, J = 7.9 Hz, 1H).LRMS:C8H5ClN2O2[M+H + ]m / z=197).

[0273] b.Synthesis of SnAr reaction

[0274] [ka]

[0318] Potassium bicarbonate (0.928 g, 9.27 mmol) was added to a solution of 3-chlorophthalic acid hydrazide (compound 4a, 1.49 g, 7.60 mmol) and compound 5 (0.807 g, 3.84 mmol) in DMSO (100 mL), and the mixture was stirred at room temperature for 24 h, after which the reaction was quenched with water (180 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7a, which was further purified by slurry in ethyl acetate to give compound 7a as an off-white solid (1.04 g, yield: 74%). Compound 7a: 1 H NMR (600 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.56 (s, 2H), 8.21 (dd, J = 7.5, 1.5 Hz, 1H), 8.06 - 8.00 (m, 2H).LRMS:C 14 H6Cl3N3O4[M+H + ]m / z=386) C. Reduction reaction synthesis

[0275] [ka]

[0319] Palladium on carbon (5%, 28.9 mg) was added to a solution of compound 7a (0.201 g, 0.520 mmol) in THF (10 mL). The solution was purged with nitrogen three times and then stirred at room temperature for 3.5 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give INT Fa as a light brown solid (0.071 g, 87.8%). INT Fa: 1 H NMR (600 MHz, DMSO-d6) 1 H NMR (600 MHz, DMSO) δ 11.92 (s, 1H), 8.16 (dd, J = 7.5, 1.5 Hz, 1H), 8.00 - 7.95 (m, 2H), 6.70 (s, 2H), 5.65 (s, 2H).LRMS:C 14 H8Cl3N3O2[M+H + ]m / z=356.

[0276] D. Synthesis of condensation reactions

[0277] [ka]

[0320] Compound 9 (56.4 mg, 0.26 mmol) was added to a solution of INT Fa (34.9 mg, 0.10 mmol) in DMF (1.0 mL). The mixture was warmed to 60° C. for 3.5 h. The mixture was cooled, water (1.0 mL) was added, and the resulting suspension was filtered. The filter cake was washed with water (1.0 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Ga as an off-white solid (47.7 mg, yield: 86). INT Ga: 1 H NMR (600 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.61 (d, J = 13.4 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.5 Hz, 1H), 8.20 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.79 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 21 H 14 Cl3N5O5[M+H + ]m / z=522.

[0278] e. Cyclization synthesis

[0279] [ka]

[0321] INT Ga (39.3 mg, 0.08 mmol) was added to a solution containing potassium acetate (16.4 mg, 0.15 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80 °C for 6 h. The resulting suspension was cooled and filtered. The filter cake was dried in an oven to give an off-white solid (21.6 mg, yield: 87.8%). Compound a: 1H NMR (600 MHz, DMSO-d6), δ 12.00 (s, 1H), 10.61 (d, J = 13.4 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.5 Hz, 1H), 8.20 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.79 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 19 H8Cl3N5O4[M+H + ]m / z=476.

[0280] Synthesis of 1-(3,5-dichloro-4-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound b)

[0281] [ka] a. Synthesis of hydrazine reaction

[0282] [ka]

[0322] Sodium acetate (2.96 g, 36.0 mmol) was added to a solution of 3-fluorophthalic anhydride (5.07 g, 30.0 mmol) in acetic acid (25 mL) and stirred. Hydrazine hydrate (1.75 mL, 36.0 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered, washed with water, and dried under vacuum for 24 h to give compound 4b as a white solid (5.13 g, yield: 95%). Compound 4b: 1 H NMR (600 MHz, DMSO-d6) δ 11.57 (s, 2H), 7.89 (p, J = 6.5 Hz, 2H), 7.69 - 7.62 (m, 1H).LRMS:C8H5FN2O2[M+H + ]m / z=181.

[0283] b.Synthesis of SnAr reaction

[0284] [ka]

[0323] Potassium bicarbonate (2.01 g, 20.01 mmol) was added to a solution of 3-fluorophthalic acid hydrazide (compound 4b, 3.08 g, 17.10 mmol) and compound 5 (1.77 g, 8.44 mmol) in DMSO (300 mL), and the mixture was stirred at room temperature for 24 h, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7b (2.8242 g), which was further purified by slurrying in ethyl acetate to give compound 7b as an off-white solid (501 g, yield: 16%). Compound 7b: 1 H NMR (600 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.57 (d, J = 4.0 Hz, 2H), 8.11 (td, J = 8.0, 4.5 Hz, 1H), 8.06 (dd, J = 8.0, 1.2 Hz, 1H), 7.82 (dd, J = 11.3, 8.2 Hz, 1H).LRMS:C 14 H6Cl2FN3O4[M+H + ]m / z=370.

[0285] C. Reduction reaction synthesis

[0286] [ka]

[0324] Palladium on carbon (5%, 37 mg) was added to a solution of compound 7b (0.301 g, 0.10 mmol) in THF (10 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 3 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give INT Fb as a light tan solid (0.283 g, 100%). INT Fb: 1 H NMR (600 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.04 (td, J = 8.0, 4.5 Hz, 1H), 8.00 (dd, J = 8.0, 1.3 Hz, 1H), 7.78 - 7.73 (m, 1H), 6.70 (s, 2H), 5.65 (s, 2H).LRMS:C 14 H8Cl2FN3O2[M+H + ]m / z=340.

[0287] D. Synthesis of condensation reactions

[0288] [ka]

[0325] Compound 9 (91.8 mg, 0.43 mmol) was added to a solution of INT Fb (50.7 mg, 0.15 mmol) in DMF (1 mL). The mixture was warmed to 60° C. for 2 h. The mixture was cooled, water was added, and the resulting suspension was filtered. The filter cake was washed with water (3 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Gb as a yellow solid (53.3 mg, yield: 76%). INT Gb: 1 H NMR (600 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.61 (d, J = 13.5 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.5 Hz, 1H), 8.08 (td, J = 8.0, 4.5 Hz, 1H), 8.04 (d, J = 6.7 Hz, 1H), 7.94 (d, J = 12.6 Hz, 1H), 7.79 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 21 H 14 Cl2FN5O5[M+H + ]m / z=506.

[0289] e. Cyclization synthesis

[0290] [ka]

[0326] INT Gb (38.5 mg, 0.078 mmol) was added to a solution containing potassium acetate (19.8 mg, 0.20 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 60° C. for 2.5 h. The resulting suspension was cooled, water was added (2.0 mL), and filtered. The filter cake was washed with water and then dried in a vacuum oven to give compound b as an off-white solid (12.1 mg, yield: 34%). Compound b: 1 H NMR (600 MHz, DMSO-d6) δ 12.32 (s, 1H), 12.01 (s, 1H), 8.92 (s, 1H), 8.10 (dt, J = 8.0, 4.0 Hz, 1H), 8.06 (dd, J = 8.0, 1.3 Hz, 1H), 7.92 (s, 2H), 7.80 (dd, J = 10.0, 8.0 Hz, 1H).LRMS:C 19 H8Cl2FN5O4[M+H + ]m / z=460.

[0291] Synthesis of 1-(3,5-dichloro-4-((5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound c)

[0292] [ka] a. Synthesis of hydrazine reaction

[0293] [ka]

[0327] Sodium acetate (1.22 g, 14.9 mmol) was added to a solution of 3-methylphthalic anhydride (2.03 g, 12.5 mmol) in acetic acid (10 mL) and stirred. Hydrazine hydrate (0.66 mL, 15.0 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered and washed with water. Water was then added to the solid and 5 M KOH was added until the pH was about 11, and the remaining solid was filtered off and discarded. The mother liquor was then acidified to about 2 and the solid formed was then filtered. The filtered solid was then dried under vacuum for 24 h to give compound 4c as a white solid (411 mg, yield: 96%). Compound 4c: 1 H NMR (600 MHz, DMSO-d6) δ 7.90 (d, J = 7.3 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 6.3 Hz, 1H), 2.80 (s, 3H), 1.75 (s, 2H).LRMS:C9H8N2O2[M+H + ]m / z=177.

[0294] b.Synthesis of SnAr reaction

[0295] [ka]

[0328] Potassium bicarbonate (263 mg, 2.63 mmol) was added to a solution of 3-methylphthalic acid hydrazide (compound 4c, 350 mg, 1.79 mmol) and compound 5 (226 mg, 1.08 mmol) in DMSO (150 mL), and the mixture was stirred at room temperature for 24 hours, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 hours to give crude compound 7g, which was further purified by slurrying in ethyl acetate to give compound 7c as an off-white solid (281 g, yield: 70%). Compound 7c: 1H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.55 (s, 2H), 8.07 (d, J = 7.5 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 2.86 (s, 3H).LRMS:C 15 H9Cl2N3O4[M+H + ]m / z=366.

[0296] C. Reduction reaction synthesis

[0297] [ka]

[0329] Palladium on carbon (5%, 44.8 mg) was added to a solution of compound 7c (281.5 g, 0.77 mmol) in THF (10 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 24 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give INT Fc as a light brown solid (215 mg, 83%). INT Fc: 1 H NMR (600 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 6.69 (s, 2H), 5.63 (s, 2H), 2.85 (s, 3H).LRMS:C 15 H 11 Cl2N3O2[M+H + ]m / z=336.

[0298] D. Synthesis of condensation reactions

[0299] [ka]

[0330] Compound 9 (65.4 mg, 0.31 mmol) was added to a solution of INT Fc (36.3 mg, 0.11 mmol) in DMF (2 mL). The mixture was warmed to 80° C. for 5 h. The mixture was cooled and the resulting suspension was filtered. The resulting suspension was cooled, water was added (2.0 mL) and filtered. The filter cake was washed with water and then dried in a vacuum oven to give INT Gc as a pale yellow solid (36.2 mg, yield: 97%). INT Gc: 1 H NMR (600 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.60 (d, J = 13.5 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.5 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.79 (s, 2H), 7.76 (d, J = 7.4 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.86 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 22 H 17 Cl2N5O5[M+H + ]m / z=502.

[0300] e. Cyclization synthesis

[0301] [ka]

[0331] INT Gc (30.6 mg, 0.06 mmol) was added to a solution containing potassium acetate (13.6 mg, 0.14 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80 °C for 5 h. The resulting suspension was cooled, water was added (2.0 mL), and filtered. The filter cake was washed with water and then dried in a vacuum oven to give compound c as a pale yellow solid (12.0 mg, yield: 44%). Compound c: 1H NMR (600 MHz, DMSO-d6) δ 12.31 (s, 1H), 11.82 (s, 1H), 8.92 (s, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J = 7.4 Hz, 1H), 2.86 (s, 3H).LRMS:C 20 H 11 Cl2N5O4[M+H + ]m / z=456.

[0302] Synthesis of 1-(3,5-dichloro-4-((6,7-dichloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound d)

[0303] [ka] a. Synthesis of hydrazine reaction

[0304] [ka]

[0332] Sodium acetate (1.36 g, 17.0 mmol) was added to a solution of 4,5-dichlorophthalic anhydride (3.01 g, 14.0 mmol) in acetic acid (16 mL) and stirred. Hydrazine hydrate (0.81 mL, 17.0 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered and washed with water. The solid was then subjected to aqueous KOH solution to dissolve the desired product and the impurities were filtered off as solids. HCl was added dropwise to the aqueous mother liquor until the pH was about 3.5 and then the solid was filtered. The solid was isolated and dried under vacuum for 24 h to give compound 4d as a white solid (3.31 g, yield: 96%). Compound 4d: 1 H NMR (600 MHz, DMSO-d6) δ 11.89 (s, 2H), 8.19 (s, 2H).LRMS:C8H4Cl2N2O2[M+H +]m / z=230.

[0305] b.Synthesis of SnAr reaction

[0306] [ka]

[0333] Potassium bicarbonate (421 mg, 4.1 mmol) was added to a solution of 4,5-dichlorophthalic acid hydrazide (compound 4d, 290.1 ​​mg, 1.26 mmol) and compound 5 (375 mg, 1.79 mmol) in DMSO (100 mL), and the mixture was stirred at room temperature for 48 h, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7d, which was further purified by column chromatography (2-10% MeOH / DCM) to give compound 7d as an off-white solid (310 mg, yield: 43%). Compound 7d: 1 H NMR (600 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.58 (s, 2H), 8.51 (s, 1H), 8.45 (s, 1H).LRMS:C 14 H5Cl4N3O4[M+MeCN+H + ]m / z=461.

[0307] C. Reduction reaction synthesis

[0308] [ka]

[0334] Palladium on carbon (5%, 180 mg) was added to a solution of compound 7d (300 mg, 0.71 mmol) in THF (40 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 20 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give a crude solid, which was further purified by column chromatography (2→10% MeOH / DCM) to give INT Fd as a pale yellow color (41.6 mg, 15%). INT Fd: 1H NMR (600 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.41 (d, J = 3.1 Hz, 2H), 6.71 (s, 2H), 5.68 (s, 2H).LRMS:C 14 H7Cl4N3O2[M+H + ]m / z=390.

[0309] D. Synthesis of condensation reactions

[0310] [ka]

[0335] Compound 9 (58.3 mg, 0.27 mmol) was added to a solution of INT Fd (35.0 mg, 0.09 mmol) in DMF (1 mL). The mixture was warmed to 60° C. for 5 h. The mixture was cooled and the resulting suspension was filtered. The resulting suspension was cooled, water was added (2.0 mL) and filtered. The filter cake was washed with water and then dried in a vacuum oven to give INT Gd as inseparable E,Z isomers as an off-white solid (38.5 mg, yield: 77%). INT G: 1 H NMR (600 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.61 (d, J = 13.4 Hz, 1H), 10.47 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 7.94 (d, J = 10.1 Hz, 1H), 7.80 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 21 H 13 Cl4N5O5[M+H + ]m / z=556.

[0311] e. Cyclization synthesis

[0312] [ka]

[0336] INT Gd (30.67 mg, 0.06 mmol) was added to a solution containing potassium acetate (11.2 mg, 0.141 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80° C. for 5 h. The resulting suspension was cooled, water was added (2.0 mL), and filtered. The filter cake was washed with water and then dried in a vacuum oven to give compound d as an off-white solid (16.4 mg, yield: 60%). Compound d: 1 H NMR (600 MHz, DMSO-d6) δ 12.32 (s, 1H), 12.29 (s, 1H), 8.92 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.92 (s, 2H).LRMS:C 19 H7Cl4N5O4[M+ACN+H + ]m / z=551.

[0313] Synthesis of 1-(3,5-dichloro-4-((6,7-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound e)

[0314] [ka] a. Synthesis of hydrazine reaction

[0315] [ka]

[0337] Sodium acetate (0.53 g, 7.0 mmol) was added to a solution of 4,5-difluorophthalic anhydride (945 mg, 5.13 mmol) in acetic acid (8.0 mL) and stirred. Hydrazine hydrate (0.32 mL, 7.0 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered, washed with water, and dried under vacuum for 24 h to give compound 4e as a white solid (970 mg, yield: 91%). Compound 4e: 1H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 2H), 8.01 (s, 2H).LRMS:C8H4F2N2O2[M+H + ]m / z=199.

[0316] b.Synthesis of SnAr reaction

[0317] [ka]

[0338] Potassium bicarbonate (313 mg, 3.13 mmol) was added to a solution of 3,6-difluorophthalic acid hydrazide (compound 4e, 511 mg, 2.58 mmol) and compound 5 (313 mg, 1.49 mmol) in DMSO (60 mL), and the mixture was stirred at room temperature for 24 h, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7e, which was further purified by column chromatography (2→10% MeOH / DCM) to give compound 7e as an off-white solid (54 mg, yield: 10%). Compound 7e: 1 H NMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.59 (s, 2H), 8.31 - 8.28 (m, 1H), 8.09 (dd, J = 10.1, 7.3 Hz, 1H).LRMS:C 14 H5Cl2F2N3O4[M+MeCN+H + ]m / z=429.

[0318] C. Reduction reaction synthesis

[0319] [ka]

[0339] Palladium on carbon (5%, 112 mg) was added to a solution of compound 7e (120 mg, 0.31 mmol) in THF (5 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 2.5 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give INT Fe as a light tan solid (53.2 mg, 48%). INT Fe: 1 H NMR (600 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.25 (ddd, J = 25.2, 10.1, 7.4 Hz, 2H), 6.88 (s, 1H), 6.71 (s, 2H), 5.68 (s, 1H).LRMS:C 14 H7Cl2F2N3O2[M+H + ]m / z=358.

[0320] D. Synthesis of condensation reactions

[0321] [ka]

[0340] Compound 9 (92.5 mg, 0.43 mmol) was added to a solution of INT Fe (52.2 mg, 0.15 mmol) in DMF (1.2 mL). The mixture was warmed to 60° C. for 3 h. The mixture was cooled, water (2 mL) was added, and the resulting suspension was filtered. The filter cake was washed with water (1 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Ge as an off-white solid (50.0 mg, yield: 71%). INT Ge: 1 H NMR (600 MHz, DMSO-d6, main isomer) δ 12.20 (s, 1H), 10.61 (d, J = 13.4 Hz, 1H), 10.47 (s, 1H), 8.49 (d, J = 13.4 Hz, 1H), 7.80 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.18 (s, 1H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 21 H 13 Cl2F2N5O5[M+H +]m / z=524.

[0322] e. Cyclization synthesis

[0323] [ka]

[0341] INT Ge (25.0 mg, 0.048 mmol) was added to a solution containing potassium acetate (15.5 mg, 0.158 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80 °C for 8 h. The resulting suspension was cooled, water was added (2.0 mL), and filtered. The filter cake was washed with water and then dried in a vacuum oven to give compound e as a tan solid (12.6 mg, yield: 82%). Compound e: 1 H NMR (600 MHz, DMSO-d6) δ 12.32 (s, 1H), 12.25 (s, 1H), 8.92 (s, 1H), 8.36 (d, J = 9.9 Hz, 1H), 8.26 (d, J = 10.0 Hz, 1H), 7.92 (s, 2H).LRMS:C 19 H7Cl2F2N5O4[M+MeCN+H + ]m / z=519.

[0324] Synthesis of 1-(3,5-dichloro-4-((5,8-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound f)

[0325] [ka] a. Synthesis of hydrazine reaction

[0326] [ka]

[0342] Sodium acetate (544 mg, 6.63 mmol) was added to a solution of 3,6-difluorophthalic anhydride (947 mg, 5.14 mmol) in acetic acid (3 mL) and stirred. Hydrazine hydrate (0.175 mL, 3.60 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered, washed with water, and dried under vacuum for 24 h to give compound 4f as a white solid (1.09, yield: 91.8%). Compound 4f: 1 H NMR (600 MHz, DMSO-d6) δ 11.57 (d, J = 157.7 Hz, 2H), 7.69 (s, 2H).LRMS:C8H4F2N2O2[M+H + ]m / z=199.

[0327] b.Synthesis of SnAr reaction

[0328] [ka]

[0343] Potassium bicarbonate (240 mg, 2.40 mmol) was added to a solution of 3,6-difluorophthalic acid hydrazide (compound 4f, 400 mg, 2.02 mmol) and compound 5 (160 mg, 0.76 mmol) in DMSO (100 mL), and the mixture was stirred at room temperature for 24 h, after which the reaction was quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7f, which was further purified by column chromatography (2→10% MeOH / DCM) to give compound 7f as a tan solid (101 g, yield: 42%). Compound 7f: 1 H NMR (600 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.55 (s, 2H), 8.05 - 7.79 (m, 2H).LRMS:C 14 H5Cl2F2N3O4[M+MeCN+H + ]m / z=429 C. Reduction reaction synthesis

[0329] [ka]

[0344] Palladium on carbon (5%, 9.6 mg) was added to a solution of compound 7f (89.4 mg, 0.23 mmol) in THF (10 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 6 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give crude INT Ff, which was further purified by column chromatography (0→4% MeOH / DCM) as a light brown solid (32.3 mg, 39%). INT Ff: 1 H NMR (600 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.95 - 7.88 (m, 1H), 7.80 (td, J = 9.9, 3.6 Hz, 1H), 6.69 (s, 2H), 5.64 (s, 2H).LRMS:C 14 H7Cl2F2N3O2[M+H + ]m / z=358.

[0330] D. Synthesis of condensation reactions

[0331] [ka]

[0345] Compound 9 (60.8 mg, 0.29 mmol) was added to a solution of INT Ff (30.6 mg, 0.09 mmol) in DMF (1 mL). The mixture was warmed to 60° C. for 5 h. The mixture was cooled, water was added (2 mL) and the resulting suspension was filtered. The filter cake was washed with water (2 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Gf as an off-white solid (36.7 mg, yield: 78%). INT Gf: 1H NMR (600 MHz, DMSO-d6, main isomer) δ 12.09 (s, 1H), 10.60 (d, J = 13.4 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.4 Hz, 1H), 7.97 - 7.94 (m, 1H), 7.85 - 7.82 (m, 1H), 7.79 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 21 H 13 Cl2F2N5O5[M+H + ]m / z=524.

[0332] e. Cyclization synthesis

[0333] [ka]

[0346] INT Gf (31.9 mg, 0.06 mmol) was added to a solution containing potassium acetate (14.0 mg, 0.14 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80° C. for 4 h. The resulting suspension was cooled, water was added (2.0 mL), and filtered. The filter cake was washed with water and then dried in a vacuum oven to give compound f as an off-white solid (23.0 mg, yield: 94%). Compound f: 1 H NMR (600 MHz, DMSO-d6) δ 12.31 (s, 1H), 12.14 (s, 1H), 8.90 (s, 1H), 7.99 - 7.96 (m, 1H), 7.91 (s, 2H), 7.86 - 7.83 (m, 1H).LRMS:C 19 H7Cl2F2N5O4[M+H + ]m / z=478.

[0334] Synthesis of 1-(3,5-dichloro-4-((5-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound h)

[0335] [ka] a. Synthesis of hydrazine reaction

[0336] [ka]

[0347] Sodium acetate (300.1 mg, 3.66 mmol) was added to a solution of 3-methyloxyphthalic anhydride (489.8 mg, 2.75 mmol) in acetic acid (2.4 mL) and stirred. Hydrazine hydrate (0.16 mL, 3.40 mmol) was then added dropwise and stirred for 15 min. The mixture was warmed to 80-90 °C for 18 h. The solid was filtered, washed with water, and dried under vacuum for 24 h to give compound 4h as a white solid (417 mg, yield: 79%). Compound 4h: 1 H NMR (600 MHz, DMSO-d6) δ 7.79 (t, J = 8.0 Hz, 1H), 7.70 - 7.55 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H).LRMS:C9H8N2O3[M+H + ]m / z=192.

[0337] b.Synthesis of SnAr reaction

[0338] [ka]

[0348] Potassium bicarbonate (313 mg, 3.13 mmol) was added to a solution of 3-methoxyphthalic hydrazide (compound 4h, 400 mg, 2.08 mmol) and compound 5 (277 g, 1.32 mmol) in DMSO (30 mL), and the mixture was stirred at room temperature for 24 h, after which the reaction was quenched with water (30 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 h to give crude compound 7h (496 mg), which was further purified by slurrying in ethyl acetate to give compound 7h as a pale yellow solid (370 mg, yield: 74%). Compound 7h: 1 H NMR (600 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.54 (s, 2H), 7.99 (t, J = 8.1 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H).LRMS:C 15 H9Cl2N3O5[M+H + ]m / z=382.

[0339] C. Reduction reaction synthesis

[0340] [ka]

[0349] Palladium on carbon (5%, 0.02 g) was added to a solution of compound 7h (251 mg, 0.66 mmol) in THF (2 mL). The solution was purged twice with nitrogen and then stirred at room temperature for 5 h under a hydrogen atmosphere. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness to give crude INT Fh. The crude material was purified by column chromatography (2→20% DCM:MeOH) to give pure INT Fh as a pale yellow solid (61.1 mg, 26.2%). INT Fh: 1H NMR (600 MHz, DMSO-d6) δ 11.53 (s, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.49 (dd, J = 8.5, 1.0 Hz, 1H), 6.69 (s, 2H), 5.62 (s, 2H), 3.92 (s, 3H).LRMS:C 15 H 11 Cl2N3O3[M+H + ]m / z=352).

[0341] D. Synthesis of condensation reactions

[0342] [ka]

[0350] Compound 9 (93 mg, 0.44 mmol) was added to a solution of INT Fh (50 mg, 0.14 mmol) in DMF (1 mL). The mixture was warmed to 80° C. for 5 h. The mixture was cooled, water was added (2 mL) and the resulting suspension was filtered. The filter cake was washed with water (2 mL) and dried under vacuum for 24 h to give a mixture of inseparable E,Z isomers of INT Gh as an off-white solid (74.9 mg, yield: 14%). INT Gh: 1 H NMR (600 MHz, DMSO-d6, main isomer) δ 11.61 (s, 1H), 10.60 (d, J = 13.5 Hz, 1H), 10.47 (s, 1H), 8.48 (d, J = 13.4 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.78 (s, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 9.6 Hz, 1H), 4.15 (q, J = 6.7 Hz, 2H), 3.93 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).LRMS:C 22 H 17 Cl2N5O6[M+H + ]m / z=518.

[0343] e. Cyclization synthesis

[0344] [ka]

[0351] INT Gh (41.0 mg, 0.08 mmol) was added to a solution containing potassium acetate (15.8 mg, 0.16 mmol), MeOH (1.0 mL), and water (1.0 mL). The mixture was purged with N2, the flask was sealed, and heated to 80 °C for 6 h. The resulting suspension was cooled and filtered. The filter cake was washed with water to give purified compound h as an off-white solid (30.2 mg, yield: 82.9%). Compound h: 1 H NMR (600 MHz, DMSO-d6) δ 12.31 (s, 1H), 11.65 (s, 1H), 8.91 (s, 1H), 7.99 (t, J = 8.2 Hz, 1H), 7.90 (s, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 3.94 (s, 3H).LRMS:C 20 H 11 Cl2N5O5[M+H + ]m / z=472.

[0345] Synthesis of 1-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound i)

[0346] [ka] a. Functional group transformation

[0352] 1-(3,5-Dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (20 mg, 0.05 mol) and sulfuric acid (0.5 mL) were added to a 3 mL vial and warmed to 75-80 °C for 5 min. The vial was cooled to room temperature, and then the solution was added to water (2 mL). The solid was filtered, washed with water, and dried under vacuum for 24 h to give compound i as a white solid (20.1 mg, yield: 98%). Compound i: 1 H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H), 12.03 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 9.9 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.14 (s, 1H), 8.11 - 8.08 (m, 1H), 8.03 (t, J = 8.3 Hz, 1H), 7.94 (s, 2H), 7.66 (s, 1H).LRMS:C 19 H 11 Cl2N5O5[M+MeCN+H + ]m / z=501.

[0347] Synthesis of 1-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (compound j)

[0348] [ka] a. Functional group transformation

[0353] 1-(3,5-Dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (51.2 mg, 0.05 mol), acetic acid (4 mL), sulfuric acid (2 mL) and water (2 mL) were added to a 20 mL vial and warmed to 100° C. for 9 days. The vial was cooled to room temperature. The solid was filtered, washed with water and dried under vacuum for 24 hours to give compound j as a white solid (45.1 mg, yield: 99%). Compound j: 1 H NMR (600 MHz, DMSO-d6) δ 12.25 (s, 1H), 12.04 (s, 1H), 8.56 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.11 - 8.07 (m, 1H), 8.04 (dd, J = 7.6, 1.5 Hz, 1H), 7.94 (s, 2H).LRMS:C 19 H 10 Cl2N4O6[M+MeCN+H + ]m / z=502.

[0349] Example 2 Biological assays

[0354] Thyroid receptor beta and thyroid receptor alpha coactivator recruitment assays were performed using the LanthaScreen™ TR-FRET TR alpha or beta coactivator assay kit (ThermoFIsher). The assay was validated using the control agonist 3,3',5-Triiodo-L-thyronine sodium salt, T3 (SIGMA). Test compounds and / or vehicle were incubated with TR alpha LBD-GST or TR beta LBD-GST and the coactivator peptide (fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO: 1)) for 30 minutes at RT. Measurement of the amount of complex formed was read spectrofluorimetrically (excitation: 337 nm, emission: 520 / 490 nm) on a PHERAstar FS instrument (BMG). A test compound-induced increase in fluorescence of more than 50 percent compared to the T3 response was used to determine the EC 50 Values ​​were calculated. Compounds were screened at 30, 10, 3, 1, 0.3, 0.1, and 0.03 μM.

[0350] [Table 2] Incorporation by Reference

[0355] All publications and patents mentioned herein are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0351] Equivalent

[0356] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0352]

[0357] While specific embodiments of the subject invention have been described, the above specification is illustrative and not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and by reference to the specification, along with such variations.

Claims

1. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [In the formula, Each R １ are independently halogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkoxy, C ３～１０ Carbocyclyl, or C ６～１４ is aryl, Each R ２ are independently halogen, C １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ is alkynyl, R ３ is halogen, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ N.R. ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -OR ｂ , -OS(=O) ２ R ａ , -OS(=O) ２ OR ｂ , -OS(=O) ２ N.R. ｃ R ｄ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or -C(=O)NR ｃ R ｄ and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R ｕ may be substituted with Existing R ４ and R ６ Each of the groups is independently hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R ｕ may be substituted with Each R ５ are independently halogen, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ N.R. ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -OR ｂ , -OS(=O) ２ R ａ , -OS(=O) ２ OR ｂ , -OS(=O) ２ N.R. ｃ R ｄ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or -C(=O)NR ｃ R ｄ and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R ｕ may be substituted with m is an integer selected from 0 to 4; n is an integer selected from 0 to 2; X is -C(R ７ ) ２ -, -O-, -NR ８ -, -S-, and -S-; Each R ７ are independently hydrogen, halogen, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ N.R. ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -OR ｂ , -OS(=O) ２ R ａ , -OS(=O) ２ OR ｂ , -OS(=O) ２ N.R. ｃ R ｄ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or -C(=O)NR ｃ R ｄ and the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R ｕ may be substituted with R ８ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ carbocyclyl, or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R ｕ may be substituted with Each R ｕ are independently halogen, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ N.R. ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -OR ｂ , -OS(=O) ２ R ａ , -OS(=O) ２ OR ｂ , -OS(=O) ２ N.R. ｃ R ｄ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ or -C(=O)NR ｃ R ｄ and alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of one or more of oxo, halogen, —CN, —OH, —OMe, —NH ２ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C １～６ Alkyl, or C １～６ may be substituted with haloalkyl; Two R's ｕ together to form oxo, or Two R's ｕ together with one or more intervening atoms, C ６～１４ Aryl, 5-14 membered heteroaryl, C ３～１０ forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R ａ is independently １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１４ aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH ２ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C １～６ Alkyl, or C １～６ may be substituted with haloalkyl; Each R ｂ are independently hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１４ aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more of oxo, halogen, -CN, -OH, -OMe, -NH ２ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C １～６ Alkyl, or C １～６ may be substituted with haloalkyl; Each R ｃ and R ｄ are independently hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Aminoalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１４ aryl, or 5-14 membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more of oxo, halogen, -CN, -OH, -OMe, -NH ２ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C １～６ Alkyl or C １～６ may be substituted with haloalkyl, Or, R ｃ , R ｄ may be, together with the nitrogen atom to which they are attached, one or more of oxo, halogen, -CN, -OH, -OMe, -NH ２ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C １～６ Alkyl, or C １～６ forming a 3- to 10-membered heterocyclyl optionally substituted by haloalkyl.

2. Each R １ are independently halogen, C １～６ Alkyl, C １～６ Alkoxy, or C ６～１４ The compound of claim 1 which is aryl.

3. 3. The compound of claim 1 or 2, wherein m is 0, 1, or 2.

4. Each R ２ are independently halogen or C １～６ The compound according to any one of claims 1 to 3, which is alkyl.

5. Each R ２ The compound according to any one of claims 1 to 4, wherein is halogen.

6. Each R ２ The compound according to any one of claims 1 to 5, wherein is chloride.

7. R ３ is -CN, -C(=O)OR ｂ or -C(=O)NR ｃ R ｄ The compound according to any one of claims 1 to 6,

8. R ３ The compound according to any one of claims 1 to 7, wherein is -CN.

9. Each R ｃ and R ｃ The compound according to any one of claims 1 to 7, wherein is H.

10. R ３ is -C(=O)NH ２ The compound according to any one of claims 1 to 7,

11. R ｂ The compound according to any one of claims 1 to 7, wherein is H.

12. R ３ The compound according to any one of claims 1 to 7, wherein is -C(=O)OH.

13. R ４ The compound according to any one of claims 1 to 12, wherein is hydrogen.

14. The compound according to any one of claims 1 to 13, wherein n is 0.

15. R ６ The compound according to any one of claims 1 to 14, wherein is hydrogen.

16. The compound according to any one of claims 1 to 15, wherein X is O.

17. 2. The compound of claim 1, selected from the compounds set forth in Table I, and pharma- ceutically acceptable salts, stereoisomers, and solvates thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, and a pharma- ceutically acceptable excipient.

19. 20. A method of activating thyroid hormone receptor (THR) beta in a patient or biological sample, comprising contacting the patient or biological sample with a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

20. 20. A method of treating a liver disease or disorder, or a lipid disease or disorder, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

21. 21. The method of claim 20, wherein the liver disease or disorder is nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease (NASH), or fatty liver disease.

22. 21. The method of claim 20, wherein the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL), or high low density lipoprotein (LDL).

23. 23. The method of claim 22, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

24. 20. Use of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, in the manufacture of a medicament for treating a disease or disorder of the liver, or a lipid disease or disorder.

25. 25. The use of claim 24, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), or fatty liver disease.

26. 25. The use of claim 24, wherein the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL), or high low density lipoprotein (LDL).

27. 27. The use according to claim 26, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

28. 20. A compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, for use in the treatment of a disease or disorder of the liver, or a lipid disease or disorder.

29. 29. The compound for use according to claim 28, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), or fatty liver disease.

30. 29. The compound for use according to claim 28, wherein the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein (HDL), or high low density lipoprotein (LDL).

31. 31. The compound for use according to claim 30, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

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