Thrbeta analogs and uses thereof

Abstract

Described herein are compounds of Formula I and pharmaceutically acceptable salts, solvates and stereoisomers thereof, and their use as thyroid hormone receptor (THR) beta activators. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 308,709, filed on February 10, 2022, and U.S. Provisional Application No. 63 / 419,790, filed on October 27, 2022, the contents of which are incorporated herein by reference.

[0003] Incorporation by Reference into the Sequence Listing

[0004] The file named "MDRI-028_001WO_SeqList_ST26.txt" was created on February 7, 2023, is 1.87KB in size, and its entire contents are incorporated herein by reference. Background Art

[0005] Thyroid hormones are essential 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 hypothalamus / pituitary / thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones have a profound effect on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0006] The biological activity of thyroid hormone is mediated by thyroid hormone receptor (TR or THR) (MALazar, Endocrine Reviews, Vol.14: pp.348-399 (1993)). TR belongs to the superfamily known as nuclear receptors. TR forms heterodimers with retinoid receptors, which are ligand-inducible transcription factors. TR has a ligand binding domain, a DNA binding domain, and an amino-terminal domain, and regulates gene expression by interacting with DNA response elements and with a variety of nuclear coactivators and co-repressors. Thyroid hormone receptors are derived from two independent genes, α and β. These different gene products produce various forms of their respective receptors through different RNA processing. The main thyroid hormone receptor isotypes are α1, α2, β1, and β2. Thyroid hormone receptors α1, β1, and β2 bind thyroid hormones. It has been shown that thyroid hormone receptor subtypes can differ in their contribution to specific biological responses. Recent studies have shown that TRβ1 plays an important role in regulating TRH (thyrotropin-releasing hormone) and regulating the effects of thyroid hormones in the liver. TRβ2 plays an important role in the regulation of TSH (thyroid stimulating hormone) (Abel et al., J. Clin. Invest., Vol. 104: pp. 291-300 (1999)). TRβ1 plays an important role in the regulation of 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)).

[0007] Efforts have been made to synthesize thyroid hormone analogs with increased thyroid hormone receptor β selectivity and / or tissue-selective effects. Such thyroid hormone mimetics can produce the desired reduction in body weight, lipids, cholesterol, and lipoproteins, and have reduced effects 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 analogs that avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones will open up new treatment pathways for patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other diseases such as hepatic steatosis and NASH, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, thyroid hormone resistance, and related diseases and conditions. Summary of the invention

[0008] In some aspects, the present application provides compounds of Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0011] 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 Carbocyclic or C 6-14 Aryl;

[0012] Each R 2 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0013] R 3 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 、-ORb 、-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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0014] R 4 and R 6 Each occurrence 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- to 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 optionally substituted by one or more R u replace;

[0015] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -SR b 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c R d 、-NRc 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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0016] m is an integer selected from 0 to 4;

[0017] n is an integer selected from 0 to 2;

[0018] X is selected from -C(R 7 )2-、-O-、-NR 8 -, and -S-;

[0019] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Replacement; and

[0020] R 8 It 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- to 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 optionally substituted by one or more R u replace;

[0021] in:

[0022] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0023] Two R's u together to form an oxo group; or

[0024] Two R's u Together with one or more intervening atoms, they form C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic group, or 3 to 10 membered heterocyclic group;

[0025] Each R a Independently 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0026] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and

[0027] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0028] or R c , R d Together with the nitrogen atom to which they are attached, they form a group optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 A 3- to 10-membered heterocyclic group substituted with a haloalkyl group.

[0029] In some aspects, the application provides methods of making the compounds described herein.

[0030] In some aspects, the present application provides a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable excipient.

[0031] In some aspects, the application provides methods of treating a disease, disorder, or condition comprising administering to a subject in need thereof any of the compounds described herein in a pharmaceutical composition.

[0032] In some aspects, the application provides any compound described herein in a pharmaceutical composition for use in treating a disease, disorder, or condition, comprising administering to a subject in need thereof.

[0033] In some aspects, the application provides use of any compound described herein in a pharmaceutical composition for the preparation of a medicament for treating a disease, disorder or condition comprising administering to a subject in need thereof.

[0034] In some aspects, the present application provides a method of activating thyroid hormone receptor (THR) β in a patient or a biological sample, the method comprising contacting the patient or the biological sample with a compound described herein in a pharmaceutical composition.

[0035] In some aspects, the application provides any compound described herein in a pharmaceutical composition for use in activating thyroid hormone receptor (THR) β in a patient or a biological sample.

[0036] In some aspects, the present application provides the use of any compound described herein in a pharmaceutical composition for the preparation of a medicament for activating thyroid hormone receptor (THR) β in a patient or a biological sample.

[0037] In some aspects, the application provides methods of treating a liver disease or disorder or a lipid disease or disorder, the method comprising administering to an individual in need thereof any of the compounds described herein in a pharmaceutical composition.

[0038] In some aspects, the application provides any compound described herein in a pharmaceutical composition for use in treating a liver disease or disorder or a lipid disease or disorder.

[0039] In some aspects, the application provides use of any compound described herein in a pharmaceutical composition for the preparation of a medicament for treating a liver disease or disorder or a lipid disease or disorder.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by ordinary technicians in the field to which this application belongs. In the specification, the singular also includes the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein do not admit to be the prior art of the claimed invention. In the event of a conflict, this specification (including definitions) shall prevail. In addition, the materials, methods and embodiments are illustrative only, not restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure shall prevail.

[0041] Other features and advantages of the application will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0043] Compounds of the present application

[0044] In some aspects, the present application provides compounds of Formula I:

[0045]

[0046] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0047] 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 Carbocyclic or C 6-14 Aryl;

[0048] Each R 2 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0049] R 3 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0050] R 4 and R 6 Each occurrence 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- to 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 optionally substituted by one or more R u replace;

[0051] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0052] m is an integer selected from 0 to 4;

[0053] n is an integer selected from 0 to 2;

[0054] X is selected from -C(R 7 )2-、-O-、-NR 8 -, and -S-;

[0055] 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, C2-6 Alkynyl, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Replacement; and

[0056] R 8 It 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, C6-14 Aryl, 5- to 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 optionally substituted by one or more R u replace;

[0057] in:

[0058] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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)Ra 、-C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0059] Two R's u together to form an oxo group; or

[0060] Two R's u Together with one or more atoms in between, they form C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic group, or 3 to 10 membered heterocyclic group;

[0061] Each R a Independently 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution;

[0062] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and

[0063] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0064] or R c , R d Together with the nitrogen atom to which they are attached, they form a group optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 A 3- to 10-membered heterocyclic group substituted with a haloalkyl group.

[0065] In some aspects, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0066] Each R 1 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic or C 6-14 Aryl;

[0067] Each R 2 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6Alkynyl;

[0068] R 3 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0069] R 4 and R 6 Each occurrence is independently 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- to 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 optionally substituted by one or more R u replace;

[0070] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace;

[0071] m is an integer selected from 0 to 4;

[0072] n is an integer selected from 0 to 2;

[0073] X is selected from -C(R 7 )2-、-O-、-NR 8 -, and -S-;

[0074] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Replacement; and

[0075] R 8 It 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- to 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 optionally substituted by one or more R u replace;

[0076] in:

[0077] 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0078] Two R's u together to form an oxo group; or

[0079] Two R's u Together with one or more atoms in between, they form C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic group, or 3 to 10 membered heterocyclic group;

[0080] Each R a Independently C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0081] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and

[0082] 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C1-6 haloalkyl substitution;

[0083] or R c , R d Together with the nitrogen atom to which they are attached, they form a group optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 A 3- to 10-membered heterocyclic group substituted with a haloalkyl group.

[0084] In some aspects, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0085] Each R 1 are independently halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0086] Each R 2 are independently halogen;

[0087] R 3 is -CN, -C(=O)OR b , or -C(=O)NR c R d ;

[0088] R 4 and R 6 Each occurrence is independently hydrogen;

[0089] m is an integer selected from 0, 1 or 2;

[0090] n is 0;

[0091] X is -O-;

[0092] Each R b independently hydrogen;

[0093] R c and R d are each independently hydrogen.

[0094] In certain embodiments, each R 1 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 6-14 Aryl.

[0095] In certain embodiments, at least one R 1 is a halogen (eg, F, Cl or Br).

[0096] In certain embodiments, at least one R1 It is F or Cl.

[0097] In certain embodiments, at least one R 1 It's F.

[0098] In certain embodiments, at least one R 1 It is Cl.

[0099] In certain embodiments, at least one R 1 It is C 1-6 Alkyl (eg, methyl, ethyl, or propyl).

[0100] In certain embodiments, at least one R 1 It's methyl.

[0101] In certain embodiments, at least one R 1 It is C 1-6 Alkoxy (eg, methoxy, ethoxy, or propoxy).

[0102] In certain embodiments, at least one R 1 It's a methoxy group.

[0103] In certain embodiments, at least one R 1 It is C 6-14 Aryl (eg, phenyl).

[0104] In certain embodiments, m is 0, 1 or 2.

[0105] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0106] In certain embodiments, each R 2 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0107] In certain embodiments, each R 2 is independently halogen (eg, F, Cl or Br).

[0108] In certain embodiments, each R 2 It's chlorine.

[0109] In certain embodiments, each R 2 Independently C 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0110] In certain embodiments, each R 2 It's methyl.

[0111] In certain embodiments, each R 2 Independently C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0112] In certain embodiments, each R 2 Independently C 2-6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0113] In certain embodiments, R 3 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- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0114] In certain embodiments, R 3 is a halogen (eg, F, Cl, or Br).

[0115] In certain embodiments, R 3 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), wherein the alkyl is optionally substituted by one or more R u replace.

[0116] In certain embodiments, R 3 It is C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0117] In certain embodiments, R 3 It is C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0118] In certain embodiments, R 3 It is C 1-6Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0119] In certain embodiments, R 3 It is C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0120] In certain embodiments, R 3 It is C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0121] In certain embodiments, R 3 It is C 6-14 Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0122] In certain embodiments, R 3 is a 5- to 14-membered heteroaryl group (e.g., pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl group is optionally substituted by one or more R u replace.

[0123] In certain embodiments, R 3 It is C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0124] In certain embodiments, R 3 is a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0125] In certain embodiments, R 3 Yes-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 Yes H, R c is H, and R d Yes H).

[0126] In certain embodiments, R 3 is -CN, -C(=O)OR b , or -C(=O)NR c R d .

[0127] In certain embodiments, R 3 Yes-CN.

[0128] In certain embodiments, each R c and R c It's H.

[0129] In certain embodiments, R 3 It is -C(=O)NH2.

[0130] In certain embodiments, Rb It's H.

[0131] In certain embodiments, R 3 It is -C(=O)OH.

[0132] In certain embodiments, R 4 It's hydrogen.

[0133] In certain embodiments, n is 0, 1, or 2.

[0134] In certain embodiments, n is 0.

[0135] In certain embodiments, R 6 It's hydrogen.

[0136] In certain embodiments, R 4 It 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- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0137] In certain embodiments, R 4 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), wherein the alkyl is optionally substituted by one or more R u replace.

[0138] In certain embodiments, R 4 It is C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0139] In certain embodiments, R 4 It is C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0140] In certain embodiments, R 4 It is C1-6 Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0141] In certain embodiments, R 4 It is C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0142] In certain embodiments, R 4 It is C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0143] In certain embodiments, R 4 It is C 6-14 Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0144] In certain embodiments, R 4 is a 5- to 14-membered heteroaryl group (e.g., pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl group is optionally substituted by one or more R u replace.

[0145] In certain embodiments, R 4 It is C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0146] In certain embodiments, R 4 is a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0147] In certain embodiments, R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0148] In certain embodiments, R 6 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), wherein the alkyl is optionally substituted by one or more R u replace.

[0149] In certain embodiments, R 6 It is C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0150] In certain embodiments, R 6 It is C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0151] In certain embodiments, R 6 It is C 1-6 Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0152] In certain embodiments, R 6 It is C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0153] In certain embodiments, R 6 It is C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0154] In certain embodiments, R 6 It is C 6-14Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0155] In certain embodiments, R 6 is a 5- to 14-membered heteroaryl group (e.g., pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl group is optionally substituted by one or more R u replace.

[0156] In certain embodiments, R 6 It is C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0157] In certain embodiments, R 6 is a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0158] 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- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0159] In certain embodiments, each R 5 is independently halogen (eg, F, Cl or Br).

[0160] In certain embodiments, each R 5 Independence is C 1-6 Alkyl (e.g., methyl, ethyl or propyl), wherein the alkyl is optionally substituted with one or more R u replace.

[0161] In certain embodiments, each R5 Independently C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0162] In certain embodiments, each R 5 Independently C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0163] In certain embodiments, each R 5 Independently C 1-6 Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0164] In certain embodiments, each R 5 Independently C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0165] In certain embodiments, each R 5 Independently C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0166] In certain embodiments, each R 5 Independently C 6-14 Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0167] In certain embodiments, each R 5 is independently a 5- to 14-membered heteroaryl (eg, pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl is optionally substituted by one or more R u replace.

[0168] In certain embodiments, each R 5 Independently C 3-10Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0169] In certain embodiments, each R 5 is independently a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0170] In certain embodiments, R 3 Yes-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 Yes H, Rc is H, and R d Yes H).

[0171] In certain embodiments, X is selected from -C(R 7 )2-、-O-、-NR 8 - and -S- (e.g., R 7 is H, halogen or C 1-6 alkyl; and R 8 Is H or C 1-6 alkyl).

[0172] In certain embodiments, X is selected from -CH2-, -CH(CH3)-, -CHCl-, -CHBr-, -NH-, or -NCH3-.

[0173] In certain embodiments, X is O.

[0174] In certain embodiments, R 7 It is 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- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0175] In certain embodiments, R 7 is a halogen (eg, F, Cl, or Br).

[0176] In certain embodiments, R 7 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), wherein the alkyl is optionally substituted by one or more R u replace.

[0177] In certain embodiments, R 7 It is C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0178] In certain embodiments, R7 It is C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0179] In certain embodiments, R 7 It is C 1-6 Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0180] In certain embodiments, R 7 It is C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0181] In certain embodiments, R 7 It is C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0182] In certain embodiments, R 7 It is C 6-14 Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0183] In certain embodiments, R 7 is a 5- to 14-membered heteroaryl group (e.g., pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl group is optionally substituted by one or more R u replace.

[0184] In certain embodiments, R 7 It is C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0185] In certain embodiments, R 7 is a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0186] In certain embodiments, R 7 Yes-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 Yes H, R c is H, and R d Yes H).

[0187] In certain embodiments, R 8 It 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 6-14Aryl, 5- to 14-membered heteroaryl, C 3-10 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u Substitution (e.g. R u is F, Cl, Br, I, -CN, -NO2, methyl or ethyl).

[0188] In certain embodiments, R 8 It is C 1-6 Alkyl (e.g., methyl, ethyl, or propyl), wherein the alkyl is optionally substituted by one or more R u replace.

[0189] In certain embodiments, R 8 It is C 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl or hexenyl), wherein the alkenyl is optionally substituted with one or more R u replace.

[0190] In certain embodiments, R 8 It is C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl), wherein the alkynyl is optionally substituted with one or more R u replace.

[0191] In certain embodiments, R 8 It is C 1-6 Haloalkyl (e.g., C 1-6 alkyl), wherein the haloalkyl is optionally substituted by one or more R u replace.

[0192] In certain embodiments, R 8 It is C 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl), wherein the hydroxyalkyl is optionally substituted by one or more R u replace.

[0193] In certain embodiments, R 8 It is C 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl), wherein the aminoalkyl group is optionally substituted by one or more R u replace.

[0194] In certain embodiments, R 8 It is C 6-14Aryl (e.g., phenyl or naphthyl), wherein the aryl group is optionally substituted by one or more R u replace.

[0195] In certain embodiments, R 8 is a 5- to 14-membered heteroaryl group (e.g., pyrrolyl, furanyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl), wherein the heteroaryl group is optionally substituted by one or more R u replace.

[0196] In certain embodiments, R 8 It is C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl), wherein the carbocyclic group is optionally substituted by one or more R u replace.

[0197] In certain embodiments, R 8 is a 3- to 10-membered heterocyclyl (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl), wherein the heterocyclyl is optionally substituted by one or more R u replace.

[0198] 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- to 14-membered heteroaryl, C 3-10 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0199] In certain embodiments, each R u is independently a halogen (eg, F, Cl, or Br).

[0200] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0201] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0202] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 2-6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0203] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 1-6 Haloalkyl (e.g., C 1-6 alkyl).

[0204] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl).

[0205] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl).

[0206] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 6-14 Aryl (eg, phenyl or naphthyl).

[0207] In certain embodiments, each R u is independently a 5- to 14-membered heteroaryl group optionally substituted with one or more of the substituents described above (eg, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl).

[0208] In certain embodiments, each R u is independently C optionally substituted by one or more of the above substituents 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0209] In certain embodiments, each R uis independently a 3- to 10-membered heterocyclyl group optionally substituted with one or more of the substituents described above (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl).

[0210] In certain embodiments, each R u 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 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 Yes H, R c is H, and R d Yes H).

[0211] In certain embodiments, both R u together to form an oxo group; or two R u Together with one or more atoms in between, they form C 6-14Aryl, 5- to 14-membered heteroaryl, C 3-10 a carbocyclic group, or a 3- to 10-membered heterocyclic group.

[0212] In certain embodiments, both R u Together with one or more atoms located between them (e.g. C) form C 6-14 Aryl (eg, phenyl or naphthyl).

[0213] In certain embodiments, both R u Together with one or more intervening atoms (eg N, O or S) form a 5- to 14-membered heteroaryl group (eg pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl).

[0214] In certain embodiments, both R u Together with one or more atoms located between them (e.g. C) form C 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0215] In certain embodiments, both 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).

[0216] In certain embodiments, each R a Independently 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- to 14-membered heteroaryl, C 3-10 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0217] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0218] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0219] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 2-6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0220] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 1-6 Haloalkyl (e.g., C 1-6 alkyl).

[0221] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl).

[0222] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl).

[0223] In certain embodiments, each R a Independently C 6-14 Aryl (eg, phenyl or naphthyl).

[0224] In certain embodiments, each R a is independently a 5- to 14-membered heteroaryl group optionally substituted with one or more of the substituents described above (eg, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl).

[0225] In certain embodiments, each R a is independently C optionally substituted by one or more of the above substituents 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0226] In certain embodiments, each R a is independently a 3- to 10-membered heterocyclyl group optionally substituted with one or more of the substituents described above (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl).

[0227] 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- to 14-membered heteroaryl, C 3-10 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0228] In certain embodiments, each R b are independently hydrogen.

[0229] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0230] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0231] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 2-6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0232] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 1-6 Haloalkyl (e.g., C 1-6 alkyl).

[0233] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl).

[0234] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl).

[0235] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 6-14 Aryl (eg, phenyl or naphthyl).

[0236] In certain embodiments, each R b is independently a 5- to 14-membered heteroaryl group optionally substituted with one or more of the substituents described above (eg, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl).

[0237] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0238] In certain embodiments, each R b is independently a 3- to 10-membered heterocyclyl group optionally substituted with one or more of the substituents described above (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl).

[0239] In certain embodiments, 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 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0240] In certain embodiments, R c and R dare each independently C optionally substituted by one or more of the above substituents 1-6 Alkyl (eg, methyl, ethyl or propyl).

[0241] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 2-6 alkenyl (e.g., ethynyl, propenyl, butenyl, pentenyl, or hexenyl).

[0242] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 2-6 Alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0243] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 1-6 Haloalkyl (e.g., C 1-6 alkyl).

[0244] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 1-6 Hydroxyalkyl (e.g., C 1-6 alkyl).

[0245] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 1-6 Aminoalkyl (e.g., C substituted with one or more amino groups) 1-6 alkyl).

[0246] In certain embodiments, R c and R d are each independently C optionally substituted by one or more of the above substituents 6-14 Aryl (eg, phenyl or naphthyl).

[0247] In certain embodiments, R c and R d Each is independently a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents as described above (eg, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl).

[0248] In certain embodiments, each R b is independently C optionally substituted by one or more of the above substituents 3-10 Carbocyclic groups (e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl).

[0249] In certain embodiments, R c and R d Each is independently a 3- to 10-membered heterocyclyl group optionally substituted with one or more of the substituents described above (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl).

[0250] In certain embodiments, R c , R d Together with the nitrogen atom to which they are attached, they form a group optionally substituted with one or more 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, they form a 3- to 10-membered heterocyclic group (eg, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl) optionally substituted with one or more substituents as described above.

[0251] In certain embodiments, the compound has Formula Ia,

[0252]

[0253] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0254] In certain embodiments, the compound is selected from the compounds described in Table 1, and pharmaceutically acceptable salts, stereoisomers, and solvates thereof.

[0255] In certain embodiments, the compound is selected from the compounds described in Table 1.

[0256] Table I

[0257]

[0258]

[0259]

[0260] Other forms of the compounds disclosed herein

[0261] Pharmaceutically acceptable salts

[0262] In some embodiments, the compounds disclosed herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0263] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a variety of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified free form of the compound with a suitable acid or base separately and isolating the salt thus formed.

[0264] Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with an inorganic acid, an organic acid, or an inorganic base, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butane-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexane-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, 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, toluenesulfonate, undeconate, and xylenesulfonate.

[0265] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and 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, Acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0266] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base such as a pharmaceutically acceptable hydroxide, carbonate, bicarbonate or sulfate of a metal cation, with ammonia or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, calcium and magnesium, and aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0267] Representative organic amines useful for forming 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-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0268] Solvate

[0269] 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 referred to as "solvates." For example, complexes with water are referred to as "hydrates." Solvates are within the scope of the present invention.

[0270] Those skilled in the art of organic chemistry will also appreciate that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary between solvates and solvates. Therefore, all crystalline forms or pharmaceutically acceptable solvates thereof are contemplated and are encompassed within the scope of the present invention.

[0271] In some embodiments, the compounds described herein exist as solvates. The present application provides methods for treating diseases by administering such solvates. The present application also provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0272] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcohol solvates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein can exist in non-solvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0273] Isomers / stereoisomers

[0274] 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."

[0275] In some embodiments, compounds described herein exist as geometric isomers. In some embodiments, compounds described herein have one or more double bonds. Compounds disclosed herein include all cis (cis), trans (trans), cis (syn), trans (anti), heterolateral (E) and homolateral (Z) isomers and their corresponding mixtures. All geometric forms of compounds disclosed herein are considered and are encompassed within the scope of the present invention.

[0276] In some embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds disclosed herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. All diastereoisomers, enantiomers and epimeric forms of the compounds disclosed herein are considered and are included within the scope of the present invention.

[0277] In other embodiments of the compounds and methods provided herein, the mixture of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used for applications described herein. In some embodiments, by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating diastereomers, and reclaiming optically pure enantiomers, the compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably separated by separation / resolving techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are subsequently recovered.

[0278] Tautomer

[0279] In some embodiments, the compounds described herein exist as tautomers.The compounds described herein include all possible tautomers within the formulas described herein.

[0280] Tautomers are compounds that are interconvertible by hydrogen atom migration associated with the conversion of single bonds and adjacent double bonds. In the bonding arrangements that may tautomerize, there is a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are considered and are encompassed within the scope of the present invention. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0281] Preparation of compounds

[0282] The compounds used in the reactions described herein are prepared 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" were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA); Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka); Apin Chemicals (Milton Park, UK); Avocado Research (Lancashire, UK); BDH (Toronto, Canada); Bionet (Cornwall, UK); Chem Service (West Chester, PA); Crescent Chemical (Hauppauge, NY); Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY); Fisher Scientific (Pittsburgh, PA); Fisons Chemicals (Leicestershire, UK); Frontier Scientific (Logan, UT); ICN Biomedicals (Costa Mesa, CA); Key Organics (Cornwall, UK); Lancaster Synthesis (Windham, NH); Maybridge Chemical (Cornwall, UK); Parish Chemical (Orem, UT); Pfaltz & Bauer (Waterbury, CN); Polyorganix (Houston, TX); Pierce Chemical (Rockford, IL); Riedel de Haen (Hanover, Germany); Spectrum Quality Products (New Brunswick, NJ); TCI America (Portland, OR); Trans World Chemicals (Rockville, MD); and Wako Chemicals USA (Richmond, VA).

[0283] Suitable reference books and papers that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions", 2nd Ed., WA 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. Other suitable reference books and papers that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (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 Edition (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. (editor), "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, T.W.G., "Organic Chemistry" 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "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, 8 volumes in total; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes in total.

[0284] Specific and similar reactants may optionally be identified by an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, as well as by online identification. Chemicals known in the catalog but not commercially available are optionally prepared by custom chemical synthesis agencies, many of which provide custom synthesis services for standard chemical supply agencies (such as those listed above). References for the preparation and selection of pharmaceutical salts of the compounds described herein are P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0285] Using LanthaScreen TM The TR-FRET TRα or β coactivator assay kit (ThermoFIsher) was used to perform thyroid hormone receptor β and thyroid hormone receptor α coactivator recruitment assays. The control agonist 3,3',5-triiodo-L-thyronine sodium salt T3 (SIGMA) was used to validate the assay. The test compound and / or vehicle was incubated with TRαLBD-GST or TRβLBD-GST and coactivator peptide (fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO: 1)) at RT for 30 minutes. The amount of complex formed was read by fluorescence spectroscopy (excitation: 337nm, emission: 520 / 490nm) on a PHERAstar FS instrument (BMG). EC50 values ​​were calculated using an increase in fluorescence induced by the test compound that was greater than 50% relative to the T3 response. Compounds were screened at 30, 10, 3, 1, 0.3, 0.1 and 0.03 μM.

[0286] Pharmaceutical composition

[0287] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) based on the selected route of administration and, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 stSelection was based on standard pharmaceutical practice as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0288] Therefore, the present application provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0289] In some embodiments, the compound described herein is substantially pure, wherein it contains 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 synthesis byproducts produced in one or more steps of the synthetic method.

[0290] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration and frequency of application will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the concrete form of the active ingredient and the method of administration. Usually, suitable dosage and treatment regimen provide compositions in an amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical results, such as more frequent complete or partial remission, or longer disease-free and / or overall survival, or the alleviation of symptom severity). Optimal dose is usually determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0291] 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 application 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 tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, ointments, lotions, eye drops or ear drops. In some embodiments, the pharmaceutical composition is formulated into tablets.

[0292] Suitable dosages and dosing regimens are determined by conventional range determination techniques known to those of ordinary skill in the art. Typically, treatment is started with a smaller dose that is less than the optimal dose of the compound disclosed herein. Thereafter, the dose is increased in small increments until the optimal effect in the case is achieved. In some embodiments, the methods of the present invention involve administering about 0.1 μg to about 50 mg of at least one compound described herein per kg of individual body weight. For a 70 kg patient, a dose of about 10 μg to about 200 mg of the compound disclosed herein is more typically used, depending on the individual's physiological response.

[0293] Treatment

[0294] In one aspect, the present application provides a method of activating thyroid hormone receptor (THR) β in a patient or a biological sample, the method comprising contacting the patient or the biological sample with a compound described herein or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

[0295] In one aspect, the present application provides a method of treating a liver disease or disorder or a lipid disease or disorder, the method comprising administering to a patient in need thereof a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0296] In certain embodiments, the liver disease or disorder is nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or fatty liver disease.

[0297] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), or high low-density lipoprotein (LDL).

[0298] In certain embodiments, the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

[0299] In another aspect, the present application provides use of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, in the preparation of a medicament for treating a liver disease or disorder or a lipid disease or disorder.

[0300] In certain embodiments, the liver disease or disorder is NAFLD, NASH, or fatty liver disease.

[0301] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.

[0302] In certain embodiments, the hypercholesterolemia is HeFH or HoFH.

[0303] In yet another aspect, the present application provides a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, for use in treating a liver disease or disorder, or a lipid disease or disorder.

[0304] In certain embodiments, the liver disease or disorder is NAFLD, NASH, or fatty liver disease.

[0305] In certain embodiments, the lipid disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.

[0306] In certain embodiments, the hypercholesterolemia is HeFH or HoFH.

[0307] Synthesis of compounds

[0308] In some aspects, the present application provides methods of preparing the compounds disclosed herein.

[0309] In some aspects, the present application provides methods of preparing a compound comprising one or more steps as described herein.

[0310] In some aspects, the application provides compounds obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein.

[0311] In some aspects, the application provides intermediates suitable for use in the methods of preparing the compounds described herein.

[0312] In embodiments, the compounds described herein are prepared according to the following Scheme 1, Scheme 2 or Scheme 3:

[0313] Route 1:

[0314]

[0315] Route 2:

[0316]

[0317] Route 3:

[0318]

[0319] The compounds of the present application can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0320] In the descriptions of synthetic methods described herein, as well as in any referenced synthetic methods for preparing starting materials, it is 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 skilled in the art.

[0321] Those skilled in the art of organic synthesis will appreciate that the functionality present on the various parts of the molecule must be compatible with the reagents and reaction conditions employed.

[0322] It should be understood that during the synthesis of the compounds of this application in the method defined herein, or during the synthesis of some starting materials, it may be necessary to protect certain substituents to prevent their undesirable reactions. A skilled chemist will understand when such protection is needed, and how such a protecting group is placed in the appropriate position, and then removed. For the example of protecting groups, please refer to one of the many general texts on this theme, such as Theodora Green's "Protective Groups in Organic Synthesis" (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to skilled chemists suitable for removing the protecting groups in question, and such methods are selected to realize the removal of protecting groups, while the interference of groups elsewhere in the molecule is minimal. Therefore, if reactant includes, for example, a group such as an amino, carboxyl or hydroxyl group, it may be necessary to protect the group in some reactions mentioned herein.

[0323] The resulting compounds of the present application can be isolated and purified using techniques well known in the art.

[0324] In addition, by utilizing the procedures described herein, in combination with ordinary skills in the art, additional compounds of the present application can be easily prepared. Those skilled in the art will readily appreciate that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0325] As will be understood by those skilled in the art of organic synthesis, the compounds of the present application are easily obtained by various synthetic routes, some of which are illustrated in the attached examples. Those skilled in the art will readily recognize what type of reagent and reaction conditions will be used to obtain the compounds of the present application, and how to apply and adjust them in any particular case (whether necessary or useful). In addition, some compounds of the present application can be easily synthesized by reacting other compounds of the present application under suitable conditions, such as by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions, a specific functional group present in the compounds of the present application or its suitable precursor molecules is converted into another functional group; these methods are well known to those skilled in the art. Similarly, technicians will apply synthetic protection (or protective) groups when necessary or useful; suitable protection groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, and are described in more detail in, for example, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0326] Biological assays

[0327] Once the compounds designed, selected and / or optimized by the above methods are produced, they can be characterized using a variety of assays known to those skilled 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 described below, to determine whether they have the predicted activity, binding activity and / or binding specificity.

[0328] In addition, high throughput screening can be used to accelerate the analysis using such assays. Therefore, the activity of the molecules described herein can be quickly screened using techniques known in the art. General methods for performing high throughput screening are described in, for example, 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.

[0329] In some embodiments, the biological assay is performed using a thyroid hormone receptor beta and / or thyroid hormone receptor alpha coactivator recruitment assay.

[0330] In some embodiments, 3,3',5-triiodo-L-thyronine sodium salt, T3, is used as a control agonist to validate the assay.

[0331] In some embodiments, the test compound and / or vehicle is incubated with TRαLBD-GST or TRβLBD-GST and the coactivator peptide for 30 minutes at room temperature.

[0332] In some embodiments, the coactivator peptide is fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO: 1)).

[0333] In some embodiments, the amount of complex formed is determined by fluorescence spectroscopy reading (eg, excitation: 337 nm, emission: 520 / 490 nm).

[0334] In some embodiments, the test compound induces an increase in fluorescence that is greater than 10, 20, 30, 40, 50, 60, 70, 80, or 90% relative to the T3 response.

[0335] In some embodiments, the EC is calculated using an increase in fluorescence induced by a test compound that is greater than 50% relative to the T3 response. 50 value.

[0336] In some embodiments, compounds are screened at 30, 10, 3, 1, 0.3, 0.1, or 0.03 μM.

[0337] definition

[0338] As used in the specification and the appended claims, the following terms have the following indicated meanings unless indicated to the contrary.

[0339] Chemical Definition

[0340] 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 therein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCHPublishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0341] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EF Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0342] The present invention additionally encompasses the compounds described herein as an individual isomer substantially free of other isomers or as mixtures of various isomers.

[0343] When a numerical range is listed, it is intended to include every value and sub-range within that range. For example, "C 1-6 "Alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.

[0344] The following terms are intended to have the meanings given below, and can be used to understand the description and expected scope of the present invention. When describing the present invention, it may include compounds, pharmaceutical compositions containing such compounds, and methods using such compounds and compositions, unless otherwise specified, the following terms (if present) have the following meanings. It should also be understood that, when described in this article, any group defined below may be substituted by various substituents, and the corresponding definitions are intended to include such substituted groups within their scope as described below. Unless otherwise specified, the term "substituted" is defined as follows. It should also be understood that, when used in this article, the terms "group" and "atomic radical" may be considered interchangeable. The articles "a" and "a kind of" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an analogue" refers to an analogue or more than one analogue.

[0345] "Alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an 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, an alkyl group has 1 to 9 carbon atoms (“C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 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-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise indicated, each instance of alkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, alkyl is unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0346] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, such as 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)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-), and the like.

[0347] "Alkenyl" refers to a straight or branched chain hydrocarbon radical 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). 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the above-mentioned C 2-4 In some embodiments, alkenyl is an unsubstituted C 1-4- substituted ... 2-10 In certain embodiments, alkenyl is a substituted C 2-10 Alkenyl.

[0348] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, vinylene (-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 vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (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.

[0349] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C") 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). 2-20 In some embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 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 the alkenyl group include the above-mentioned C 2-4Alkynyl and pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"); for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, alkynyl is unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0350] "Alkyne" refers to a straight chain alkynyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Exemplary divalent alkynyl groups include, but are not limited to, substituted or unsubstituted ethynyl, substituted or unsubstituted propynyl, and the like.

[0351] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 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 (“heteroalkyl”). 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 (“heteroalkyl”). 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 (“heteroalkyl”). 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroalkyl”). 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroalkyl”). 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-2In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2-6 Unless otherwise specified, each instance of heteroalkyl is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, heteroalkyl is an unsubstituted heteroalkyl. 1-10 In certain embodiments, heteroalkyl is substituted heteroC 1-10 alkyl.

[0352] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2-10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 In some embodiments, a heteroalkenyl group has 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 1 heteroatom (“heteroC 2-3 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl group”) or substituted (a “substituted heteroalkenyl group”) with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, heteroalkenyl is a substituted heteroC 2-10 Alkenyl.

[0353] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl"). 2-10 In 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, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 In some embodiments, a heteroalkynyl group has 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 1 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 (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroalkynyl group. 2-10 In certain embodiments, heteroalkynyl is substituted heteroC 2-10 Alkynyl.

[0354] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, 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 straight carbon divalent chain. "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents described herein.

[0355] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) radical having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "aryl"; e.g., anthracenyl).

[0356] "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, Coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalbenzene, penta-2,4-diene, pentacene, cyclopentadiene, pentaphene, perylene, phenazone, phenanthracene, phenanthracene, pyrene, pyranthracene, rubyne, terphenylene and ternaphthylene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C 6-14In certain embodiments, aryl is substituted C 6-14 Aryl.

[0357] In certain embodiments, aryl is replaced by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, hydroxyl, C 1-6 Alkoxy and amino groups are substituted.

[0358] "Fused aryl" refers to an aryl group that has two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0359] "Aralkyl" is a subset of alkyl and aryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0360] "Heteroaryl" refers to a group of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in common in the cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

[0361] "Heteroaryl" also includes a ring system in which a heteroaromatic ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the point of attachment is on the heteroaromatic ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaromatic ring system. "Heteroaryl" also includes a ring system in which a heteroaromatic ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaromatic ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0362] In some embodiments, heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In some embodiments, heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, heteroaryl is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") by one or more substituents. In certain embodiments, heteroaryl is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-membered to 14-membered heteroaryl group.

[0363] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, pyridinyl. 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, azepine, oxapine, and thiapine. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0364] "Heteroaralkyl" is a subset of alkyl and heteroaryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0365] "Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon radical having 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("Carbocyclyl"). 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, a 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 Carbocyclic groups include, but are 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 Carbocyclic groups include but are not limited to the above C 3-6Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the above C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 )wait.

[0366] As described in the foregoing examples, in certain embodiments, carbocyclyl is a monocycle ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclyl ring, and in such a case, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise indicated, each example of carbocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0367] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl ("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) 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the cycloalkyl group include the above-mentioned C 5-6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, cycloalkyl is unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0368] "Heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits.

[0369] The heterocyclic radical can be a monocyclic ("monocyclic heterocyclic radical") or a fused, bridged or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclic radical"), and can be saturated or can be partially unsaturated. The heterocyclic bicyclic ring system can include one or more heteroatoms in one or both rings. "Heterocyclic radical" also includes a ring system in which the heterocyclic ring as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic or heterocyclic ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. "Heterocyclic radical" also includes a ring system in which the heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Unless otherwise indicated, each instance of a heterocyclic radical is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic radical") or substituted ("substituted heterocyclic radical") by one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0370] In some embodiments, heterocyclyl is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, heterocyclyl is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0371] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiocanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dialkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0372] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, sulfur, boron, phosphorus and silicon heteroatoms, as long as the valence permits. Hetero can be applied to any hydrocarbon group having 1 to 5, especially 1 to 3 heteroatoms as described above.

[0373] "Acyl" refers to the group -C(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, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are 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).

[0374] "Acylamino" refers to the group -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, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are as defined herein. Exemplary "acylamino" include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino.

[0375] "Acyloxy" refers to the group -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, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.

[0376] "Alkoxy" refers to a group -OR, where R is a 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, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are as defined herein. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, for example, having 1 to 6 carbon atoms. More specific alkoxy groups have between 1 and 4 carbon atoms.

[0377] "Azide" refers to the group -N3.

[0378] "Carbamoyl" or "amido" refers to the group -C(=O)NH2.

[0379] "Amino" refers to the group -NH2.

[0380] "Oxo" refers to =0.

[0381] "Thioketo" refers to the group =S.

[0382] "Carboxy" refers to the group -C(=O)OH.

[0383] "Cyano" refers to the radical -CN.

[0384] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is fluoro or chloro.

[0385] "Hydroxy" refers to the radical -OH.

[0386] "Nitro" refers to the radical -NO2.

[0387] These and other exemplary substituents are described in greater detail in the Detailed Description, Examples, and Claims.The present invention is not intended to be limited in any manner by the foregoing list of exemplary substituents.

[0388] Other definitions

[0389] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government, or equivalent agencies in countries outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans.

[0390] "Pharmaceutically acceptable salt" refers to a salt of the 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. Specifically, such salts include: (1) acid addition salts, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or 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-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions; or salts formed by coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0391] "Solvate" refers to a form of a compound that is associated with a solvent or water (also referred to as a "hydrate"), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention can be prepared, for example, in a crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0392] 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."

[0393] 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, 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 and described by the R- and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and are designated as right- or left-handed (i.e., (+)- or (-)-isomers, respectively). A chiral compound can exist as an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0394] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and differ in the replacement of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium by the movement of electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomeric forms can be relevant to the achievement of optimal chemical reactivity and biological activity of the compound of interest.

[0395] As used herein, an enantiomerically pure compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., 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 relative to the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound 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 the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0396] Unless otherwise indicated, the term "enantiomerically pure (R)-compound" as used herein refers to at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and up to about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (S)-compound and up to about 0.1% by weight of the (S)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0397] Unless otherwise indicated, the term "enantiomerically pure (S)-compound" or "(S)-compound" as used herein refers to at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and up to about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and up to about 0.1% by weight of the (R)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0398] In the compositions provided herein, the enantiomerically pure compound or its pharmaceutically acceptable salt, solvate or hydrate may be present 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 an excipient and about 10% by weight of an enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may, for example, comprise at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound by 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 an excipient and about 10% by weight of an enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may, for example, contain at least about 95 weight % of the (S)-compound based on the total weight of the compound and up to about 5 weight % of the (R)-compound based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

[0399] The compounds of the present invention may possess one or more asymmetric centers; such compounds may therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0400] 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 other, thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0401] "Individuals" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric individuals (e.g., infants, children, adolescents) or adult individuals (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the individual is a human. In certain embodiments, the individual is a non-human animal. The terms "human," "patient," and "individual" are used interchangeably herein.

[0402] "Effective amount" refers to the amount of a compound that, when administered to an individual to treat or prevent a disease, is sufficient to achieve such treatment or prevention. "Effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the individual to be treated. "Therapeutically effective amount" refers to an effective amount for therapeutic treatment. "Prophylactically effective amount" refers to an effective amount for preventive treatment.

[0403] "Prevention," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or condition (i.e., causing at least one clinical symptom of a disease not to develop in an individual who has not been exposed to the disease-causing agent or who is susceptible to the disease prior to the onset of the disease).

[0404] In one embodiment, "treatment" or "therapeutic treatment" of any disease or condition refers to ameliorating the disease or condition (i.e., preventing the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treatment" refers to improving at least one physical parameter that may not be discernible by the individual. In another embodiment, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In another embodiment, "treatment" involves slowing the progression of the disease.

[0405] When referring to a number or a numerical range, the term "about" refers to the number or numerical range referred to plus or minus a certain percentage of the value, such as 5%, 10% or 15% of the value. For example, about 100 includes 95 to 105, 90 to 110, or 85 to 115.

[0406] The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude other specific embodiments, such as embodiments of any composition of matter, composition, method or process, etc. described herein, "consisting of" or "consisting essentially of" the described features.

[0407] The phrase "and / or" as used herein in the specification and claims should be understood to refer to "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately 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 combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising", "A and / or B" may refer to only A (optionally including elements other than B) in one embodiment; to only B (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in another embodiment; and so on.

[0408] As used herein in the 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" should be interpreted as inclusive, i.e., including at least one of a plurality or listed elements, but also including more than one, and optionally other unlisted items. Only terms that clearly indicate the opposite, such as "only one" or "exactly one", or "consisting of..." used in the claims, refer to only one element in a list of one or more elements. Generally, the term "or" used in this article should only be interpreted as indicating exclusive substitution (i.e., "one or the other but not both") when preceding an exclusive term, such as "either", "one of them", "only one of them", or "exactly one of them". When used in the claims, "consisting essentially of..." should have the ordinary meaning used in the field of patent law.

[0409] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements referred to by the phrase "at least one" may optionally be present, whether or not they are related to those specifically identified. Thus, as a non-limiting example, "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") may refer to at least one A, optionally including more than one A, with no B (and optionally including elements other than B) in one embodiment; at least one B, optionally including more than one B, with no A (and optionally including elements other than A) in another embodiment; at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements) in another embodiment; and so on.

[0410] Although the present invention has been described in conjunction with various embodiments and examples, the present invention is not intended to be limited to these embodiments or examples. On the contrary, the present invention includes various substitutions, modifications and equivalents that will be understood by those skilled in the art.

[0411] Although various inventive embodiments have been described and illustrated herein, a person of ordinary skill in the art will readily appreciate a variety of other means and / or structures for performing functions and / or obtaining results and / or one or more advantages described herein, and each of these changes and / or modifications is considered to be within the scope of the inventive embodiments described herein. More generally, it will be readily understood by those skilled in the art that all parameters, dimensions, materials, and configurations described herein are exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on the specific application in which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents of the specific inventive embodiments described herein. Therefore, it should be understood that the foregoing embodiments are given only by way of example, and within the scope of the appended claims and their equivalents, embodiments of the present invention may be implemented in a manner different from that specifically described and claimed. The inventive embodiments of the present application relate 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, if these features, systems, articles, materials, kits, and / or methods are not mutually contradictory, is included within the scope of the invention of the present application.

[0412] The claims should not be construed as limited to the described order or elements unless indicated to that effect. It should be understood that various changes in form and details may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments falling within the spirit and scope of the following claims and their equivalents are claimed. Example

[0413] In order to more fully understand the invention described herein, 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 in any way as limiting the scope thereof.

[0414] Example 1 - Synthesis Procedure

[0415] 4-(2,6-Dichloro-4-nitrophenoxy)phthalazin-1(2H)-one (Compound 7g)

[0416]

[0417] Potassium carbonate (2.60g, 18.50mmol) was added to a solution of phthaloyl hydrazide (compound 4g, 2.00g, 12.33mmol) and compound 5 (1.81g, 8.63mmol) in DMF (20mL), and the mixture was stirred at room temperature for 3 hours, and then the reaction was quenched with water (60mL). The resulting suspension was filtered. The filter cake was washed with water (20mL) and dried under vacuum for 24 hours to obtain crude compound 3 (2.98g), which was further purified by slurrying in ethyl acetate to obtain compound 7g as an off-white solid (2.20g, yield: 50%).

[0418] Compound 7g: 1 H NMR (600MHz, DMSO-d6) δ12.09(s,1H),8.55(s,2H),8.32(d,J=7.5Hz,1H),8.23(d,J=7.8Hz,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 for C 14 H8Cl2N3O4[M+H + ]m / z=352.

[0419] 4-(4-Amino-2,6-dichlorophenoxy)phthalazin-1(2H)-one (Intermediate Fg)

[0420]

[0421] 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 with nitrogen twice and then stirred at room temperature for 5 hours under a hydrogen atmosphere. The mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness to give Intermediate Fg as a light brown solid (0.098 g, 107%).

[0422] Intermediate Fg: 1 H NMR(600MHz,DMSO-d6)δ11.86(s,1H),8.28(d,J=7.7Hz,1H),8.19(d,J=7.8H z,1H),8.05–8.01(m,1H),8.00–7.95(m,1H),6.71(s,2H),5.64(s,2H,NH2). 13 CNMR (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, for C 14 H 10 Cl2N3O2[M+H + ]m / z=322.

[0423] (E,Z)-(2-cyano-3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)acryloyl)urethane ethyl ester (Intermediate Gg)

[0424]

[0425] Compound 9 (0.97 g, 4.57 mmol) was added to a solution of intermediate Fg (0.50 g, 20 1.55 mmol) in ACN (10 mL). The mixture was warmed to 80 ° C for 5 hours. 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 hours to give an inseparable mixture of E, Z isomers of intermediate Gg as an off-white solid (0.52 g, yield: 69%).

[0426] Intermediate Gg: 1H NMR (600 MHz, DMSO-d6, major 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 = 7.1 Hz, 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 for C 21 H 15 Cl2N5O5[M+H + ]m / z=488.

[0427] 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)

[0428]

[0429] Intermediate 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 obtain compound g containing trace amounts of acetic acid as an off-white solid (0.040 g, yield: 22%).

[0430] Next, compound g (0.014 g, 0.032 mmol) containing traces of acetic acid was 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, yield: 55%).

[0431] Compound g: 1H NMR(600MHz,DMSO-d6)δ12.31(s,1H),12.05(s,1H),8.92(s,1H),8.32(d,J=7.7Hz,1 H), 8.25 (d, J = 7.8Hz, 1H), 8.09 (t, J = 7.2Hz, 1H), 8.03 (t, J = 7.2Hz, 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 for C 21 H 13 Cl2N6O4[M+ACN+H + ]m / z=483.

[0432] 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)

[0433]

[0434] Route A. 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

[0435] a. Synthesis of hydrazine reaction

[0436]

[0437] Sodium acetate (2.70 g, 33.0 mmol) is 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) is then added dropwise and stirred for 15 min. The mixture is warmed to 80-90 ° C for 18 hours. The solid is filtered and washed with water. The solid is then treated with KOH aqueous solution to dissolve the desired product and solid impurities are filtered out. HCl is added dropwise to the aqueous mother liquor until pH ~ 3.5, and then the solid is filtered. The solid is separated and vacuum dried for 24 hours to obtain compound 4a as a white solid (4.53 g, yield: 84%).

[0438] Compound 4a: 1H NMR (600 MHz, DMSO-d6) δ11.66 (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, for C8H5ClN2O2 [M+H + ]m / z=197).

[0439] b.Synthesis of SnAr reaction

[0440]

[0441] Potassium bicarbonate (0.928g, 9.27mmol) is added to a solution of 3-chlorophthalic acid hydrazide (compound 4a, 1.49g, 7.60mmol) and compound 5 (0.807g, 3.84mmol) in DMSO (100mL), and the mixture is stirred at room temperature for 24 hours, and then the reaction is quenched with water (180mL). The resulting suspension is filtered. The filter cake is washed with water (20mL) and dried under vacuum for 24 hours to obtain crude compound 7a, which is further purified by slurrying in ethyl acetate to obtain compound 7a as an off-white solid (1.04g, yield: 74%).

[0442] 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, for C 14 H6Cl3N3O4[M+H + ]m / z=386)

[0443] c. Synthesis by reduction reaction

[0444]

[0445] Palladium / 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 hours under a hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give intermediate Fa as a light brown solid (0.071 g, 87.8%). Intermediate Fa: 1 HNMR (600MHz, DMSO-d6) 1H 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, for C 14 H8Cl3N3O2[M+H + ]m / z=356.

[0446] d. Synthesis by condensation reaction

[0447]

[0448] Compound 9 (56.4 mg, 0.26 mmol) was added to a solution of intermediate Fa (34.9 mg, 0.10 mmol) in DMF (1.0 mL). The mixture was warmed to 60 ° C for 3.5 hours. 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 hours to obtain an inseparable mixture of E, Z isomers of intermediate Ga as an off-white solid (47.7 mg, yield: 86). Intermediate Ga: 1 H NMR (600MHz, DMSO-d6) δ12.00(s,1H),10.61(d,J=13.4Hz,1H),10.47(s,1H),8.48(d,J=13.5Hz,1H),8. 20(dd,J=7.6,1.6Hz,1H),8.04–7.98(m,2H),7.79(s,2H),4.15(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H). LRMS, for C 21 H 14 Cl3N5O5[M+H + ]m / z=522.

[0449] e. Synthesis by cyclization reaction

[0450]

[0451] Intermediate 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 hours. 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%).

[0452] Compound a: 1H NMR(600MHz,DMSO-d6),δ12.00(s,1H),10.61(d,J=13.4Hz,1H),10.47(s,1H),8.48(d,J=13.5Hz,1H),8 .20(dd,J=7.6,1.6Hz,1H),8.04–7.98(m,2H),7.79(s,2H),4.15(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H). LRMS, for C 19 H8Cl3N5O4[M+H + ]m / z=476.

[0453] 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)

[0454]

[0455] Route B. 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

[0456] a. Synthesis of hydrazine reaction

[0457]

[0458] 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 hours. The solid was filtered, washed with water, and vacuum dried for 24 hours to obtain compound 4b as a white solid (5.13 g, yield: 95%).

[0459] Compound 4b: 1 H NMR (600 MHz, DMSO-d6) δ11.57 (s, 2H), 7.89 (p, J = 6.5 Hz, 2H), 7.69–7.62 (m, 1H). LRMS for C8H5FN2O2 [M+H + ]m / z=181.

[0460] b.Synthesis of SnAr reaction

[0461]

[0462] 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 hours, and the reaction was then 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 obtain crude compound 7b (2.8242 g), which was further purified by slurrying in ethyl acetate to obtain compound 7b as an off-white solid (501 g, yield: 16%).

[0463] 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, for C 14 H6Cl2FN3O4[M+H + ]m / z=370.

[0464] c. Synthesis by reduction reaction

[0465]

[0466] 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 with nitrogen twice and then stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give intermediate Fb as a light brown solid (0.283 g, 100%).

[0467] Intermediate Fb: 1 H NMR (600MHz, DMSO-d6) δ11.89(s,1H),8.04(td,J=8.0,4.5Hz,1H),8.00(dd,J=8.0,1.3Hz,1H),7.78–7.73(m,1H),6.70(s,2H),5.65(s,2H). LRMS, for C 14 H8Cl2FN3O2[M+H + ]m / z=340.

[0468] d. Synthesis by condensation reaction

[0469]

[0470] Compound 9 (91.8 mg, 0.43 mmol) was added to a solution of intermediate Fb (50.7 mg, 0.15 mmol) in DMF (1 mL). The mixture was warmed to 60 ° C for 2 hours. 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 hours to give an inseparable mixture of E, Z isomers of intermediate Gb as a yellow solid (53.3 mg, yield: 76%).

[0471] Intermediate Gb: 1 H NMR (600MHz, DMSO-d6) δ11.97(s,1H),10.61(d,J=13.5Hz,1H),10.47(s,1H),8.48(d,J=13.5Hz,1H),8.08(td,J=8.0 ,4.5Hz,1H),8.04(d,J=6.7Hz,1H),7.94(d,J=12.6Hz,1H),7.79(s,2H),4.15(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H). LRMS, for C 21 H 14 Cl2FN5O5[M+H + ]m / z=506.

[0472] e. Synthesis by cyclization reaction

[0473]

[0474] Intermediate Gb (38.5 mg, 0.078 mmol) is added to a solution containing potassium acetate (19.8 mg, 0.20 mmol), MeOH (1.0 mL) and water (1.0 mL). The mixture is purged with N2, the flask is sealed, and heated to 60 ° C for 2.5 hours. The resulting suspension is cooled, water (2.0 mL) is added and filtered. The filter cake is washed with water and then dried in a vacuum oven to obtain compound b as an off-white solid (12.1 mg, yield: 34%).

[0475] Compound b: 1 H NMR(600MHz,DMSO-d6)δ12.32(s,1H),12.01(s,1H),8.92(s,1H),8.10(dt,J=8.0, 4.0Hz, 1H), 8.06 (dd, J = 8.0, 1.3Hz, 1H), 7.92 (s, 2H), 7.80 (dd, J = 10.0, 8.0Hz, 1H). LRMS, for C 19 H8Cl2FN5O4[M+H +]m / z=460.

[0476] 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)

[0477]

[0478] Route C. 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

[0479] a. Synthesis of hydrazine reaction

[0480]

[0481] 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 hours. The solid was filtered and washed with water. Water was then added to the solid and 5 M KOH was added until pH ~ 11, the residual solid was filtered out and discarded. The mother liquor was then acidified to ~ 2, and the formed solid was then filtered. The filtered solid was then vacuum dried for 24 hours to obtain compound 4c as a white solid (411 mg, yield: 96%).

[0482] Compound 4c: 1 H NMR (600 MHz, DMSO-d6) δ7.90 (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 for C9H8N2O2 [M+H + ]m / z=177.

[0483] b.Synthesis of SnAr reaction

[0484]

[0485] Potassium bicarbonate (263mg, 2.63mmol) was added to a solution of 3-methylphthalic hydrazide (compound 4c, 350mg, 1.79mmol) and compound 5 (226mg, 1.08mmol) in DMSO (150mL), and the mixture was stirred at room temperature for 24 hours, and then quenched with water (60mL). The resulting suspension was filtered. The filter cake was washed with water (20mL) and dried under vacuum for 24 hours to obtain crude compound 7g, which was further purified by slurrying in ethyl acetate to obtain compound 7c as an off-white solid (281g, yield: 70%).

[0486] Compound 7c: 1 H 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, for C 15 H9Cl2N3O4[M+H + ]m / z=366.

[0487] c. Synthesis by reduction reaction

[0488]

[0489] 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 with nitrogen twice and then stirred at room temperature for 24 hours under a hydrogen atmosphere. The mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness to give intermediate Fc as a light brown solid (215 mg, 83%).

[0490] Intermediate 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, for C 15 H 11 Cl2N3O2[M+H + ]m / z=336.

[0491] d. Synthesis by condensation reaction

[0492]

[0493] Compound 9 (65.4 mg, 0.31 mmol) was added to a solution of intermediate Fc (36.3 mg, 0.11 mmol) in DMF (2 mL). The mixture was warmed to 80 ° C for 5 hours. The mixture was cooled and the resulting suspension was filtered. The resulting suspension was cooled, water (2.0 mL) was added and filtered. The filter cake was washed with water and then dried in a vacuum oven to obtain intermediate Gc as a light yellow solid (36.2 mg, yield: 97%).

[0494] Intermediate Gc: 1 H NMR (600MHz, DMSO-d6) δ11.78(s,1H),10.60(d,J=13.5Hz,1H),10.47(s,1H),8.48(d,J=13.5Hz,1H),8.05(d,J=7.8Hz,1 H), 7.91 (d, J = 7.9Hz, 1H), 7.79 (s, 2H), 7.76 (d, J = 7.4Hz, 1H), 4.15 (q, J = 7.1Hz, 2H), 2.86 (s, 3H), 1.25 (t, J = 7.1Hz, 3H). LRMS, for C 22 H 17 Cl2N5O5[M+H + ]m / z=502.

[0495] e. Synthesis by cyclization reaction

[0496]

[0497] Intermediate Gc (30.6 mg, 0.06 mmol) is added to a solution containing potassium acetate (13.6 mg, 0.14 mmol), MeOH (1.0 mL) and water (1.0 mL). The mixture is purged with N2, the flask is sealed, and heated to 80 ° C for 5 hours. The resulting suspension is cooled, and water (2.0 mL) is added and filtered. The filter cake is washed with water and then dried in a vacuum oven to obtain compound c as a light yellow solid (12.0 mg, yield: 44%).

[0498] Compound c: 1 H 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, for C 20 H 11 Cl2N5O4[M+H +]m / z=456.

[0499] 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)

[0500]

[0501] Route D. 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

[0502] a. Synthesis of hydrazine reaction

[0503]

[0504] 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 hours. The solid was filtered and washed with water. The solid was then treated with KOH aqueous solution to dissolve the desired product and filter out solid impurities. HCl was added dropwise to the aqueous mother liquor until pH ~ 3.5, and then the solid was filtered. The solid was separated and vacuum dried for 24 hours to obtain compound 4d as a white solid (3.31 g, yield: 96%).

[0505] Compound 4d: 1 H NMR (600 MHz, DMSO-d6) δ11.89 (s, 2H), 8.19 (s, 2H). LRMS for C8H4Cl2N2O2 [M+H + ]m / z=230.

[0506] b.Synthesis of SnAr reaction

[0507]

[0508] Potassium bicarbonate (421mg, 4.1mmol) is added to a solution of 4,5-dichlorophthalic acid hydrazide (compound 4d, 290.1mg, 1.26mmol) and compound 5 (375mg, 1.79mmol) in DMSO (100mL), and the mixture is stirred at room temperature for 48 hours, and then the reaction is quenched with water (60mL). The resulting suspension is filtered. The filter cake is washed with water (20mL) and dried under vacuum for 24 hours to obtain crude compound 7d, which is further purified by column chromatography (2-10% MeOH / DCM) to obtain compound 7d as an off-white solid (310mg, yield: 43%).

[0509] Compound 7d: 1 H NMR (600MHz, DMSO-d6) δ12.33 (s, 1H), 8.58 (s, 2H), 8.51 (s, 1H), 8.45 (s, 1H). LRMS, for C14H5Cl4N3O4 [M+MeCN+H + ]m / z=461.

[0510] c. Synthesis by reduction reaction

[0511]

[0512] Palladium / 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 with nitrogen twice and then stirred at room temperature for 20 hours 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 intermediate Fd, which was light yellow (41.6 mg, 15%).

[0513] Intermediate Fd: 1 H 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, for C 14 H7Cl4N3O2[M+H + ]m / z=390.

[0514] d. Synthesis by condensation reaction

[0515]

[0516] Compound 9 (58.3 mg, 0.27 mmol) was added to a solution of intermediate Fd (35.0 mg, 0.09 mmol) in DMF (1 mL). The mixture was warmed to 60 ° C for 5 hours. The mixture was cooled and the resulting suspension was filtered. The resulting suspension was cooled, water (2.0 mL) was added and filtered. The filter cake was washed with water and then dried in a vacuum oven to obtain the inseparable E, Z isomers of intermediate Gd as off-white solids (38.5 mg, yield: 77%).

[0517] Intermediate 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 for C 21 H 13 Cl4N5O5[M+H + ]m / z=556.

[0518] e. Synthesis by cyclization reaction

[0519]

[0520] Intermediate 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 hours. The resulting suspension was cooled, water (2.0 mL) was added and filtered. The filter cake was washed with water and then dried in a vacuum oven to obtain compound d as an off-white solid (16.4 mg, yield: 60%).

[0521] 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, for C 19 H7C l4 N5O4[M+ACN+H + ]m / z=551.

[0522] 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)

[0523]

[0524] Route E. 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

[0525] a. Synthesis of hydrazine reaction

[0526]

[0527] 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 hours. The solid was filtered, washed with water, and vacuum dried for 24 hours to obtain compound 4e as a white solid (970 mg, yield: 91%).

[0528] Compound 4e: 1 H NMR (600 MHz, DMSO-d6) δ11.76 (s, 2H), 8.01 (s, 2H). LRMS for C8H4F2N2O2 [M+H + ]m / z=199.

[0529] b.Synthesis of SnAr reaction

[0530]

[0531] 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 hours, and then 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 obtain crude compound 7e, which was further purified by column chromatography (2→10% MeOH / DCM) to obtain compound 7e as an off-white solid (54 mg, yield: 10%).

[0532] Compound 7e: 1H 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 for C 14 H5Cl2F2N3O4[M+MeCN+H + ]m / z=429.

[0533] c. Synthesis by reduction reaction

[0534]

[0535] 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 with nitrogen twice and then stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give intermediate Fe as a light brown solid (53.2 mg, 48%).

[0536] Intermediate 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, for C 14 H7Cl2F2N3O2[M+H + ]m / z=358.

[0537] d. Synthesis by condensation reaction

[0538]

[0539] Compound 9 (92.5 mg, 0.43 mmol) was added to a solution of intermediate Fe (52.2 mg, 0.15 mmol) in DMF (1.2 mL). The mixture was warmed to 60 ° C for 3 hours. 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 hours to obtain a mixture of inseparable E, Z isomers of intermediate Ge as an off-white solid (50.0 mg, yield: 71%).

[0540] Intermediate Ge: 1H NMR (600 MHz, DMSO-d6, major 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, for C 21 H 13 Cl2F2N5O5[M+H + ]m / z=524.

[0541] e. Synthesis by cyclization reaction

[0542]

[0543] Intermediate Ge (25.0 mg, 0.048 mmol) is added to a solution containing potassium acetate (15.5 mg, 0.158 mmol), MeOH (1.0 mL) and water (1.0 mL). The mixture is purged with N2, the flask is sealed, and heated to 80 ° C for 8 hours. The resulting suspension is cooled, water (2.0 mL) is added and filtered. The filter cake is washed with water and then dried in a vacuum oven to obtain compound e as a tan solid (12.6 mg, yield: 82%).

[0544] 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, for C 19 H7Cl2F2N5O4[M+MeCN+H + ]m / z=519.

[0545] 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)

[0546]

[0547] Route F. 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

[0548] a. Synthesis of hydrazine reaction

[0549]

[0550] 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 hours. The solid was filtered, washed with water, and vacuum dried for 24 hours to obtain compound 4f as a white solid (1.09, yield: 91.8%).

[0551] Compound 4f: 1 H NMR (600 MHz, DMSO-d6) δ11.57 (d, J=157.7 Hz, 2H), 7.69 (s, 2H). LRMS for C8H4F2N2O2 [M+H + ]m / z=199.

[0552] b.Synthesis of SnAr reaction

[0553]

[0554] 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 hours, and then 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. Hour , providing crude compound 7f, which was further purified by column chromatography (2→10% MeOH / DCM) to compound 7f as a tan solid (101 g, yield: 42%).

[0555] 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, for C 14 H5Cl2F2N3O4[M+MeCN+H + ]m / z=429

[0556] c. Synthesis by reduction reaction

[0557]

[0558] Palladium / 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 with nitrogen twice and then stirred at room temperature for 6 hours under a hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give a crude intermediate Ff, which was further purified by column chromatography (0→4% methanol / DCM) to a light brown solid (32.3 mg, 39%).

[0559] Intermediate 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, for C 14 H7Cl2F2N3O2[M+H + ]m / z=358.

[0560] d. Synthesis by condensation reaction

[0561]

[0562] Compound 9 (60.8 mg, 0.29 mmol) was added to a solution of intermediate Ff (30.6 mg, 0.09 mmol) in DMF (1 mL). The mixture was warmed to 60 ° C for 5 hours. The mixture was cooled, water (2 mL) was added and the resulting suspension was filtered. The filter cake was washed with water (2 mL) and dried under vacuum for 24 hours to obtain an inseparable mixture of E, Z isomers of intermediate Gf as an off-white solid (36.7 mg, yield: 78%).

[0563] Intermediate Gf: 1 H NMR (600 MHz, DMSO-d6, major 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 for C 21 H 13 Cl2F2N5O5[M+H + ]m / z=524.

[0564] e. Synthesis by cyclization reaction

[0565]

[0566] Intermediate 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 hours. The resulting suspension was cooled, water (2.0 mL) was added and filtered. The filter cake was washed with water and then dried in a vacuum oven to obtain compound f as an off-white solid (23.0 mg, yield: 94%).

[0567] 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, for C 19 H7Cl2F2N5O4[M+H + ]m / z=478.

[0568] 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)

[0569]

[0570] Route H. 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

[0571] a. Synthesis of hydrazine reaction

[0572]

[0573] Sodium acetate (300.1 mg, 3.66 mmol) was added to a solution of 3-methoxyphthalic 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 hours. The solid was filtered, washed with water, and vacuum dried for 24 hours to obtain compound 4h as a white solid (417 mg, yield: 79%).

[0574] Compound 4h: 1H NMR (600 MHz, DMSO-d6) δ7.79 (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 for C9H8N2O3 [M+H + ]m / z=192.

[0575] b.Synthesis of SnAr reaction

[0576]

[0577] Potassium bicarbonate (313mg, 3.13mmol) is added to a solution of 3-methoxyphthalic acid hydrazide (compound 4h, 400mg, 2.08mmol) and compound 5 (277g, 1.32mmol) in DMSO (30mL), and the mixture is stirred at room temperature for 24 hours, and then the reaction is quenched with water (30mL). The resulting suspension is filtered. The filter cake is washed with water (20mL) and dried under vacuum for 24 hours to obtain crude compound 7h (496mg), which is further purified by slurrying in ethyl acetate to obtain compound 7h as a light yellow solid (370mg, yield: 74%).

[0578] 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, for C 15 H9Cl2N3O5[M+H + ]m / z=382.

[0579]

[0580] Palladium / carbon (5%, 0.02g) was added to a solution of compound 7h (251mg, 0.66mmol) in THF (2mL). The solution was purged with nitrogen twice and then stirred at room temperature for 5 hours under a hydrogen atmosphere. The mixture was filtered through a celite pad, and the filtrate was concentrated to dryness to give a crude intermediate Fh. The crude material was purified by column chromatography (2→20% DCM: MeOH) to give pure intermediate Fh as a light yellow solid (61.1mg, 26.2%).

[0581] Intermediate Fh: 1H NMR (600MHz, DMSO-d6) δ11.53(s,1H),7.93(t,J=8.1Hz,1H),7.68(d,J=6.9Hz,1H),7.49(dd,J=8.5,1.0Hz,1H),6.69(s,2H),5.62(s,2H),3.92(s,3H). LRMS, for C 15 H 11 Cl2N3O3[M+H + ]m / z=352).

[0582] d. Synthesis by condensation reaction

[0583]

[0584] Compound 9 (93 mg, 0.44 mmol) was added to a solution of intermediate Fh (50 mg, 0.14 mmol) in DMF (1 mL). The mixture was warmed to 80 ° C for 5 hours. The mixture was cooled, water (2 mL) was added and the resulting suspension was filtered. The filter cake was washed with water (2 mL) and dried under vacuum for 24 hours to give an inseparable mixture of E, Z isomers of intermediate Gh as an off-white solid (74.9 mg, yield: 14%).

[0585] Intermediate Gh: 1 H NMR (600 MHz, DMSO-d6, major 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, for C 22 H 17 Cl2N5O6[M+H + ]m / z=518.

[0586] e. Synthesis by cyclization reaction

[0587]

[0588] Intermediate 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 obtain purified compound h as an off-white solid (30.2 mg, yield: 82.9%).

[0589] 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, for C 20 H 11 Cl2N5O5[M+H + ]m / z=472.

[0590] 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)

[0591]

[0592] Route I. 1-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0593] a. Functional group transformation

[0594] 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 the solution was added to water (2 mL). The solid was filtered, washed with water and dried under vacuum for 24 hours to give compound i as a white solid (20.1 mg, yield: 98%).

[0595] Compound i: 1H NMR (600MHz, DMSO-d6) δ12.12(s,1H),12.03(s,1H),8.37(s,1H),8.32(d,J=9.9Hz,1H),8.25(d,J=6 .8Hz,1H),8.14(s,1H),8.11–8.08(m,1H),8.03(t,J=8.3Hz,1H),7.94(s,2H),7.66(s,1H).LRMS, for C 19 H 11 Cl2N5O5[M+MeCN+H + ]m / z=501.

[0596] 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)

[0597]

[0598] Route J. 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

[0599] a. Functional group transformation

[0600] 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%).

[0601] 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 for C 19 H 10 Cl2N4O6[M+MeCN+H + ]m / z=502.

[0602] Example 2 - Biological Assays

[0603] Using LanthaScreen TM The TR-FRET TRα or β coactivator assay kit (ThermoFIsher) was used to perform the thyroid hormone receptor β and thyroid hormone receptor α coactivator recruitment assays. The control agonist 3,3',5-triiodo-L-thyronine sodium salt T3 (SIGMA) was used to validate the assay. The test compounds and / or vehicle were incubated with TRαLBD-GST or TRβLBD-GST and the coactivator peptide (fluorescein-SRC2-2 (LKEKHKILHRLLQDSSSPV) (SEQ ID NO: 1)) at room temperature for 30 minutes. The amount of complex formed was read by fluorescence spectroscopy (excitation: 337 nm, emission: 520 / 490 nm) on a PHERAstar FS instrument (BMG). The EC was calculated using a fluorescence increase induced by the test compound greater than 50% relative to the T3 response. 50 Compounds were screened at 30, 10, 3, 1, 0.3, 0.1 and 0.03 μM.

[0604] Table 1.

[0605]

[0606] Incorporated by Reference

[0607] All publications and patents mentioned herein are 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 event of a conflict, the present application, including any definitions herein, will control.

[0608] Equivalent solution

[0609] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents and reference to "a cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0610] Although specific embodiments of the present invention have been discussed, the above description is exemplary rather than restrictive. After reading this specification and the following claims, many variations of the present invention will become apparent to those skilled in the art. The entire scope of the present invention should be determined by reference to the full scope of the claims and their equivalents and the specification and these variations.

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 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 Carbocyclic or C 6-14 Aryl; Each R 2 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 3 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; R 4 and R 6 Each occurrence 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- to 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 optionally substituted by one or more R u replace; 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; m is an integer selected from 0 to 4; n is an integer selected from 0 to 2; X is selected from -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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; and R 8 It 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- to 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 optionally substituted by one or more R u replace; in: 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- to 14-membered heteroaryl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, -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 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 haloalkyl substitution; Two R's u together to form an oxo group; or Two R's u Together with one or more atoms in between, they form C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic group, or 3 to 10 membered heterocyclic group; Each R a Independently 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 haloalkyl substitution; 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; and 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 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-14 wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 Haloalkyl substitution; or R c , R d Together with the nitrogen atom to which they are attached, they form a group optionally substituted with one or more oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 Alkyl or C 1-6 A 3- to 10-membered heterocyclic group substituted with a haloalkyl group.

2. The compound according to claim 1, wherein each R 1 are independently halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 6-14 Aryl.

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

4. The compound according to any one of claims 1 to 3, wherein each R 2 are independently halogen or C 1-6 alkyl.

5. The compound according to any one of claims 1 to 4, wherein each R 2 It's a halogen.

6. A compound according to any one of claims 1 to 5, wherein each R 2 It's chlorine.

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

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

9. The compound according to any one of claims 1 to 7, wherein each R c and R c It's H.

10. A compound according to any one of claims 1 to 7, wherein R 3 It is -C(=O)NH2.

11. A compound according to any one of claims 1 to 7, wherein R b It's H.

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

13. A compound according to any one of claims 1 to 12, wherein R 4 It's hydrogen.

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

15. A compound according to any one of claims 1 to 14, wherein R 6 It's hydrogen.

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

17. The compound of claim 1, wherein the compound is selected from the compounds described in Table 1, and pharmaceutically acceptable salts, stereoisomers, and solvates thereof.

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

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

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

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

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

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

25. Use according to claim 24, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or fatty liver disease.

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

28. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, for use in treating a liver disease or disorder or a lipid disease or disorder.

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

30. 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. 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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