Substituted Fused Bicyclic Macrocycles and Related Methods of Treatment - Patent application

Abstract

The present invention provides compounds useful as orexin-2 receptor agonists for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 193,243, filed May 26, 2021, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to substituted macrocyclic compounds, particularly to substituted macrocyclic compounds having agonist activity. [Background technology]

[0003] Background of the Invention Orexin is a neuropeptide synthesized and released by a subpopulation of neurons in the lateral hypothalamus and surrounding areas. It consists of two subtypes: orexin A and orexin B. Orexin A and orexin B bind to orexin receptors (ORs), which are G protein-coupled receptors preferentially expressed in the brain. There are two subtypes of orexin receptors (type 1 and type 2) (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is known to be important for various central nervous system functions, such as maintaining wakefulness, energy homeostasis, reward processing, and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0004] Narcolepsy is a neurological disorder that causes excessive daytime sleepiness, sudden attacks of muscle paralysis (cataplexy), and disrupted sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). Narcolepsy is known to be caused by the degeneration of orexin neurons. Narcoleptic symptoms can be modeled in transgenic mice genetically engineered to degenerate orexin neurons, and these symptoms can be reversed by intracerebroventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies of orexin-2 receptor knockout mice suggest that the orexin-2 receptor plays a preferential role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999; Neuron, Vol. 38, 715-730, 2003). Thus, orexin-2 receptor agonists may be therapeutic agents for other disorders that exhibit excessive daytime sleepiness, such as narcolepsy or Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0005] Compounds having agonist activity at the orexin-2 receptor are hypothesized to be useful as novel therapeutic agents for conditions such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndromes, disturbances of consciousness such as coma, narcolepsy syndromes, hypersomnolence syndromes characterized by excessive sleepiness (e.g. in Parkinson's disease, Guillain-Barré syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndromes, heart failure, diseases related to bone loss or sepsis. (Cell Metabolism, Vol. 9, 64-76, 2009;Neuroscience, Vol. 121, 855-863, 2003;Respiration, Vol. 71, 575-579, 2004;Peptides, Vol. 23, 1683-1688, 2002;WO 2015 / 073707;Journal of the American College of Cardiology, Vol. 66, 2015, pages 2522-2533;WO 2015 / 048091;WO 2015 / 147240).

[0006] Several compounds with orexin-2 receptor agonist activity have been reported (U.S. Patent No. 8,258,163; WO 2015 / 088000; WO 2014 / 198880; Journal of Medicinal Chemistry, Vol. 58, pages 7931-7937; US 20190040010; US 20190031611; US ​​20170226137). However, these compounds are considered unsatisfactory in terms of, for example, activity, pharmacokinetics, brain / central nervous system penetration, or safety, and the development of improved compounds with orexin-2 receptor agonist activity is desirable. Summary of the Invention

[0007] Summary of the Invention The present invention contemplates providing fused bicyclic macrocycle compounds that have orexin-2 receptor agonist activity.

[0008] Thus, in a first aspect, the present invention provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), and C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0009] In one embodiment, a compound of formula I: [ka] Provided herein are compounds of formula IA having the structure: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0010] Formula II-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0011] In another embodiment, a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0012] Formula III-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0013] In another embodiment, a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0014] Formula IV-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0015] In another embodiment, a compound of formula IV: [ka] Provided herein is a compound of formula IV-A having the structure: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0016] Formula VA: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0017] In another embodiment, a compound of formula V: [ka] Provided herein are compounds of formula VA having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0018] Formula VI-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0019] In another embodiment, a compound of formula VI: [ka] Provided herein is a compound of formula VI-A having the structure: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0020] Also provided herein is a pharmaceutical composition comprising a compound of any of Formulas IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] In another aspect, provided herein is a method of treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, provided herein is a method of treating cataplexy in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description of the Invention Provided herein are compounds useful for treating narcolepsy or cataplexy in a subject, e.g., compounds of formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof.

[0024] In a non-limiting aspect, these compounds can modulate orexin-2 receptors. In certain embodiments, the compounds provided herein are considered to be orexin-2 agonists. Thus, in one aspect, the compounds provided herein are useful for treating narcolepsy in a subject by acting as orexin-2 receptor agonists.

[0025] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific examples, either individually or as part of a larger group.

[0026] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0027] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting.

[0028] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value, such as an amount, a temporal duration, etc., the term "about" is meant to encompass variations of ±20% or ±10%, e.g., ±5%, ±1%, and ±0.1%, from the specified value, as such variations are appropriate for performing the disclosed methods.

[0029] As used herein, the term "EC 50 " refers to the concentration of a compound required to achieve an effect that is 50% of the maximum observed effect of the compound.

[0030] The term "agonist," as used herein, refers to a compound that, when contacted with a target of interest (e.g., an orexin-2 receptor), produces an increase in the magnitude of a particular activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.

[0031] The terms "treat," "treated," "treating," or "treatment" include the decrease or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment involves contacting the orexin-2 receptor with an effective amount of a compound of the invention for conditions associated with narcolepsy or cataplexy.

[0032] As used herein, the term "prevent" or "prevention" means the absence of a disorder or disease occurring if none had occurred, or the absence of further onset of a disorder or disease if onset of a disorder or disease has already occurred. The ability of something to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0033] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline, and murine mammals. Preferably, the patient, subject, or individual is human.

[0034] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide a desired biological result. This result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0035] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0036] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an acid or base moiety present into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, with non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. The phrase "pharmaceutically acceptable salts" is not limited to mono- or 1:1 salts. For example, "pharmaceutically acceptable salts" also include bis-salts, such as bis-hydrochlorides. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0037] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention with a pharmaceutically acceptable carrier.Pharmaceutical compositions facilitate the administration of compounds to patients or subjects.Multiple techniques for administering compounds exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, intraocular, pulmonary and topical administration.

[0038] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating substance, involved in carrying or transporting a compound useful in the present invention into or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, such as the compound useful in the present invention, and not toxic to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate-buffered solutions; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0039] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful in the present invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may also include pharmaceutically acceptable salts of the compounds useful in the present invention. Other additional ingredients that may be included in pharmaceutical compositions used to practice the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0040] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the indicated number of carbon atoms (i.e., C 1-6 Alkyl means alkyl having 1 to 6 carbon atoms, including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0041] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0042] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbyl group, e.g., having 1 to 4 carbon atoms, which is either straight-chained or branched. This term illustratively includes methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), and the like.

[0043] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups (e.g., C2-C8-alkenyl) include, but are not limited to, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0044] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group. Alkynyl groups (e.g., C2-C8-alkynyl) include, but are not limited to, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl, and the like.

[0045] As used herein, the term "alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0046] As used herein, the term "cycloalkyl" refers to a non-aromatic carbocyclic ring system that is partially or fully saturated and has one, two, or three rings, where such rings may be fused. The term "fused" means that a second ring is present (i.e., linked or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature, with each individual ring within the bicycle varying from 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

[0047] As used herein, the term "heterocyclyl" means a non-aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings, where such rings may be fused, where fusion is defined above. Heterocyclyl also includes bicyclic structures which may be bridged or spirocyclic in nature, where each individual ring within the bicycle varies from 3 to 8 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxyzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, and the like. For example, the term "heterocyclyl" can include a 4- to 10-membered heterocyclyl, a 4- to 7-membered heterocyclyl, a 5- to 10-membered heterocyclyl, a 6- to 10-membered heterocyclyl, a 4- to 6-membered heterocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 7-membered heterocyclyl, an 8-membered heterocyclyl, a 9-membered heterocyclyl, or a 10-membered heterocyclyl.

[0048] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0049] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings, where such rings may be fused, fused being defined above. When rings are fused, one of the rings must be fully unsaturated, and the fused ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term "aryl" includes C6-C 10 May include aryl, C6-C8 aryl or C6 aryl (ie phenyl).

[0050] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, where such rings may be fused, where fusion is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. For example, the term "heteroaryl" can include 5- to 10-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 6-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 8-membered heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl.

[0051] Where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to the depicted moiety through different ring atoms (i.e., shown or described without indication of a particular point of attachment), it is understood that all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thiophenyl" means 2- or 3-thiophenyl, etc.

[0052] As used herein, the term "substituted" means that an atom or group of atoms has a hydrogen replaced as a substituent attached to another group.

[0053] Compounds of the Invention Thus, in a first aspect, the present invention provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0054] In one embodiment, a compound of formula I: [ka] Provided herein are compounds of formula IA having the structure: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0055] In one embodiment of Formula (I), n is 1. In another embodiment of Formula (I), n is 2. In another embodiment of Formula (I), n is 3.

[0056] In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (I), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (I), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (I), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (I), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (I), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (I), fused ring A is 6 membered heteroaryl.

[0057] In another embodiment of Formula (I), fused ring A is cyclopentyl. In another embodiment of Formula (I), fused ring A is cyclopentenyl. In another embodiment of Formula (I), fused ring A is cyclohexyl. In another embodiment of Formula (I), fused ring A is cyclohexenyl. In another embodiment of Formula (I), fused ring A is pyrrolyl. In another embodiment of Formula (I), fused ring A is pyrazolyl. In another embodiment of Formula (I), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (I), fused ring A is imidazolyl. In another embodiment of Formula (I), fused ring A is isoxazolyl. In another embodiment of Formula (I), fused ring A is tetrahydropyranyl. In another embodiment of Formula (I), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (I), fused ring A is dihydropyranyl. In another embodiment of formula (I), fused ring A is dihydrofuranyl.

[0058] In another embodiment of formula (I), Y is NR 10 In another embodiment of Formula (I), Y is O. In another embodiment of Formula (I), Y is absent. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl and Y is NR 10In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (I), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (I), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (I), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (I), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0059] In another embodiment of Formula (I), T is CR1R2. In another embodiment of Formula (I), T is O. In another embodiment of Formula (I), W is CR4R5. In another embodiment of Formula (I), W is O. In another embodiment of Formula (I), T is CR1R2 and W is CR4R5. In another embodiment of Formula (I), T is O and W is CR4R5. In another embodiment of Formula (I), T is CR1R2 and W is O.

[0060] In another embodiment of Formula (I), V is CR3. In another embodiment of Formula (I), V is N.

[0061] In another embodiment of Formula (I), T is CR1R2 and V is CR3. In another embodiment of Formula (I), T is O and V is CR3. In another embodiment of Formula (I), T is CR1R2 and V is N. In another embodiment of Formula (I), T is O and V is N.

[0062] In another embodiment of Formula (I), W is CR4R5 and V is CR3. In another embodiment of Formula (I), W is O and V is CR3. In another embodiment of Formula (I), W is CR4R5 and V is N. In another embodiment of Formula (I), W is O and V is N.

[0063] In another embodiment of Formula (I), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (I), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (I), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (I), T is CR1R2, W is O and V is N. In another embodiment of Formula (I), T is O, W is CR4R5 and V is CR3.

[0064] In another embodiment of Formula (I), E is H. In another embodiment of Formula (I), E is hydroxyl. In another embodiment of Formula (I), E is NR a R b In another embodiment of Formula (I), E is C(=O)NR a R b In another embodiment of formula (I), E is C1-C3 alkylene-NR a R bIn another embodiment of Formula (I), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (I), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (I), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (I), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (I), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (I), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (I), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted C6-C 10 In another embodiment of formula (I), E is a C-C aryl substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. 10 In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C6-C 10In another embodiment of formula (I), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (I), E is unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (I), E is 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0065] In another embodiment of Formula (I), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (I), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (I), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (I), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (I), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (I), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0066] In another embodiment of formula (I), E is NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0067] In another embodiment of formula (I), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0068] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0069] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0070] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0071] In another embodiment of Formula (I), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is methyl. In another embodiment of Formula (I), E is trifluoromethyl. In another embodiment of Formula (I), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (I), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (I), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0072] In another embodiment of formula (I), R 14 is H. In another embodiment of formula (I), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R 15 and R 16 are each H. In another embodiment of formula (I), R 15 is unsubstituted C1-C3 alkyl, and R 16 is H. In another embodiment of formula (I), R 16is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (I), each R 17 and R 18 is H. In another embodiment of formula (I), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (I), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (I), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (I), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0073] In another embodiment of Formula (I), m is 1. In another embodiment of Formula (I), m is 2. In another embodiment of Formula (I), m is 3. In another embodiment of Formula (I), m is 4. In another embodiment of Formula (I), m is 1, 2 or 3. In another embodiment of Formula (I), m is 2, 3 or 4. In another embodiment of Formula (I), m is 1 or 2. In another embodiment of Formula (I), m is 3 or 4.

[0074] In another embodiment of Formula (I), Y is O and m is 1. In another embodiment of Formula (I), Y is O and m is 2. In another embodiment of Formula (I), Y is O and m is 3. In another embodiment of Formula (I), Y is O and m is 4. In another embodiment of Formula (I), Y is O and m is 1, 2 or 3. In another embodiment of Formula (I), Y is O and m is 2, 3 or 4. In another embodiment of Formula (I), Y is O and m is 1 or 2. In another embodiment of Formula (I), Y is O and m is 3 or 4.

[0075] In another embodiment of Formula (I), Y is absent and m is 1. In another embodiment of Formula (I), Y is absent and m is 2. In another embodiment of Formula (I), Y is absent and m is 3. In another embodiment of Formula (I), Y is absent and m is 4. In another embodiment of Formula (I), Y is absent and m is 1, 2 or 3. In another embodiment of Formula (I), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (I), Y is absent and m is 1 or 2. In another embodiment of Formula (I), Y is absent and m is 3 or 4.

[0076] In another embodiment of formula (I), Y is NR 10 and m is 1. In another embodiment of formula (I), Y is NR 10 and m is 2. In another embodiment of formula (I), Y is NR 10 and m is 3. In another embodiment of formula (I), Y is NR 10 and m is 4. In another embodiment of formula (I), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (I), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (I), Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), Y is NR 10 and m is 3 or 4.

[0077] In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (I), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (I), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (I), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (I), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (I), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0078] In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0079] In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0080] In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1 and Y is NR 10 In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0081] In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0082] In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0083] In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (I), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0084] In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (I), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0085] In another embodiment of Formula (I), R1, R2, R4 and R5 are each H. In another embodiment of Formula (I), R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of Formula (I), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are each H. In another embodiment of Formula (I), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0086] In another embodiment of Formula (I), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (I), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (I), R6, R7, R8, R9, and R 11 In another embodiment of formula (I), one or more of R, R, R, R and R are fluorine. 11 In another embodiment of formula (I), one or more of R 12 and R 13 In another embodiment of formula (I), one or more of R 12 and R 13 One or more of is deuterium.

[0087] In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 1. In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18is H. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 1. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 1.

[0088] Each of the embodiments described herein with respect to compounds of formula I also applies to compounds of formula IA.

[0089] Formula II-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0090] In another embodiment, a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0091] In one embodiment of Formula (II), n is 1. In another embodiment of Formula (II), n is 2. In another embodiment of Formula (II), n is 3.

[0092] In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (II), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (II), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (II), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (II), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (II), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (II), fused ring A is 6 membered heteroaryl.

[0093] In another embodiment of Formula (II), fused ring A is cyclopentyl. In another embodiment of Formula (II), fused ring A is cyclopentenyl. In another embodiment of Formula (II), fused ring A is cyclohexyl. In another embodiment of Formula (II), fused ring A is cyclohexenyl. In another embodiment of Formula (II), fused ring A is pyrrolyl. In another embodiment of Formula (II), fused ring A is pyrazolyl. In another embodiment of Formula (II), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (II), fused ring A is imidazolyl. In another embodiment of Formula (II), fused ring A is isoxazolyl. In another embodiment of Formula (II), fused ring A is tetrahydropyranyl. In another embodiment of Formula (II), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (II), fused ring A is dihydropyranyl. In another embodiment of formula (II), fused ring A is dihydrofuranyl.

[0094] In another embodiment of formula (II), Y is NR 10In another embodiment of Formula (II), Y is O. In another embodiment of Formula (II), Y is absent. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl and Y is NR 10 In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (II), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (II), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (II), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (II), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0095] In another embodiment of Formula (II), T is CR1R2. In another embodiment of Formula (II), T is O. In another embodiment of Formula (II), W is CR4R5. In another embodiment of Formula (II), W is O. In another embodiment of Formula (II), T is CR1R2 and W is CR4R5. In another embodiment of Formula (II), T is O and W is CR4R5. In another embodiment of Formula (II), T is CR1R2 and W is O.

[0096] In another embodiment of Formula (II), V is CR3. In another embodiment of Formula (II), V is N.

[0097] In another embodiment of Formula (II), T is CR1R2 and V is CR3. In another embodiment of Formula (II), T is O and V is CR3. In another embodiment of Formula (II), T is CR1R2 and V is N. In another embodiment of Formula (II), T is O and V is N.

[0098] In another embodiment of Formula (II), W is CR4R5 and V is CR3. In another embodiment of Formula (II), W is O and V is CR3. In another embodiment of Formula (II), W is CR4R5 and V is N. In another embodiment of Formula (II), W is O and V is N.

[0099] In another embodiment of Formula (II), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (II), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (II), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (II), T is CR1R2, W is O and V is N. In another embodiment of Formula (II), T is O, W is CR4R5 and V is CR3.

[0100] In another embodiment of Formula (II), E is H. In another embodiment of Formula (II), E is hydroxyl. In another embodiment of Formula (II), E is NR a R b In another embodiment of formula (II), E is C(=O)NR a R b In another embodiment of formula (II), E is C1-C3 alkylene-NR a R bIn another embodiment of Formula (II), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (II), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (II), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (II), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (II), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (II), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (II), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted C6-C 10 In another embodiment of formula (II), E is a C6-C aryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of formula (II), E is unsubstituted C1-C3 alkylene-(C6-C 10In another embodiment of formula (II), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (II), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (II), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0101] In another embodiment of Formula (II), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (II), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (II), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (II), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (II), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (II), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0102] In another embodiment of formula (II), E is NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0103] In another embodiment of formula (II), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0104] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0105] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0106] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0107] In another embodiment of Formula (II), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is methyl. In another embodiment of Formula (II), E is trifluoromethyl. In another embodiment of Formula (II), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (II), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (II), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0108] In another embodiment of formula (II), R 14 is H. In another embodiment of formula (II), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (II), R 15 and R 16 are each H. In another embodiment of formula (II), R 15 is unsubstituted C1-C3 alkyl, and R 16 is H. In another embodiment of formula (II), R16 is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (II), each R 17 and R 18 is H. In another embodiment of formula (II), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (II), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (II), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (II), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0109] In another embodiment of Formula (II), m is 1. In another embodiment of Formula (II), m is 2. In another embodiment of Formula (II), m is 3. In another embodiment of Formula (II), m is 4. In another embodiment of Formula (II), m is 1, 2 or 3. In another embodiment of Formula (II), m is 2, 3 or 4. In another embodiment of Formula (II), m is 1 or 2. In another embodiment of Formula (II), m is 3 or 4.

[0110] In another embodiment of Formula (II), Y is O and m is 1. In another embodiment of Formula (II), Y is O and m is 2. In another embodiment of Formula (II), Y is O and m is 3. In another embodiment of Formula (II), Y is O and m is 4. In another embodiment of Formula (II), Y is O and m is 1, 2 or 3. In another embodiment of Formula (II), Y is O and m is 2, 3 or 4. In another embodiment of Formula (II), Y is O and m is 1 or 2. In another embodiment of Formula (II), Y is O and m is 3 or 4.

[0111] In another embodiment of Formula (II), Y is absent and m is 1. In another embodiment of Formula (II), Y is absent and m is 2. In another embodiment of Formula (II), Y is absent and m is 3. In another embodiment of Formula (II), Y is absent and m is 4. In another embodiment of Formula (II), Y is absent and m is 1, 2 or 3. In another embodiment of Formula (II), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (II), Y is absent and m is 1 or 2. In another embodiment of Formula (II), Y is absent and m is 3 or 4.

[0112] In another embodiment of formula (II), Y is NR 10 and m is 1. In another embodiment of formula (II), Y is NR 10 and m is 2. In another embodiment of formula (II), Y is NR 10 and m is 3. In another embodiment of formula (II), Y is NR 10 and m is 4. In another embodiment of formula (II), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (II), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (II), Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), Y is NR 10 and m is 3 or 4.

[0113] In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (II), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (II), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (II), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (II), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (II), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0114] In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0115] In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0116] In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0117] In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10and m is 3 or 4. In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0118] In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0119] In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (II), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0120] In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (II), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0121] In another embodiment of Formula (II), R1, R2, R4 and R5 are each H. In another embodiment of Formula (II), R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of Formula (II), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are each H. In another embodiment of Formula (II), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0122] In another embodiment of Formula (II), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (II), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (II), R6, R7, R8, R9, and R 11 In another embodiment of formula (II), one or more of R, R, R, R and R are fluorine. 11 In another embodiment of formula (II), one or more of R 12 and R 13 In another embodiment of formula (II), one or more of R 12 and R 13 One or more of is deuterium.

[0123] In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 1. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18is H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 1. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 1.

[0124] Each of the embodiments described herein with respect to compounds of formula II also applies to compounds of formula II-A.

[0125] Formula III-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0126] In another embodiment, a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 teeth 、 selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0127] In one embodiment of Formula (III), n is 1. In another embodiment of Formula (III), n is 2. In another embodiment of Formula (III), n is 3.

[0128] In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (III), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (III), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (III), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (III), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (III), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (III), fused ring A is 6 membered heteroaryl.

[0129] In another embodiment of Formula (III), fused ring A is cyclopentyl. In another embodiment of Formula (III), fused ring A is cyclopentenyl. In another embodiment of Formula (III), fused ring A is cyclohexyl. In another embodiment of Formula (III), fused ring A is cyclohexenyl. In another embodiment of Formula (III), fused ring A is pyrrolyl. In another embodiment of Formula (III), fused ring A is pyrazolyl. In another embodiment of Formula (III), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (III), fused ring A is imidazolyl. In another embodiment of Formula (III), fused ring A is isoxazolyl. In another embodiment of Formula (III), fused ring A is tetrahydropyranyl. In another embodiment of Formula (III), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (III), fused ring A is dihydropyranyl. In another embodiment of formula (III), fused ring A is dihydrofuranyl.

[0130] In another embodiment of formula (III), Y is NR 10 In another embodiment of Formula (III), Y is O. In another embodiment of Formula (III), Y is absent. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl and Y is NR 10 In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (III), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (III), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (III), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (III), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0131] In another embodiment of Formula (III), T is CR1R2. In another embodiment of Formula (III), T is O. In another embodiment of Formula (III), W is CR4R5. In another embodiment of Formula (III), W is O. In another embodiment of Formula (III), T is CR1R2 and W is CR4R5. In another embodiment of Formula (III), T is O and W is CR4R5. In another embodiment of Formula (III), T is CR1R2 and W is O.

[0132] In another embodiment of Formula (III), V is CR3. In another embodiment of Formula (III), V is N.

[0133] In another embodiment of Formula (III), T is CR1R2 and V is CR3. In another embodiment of Formula (III), T is O and V is CR3. In another embodiment of Formula (III), T is CR1R2 and V is N. In another embodiment of Formula (III), T is O and V is N.

[0134] In another embodiment of Formula (III), W is CR4R5 and V is CR3. In another embodiment of Formula (III), W is O and V is CR3. In another embodiment of Formula (III), W is CR4R5 and V is N. In another embodiment of Formula (III), W is O and V is N.

[0135] In another embodiment of Formula (III), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (III), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (III), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (III), T is CR1R2, W is O and V is N. In another embodiment of Formula (III), T is O, W is CR4R5 and V is CR3.

[0136] In another embodiment of Formula (III), E is H. In another embodiment of Formula (III), E is hydroxyl. In another embodiment of Formula (III), E is NR a R b In another embodiment of formula (III), E is C(=O)NR a R b In another embodiment of formula (III), E is C1-C3 alkylene-NR a R bIn another embodiment of Formula (III), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (III), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (III), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (III), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (III), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (III), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (III), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is an unsubstituted C6-C 10 In another embodiment of formula (III), E is a C6-C aryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of formula (III), E is unsubstituted C1-C3 alkylene-(C6-C 10In another embodiment of formula (III), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (III), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (III), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0137] In another embodiment of Formula (III), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (III), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (III), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (III), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (III), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (III), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0138] In another embodiment of formula (III), E is NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0139] In another embodiment of formula (III), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0140] In another embodiment of formula (III), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0141] In another embodiment of formula (III), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0142] In another embodiment of formula (III), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0143] In another embodiment of Formula (III), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is methyl. In another embodiment of Formula (III), E is trifluoromethyl. In another embodiment of Formula (III), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (III), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (III), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (III), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0144] In another embodiment of formula (III), R 14 is H. In another embodiment of formula (III), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (III), R 15 and R 16 are each H. In another embodiment of formula (III), R 15 is unsubstituted C1-C3 alkyl, and R 16is H. In another embodiment of formula (III), R 16 is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (III), each R 17 and R 18 is H. In another embodiment of formula (III), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (III), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (III), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (III), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0145] In another embodiment of Formula (III), m is 1. In another embodiment of Formula (III), m is 2. In another embodiment of Formula (III), m is 3. In another embodiment of Formula (III), m is 4. In another embodiment of Formula (III), m is 1, 2 or 3. In another embodiment of Formula (III), m is 2, 3 or 4. In another embodiment of Formula (III), m is 1 or 2. In another embodiment of Formula (III), m is 3 or 4.

[0146] In another embodiment of Formula (III), Y is O and m is 1. In another embodiment of Formula (III), Y is O and m is 2. In another embodiment of Formula (III), Y is O and m is 3. In another embodiment of Formula (III), Y is O and m is 4. In another embodiment of Formula (III), Y is O and m is 1, 2 or 3. In another embodiment of Formula (III), Y is O and m is 2, 3 or 4. In another embodiment of Formula (III), Y is O and m is 1 or 2. In another embodiment of Formula (III), Y is O and m is 3 or 4.

[0147] In another embodiment of Formula (III), Y is absent and m is 1. In another embodiment of Formula (III), Y is absent and m is 2. In another embodiment of Formula (III), Y is absent and m is 3. In another embodiment of Formula (III), Y is absent and m is 4. In another embodiment of Formula (III), Y is absent and m is 1, 2 or 3. In another embodiment of Formula (III), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (III), Y is absent and m is 1 or 2. In another embodiment of Formula (III), Y is absent and m is 3 or 4.

[0148] In another embodiment of formula (III), Y is NR 10 and m is 1. In another embodiment of formula (III), Y is NR 10 and m is 2. In another embodiment of formula (III), Y is NR 10 and m is 3. In another embodiment of formula (III), Y is NR 10 and m is 4. In another embodiment of formula (III), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (III), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (III), Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), Y is NR 10 and m is 3 or 4.

[0149] In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (III), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (III), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (III), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (III), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (III), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0150] In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0151] In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0152] In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0153] In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (III), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0154] In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0155] In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (III), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (III), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0156] In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (III), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0157] In another embodiment of Formula (III), R1, R2, R4, and R5 are each H. In another embodiment of Formula (III), R1, R2, R4, and R5 are each H; R3 is H. In another embodiment of Formula (III), R1, R2, R4, and R5 are each H; R3 is H; R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (III), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0158] In another embodiment of Formula (III), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (III), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (III), R6, R7, R8, R9, and R 11 In another embodiment of formula (III), one or more of R, R, R, R, and R are fluorine. 11 In another embodiment of formula (III), one or more of R 12 and R 13 In another embodiment of formula (III), one or more of R 12 and R 13 One or more of is deuterium.

[0159] In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 1. In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 1. In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17and R 18 is H. In another embodiment of formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 1.

[0160] Each of the embodiments described herein with respect to compounds of formula III also applies to compounds of formula III-A.

[0161] Formula IV-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2, or 3; E is H, hydroxyl, NR a R b , C(=O)NR a Rb , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0162] In another embodiment, the structure of formula IV: [ka] Provided herein is a compound of formula IV-A having the formula: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0163] In one embodiment of Formula (IV), n is 1. In another embodiment of Formula (IV), n is 2. In another embodiment of Formula (IV), n is 3.

[0164] In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (IV), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (IV), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (IV), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 6 membered heteroaryl.

[0165] In another embodiment of Formula (IV), fused ring A is cyclopentyl. In another embodiment of Formula (IV), fused ring A is cyclopentenyl. In another embodiment of Formula (IV), fused ring A is cyclohexyl. In another embodiment of Formula (IV), fused ring A is cyclohexenyl. In another embodiment of Formula (IV), fused ring A is pyrrolyl. In another embodiment of Formula (IV), fused ring A is pyrazolyl. In another embodiment of Formula (IV), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (IV), fused ring A is imidazolyl. In another embodiment of Formula (IV), fused ring A is isoxazolyl. In another embodiment of Formula (IV), fused ring A is tetrahydropyranyl. In another embodiment of Formula (IV), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (IV), fused ring A is dihydropyranyl. In another embodiment of formula (IV), fused ring A is dihydrofuranyl.

[0166] In another embodiment of formula (IV), Y is NR 10 In another embodiment of Formula (IV), Y is O. In another embodiment of Formula (IV), Y is absent. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl and Y is NR 10In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (IV), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (IV), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (IV), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (IV), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0167] In another embodiment of Formula (IV), T is CR1R2. In another embodiment of Formula (IV), T is O. In another embodiment of Formula (IV), W is CR4R5. In another embodiment of Formula (IV), W is O. In another embodiment of Formula (IV), T is CR1R2 and W is CR4R5. In another embodiment of Formula (IV), T is O and W is CR4R5. In another embodiment of Formula (IV), T is CR1R2 and W is O.

[0168] In another embodiment of formula (IV), V is CR3. In another embodiment of formula (IV), V is N.

[0169] In another embodiment of Formula (IV), T is CR1R2 and V is CR3. In another embodiment of Formula (IV), T is O and V is CR3. In another embodiment of Formula (IV), T is CR1R2 and V is N. In another embodiment of Formula (IV), T is O and V is N.

[0170] In another embodiment of Formula (IV), W is CR4R5 and V is CR3. In another embodiment of Formula (IV), W is O and V is CR3. In another embodiment of Formula (IV), W is CR4R5 and V is N. In another embodiment of Formula (IV), W is O and V is N.

[0171] In another embodiment of Formula (IV), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (IV), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (IV), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (IV), T is CR1R2, W is O and V is N. In another embodiment of Formula (IV), T is O, W is CR4R5 and V is CR3.

[0172] In another embodiment of Formula (IV), E is H. In another embodiment of Formula (IV), E is hydroxyl. In another embodiment of Formula (IV), E is NR a R b In another embodiment of formula (IV), E is C(=O)NR a R b In another embodiment of formula (IV), E is C1-C3 alkylene-NR a R bIn another embodiment of Formula (IV), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (IV), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (IV), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (IV), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (IV), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (IV), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (IV), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is an unsubstituted C6-C 10 In another embodiment of formula (IV), E is a C6-C aryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of formula (IV), E is unsubstituted C1-C3 alkylene-(C6-C 10In another embodiment of formula (IV), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (IV), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (IV), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0173] In another embodiment of Formula (IV), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (IV), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (IV), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (IV), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (IV), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (IV), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0174] In another embodiment of formula (IV), E is NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0175] In another embodiment of formula (IV), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0176] In another embodiment of formula (IV), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0177] In another embodiment of formula (IV), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0178] In another embodiment of formula (IV), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0179] In another embodiment of Formula (IV), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is methyl. In another embodiment of Formula (IV), E is trifluoromethyl. In another embodiment of Formula (IV), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (IV), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (IV), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (IV), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0180] In another embodiment of formula (IV), R 14 is H. In another embodiment of formula (IV), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (IV), R 15 and R 16 are each H. In another embodiment of formula (IV), R 15 is unsubstituted C1-C3 alkyl, and R 16 is H. In another embodiment of formula (IV), R16 is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (IV), each R 17 and R 18 is H. In another embodiment of formula (IV), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (IV), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (IV), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (IV), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0181] In another embodiment of Formula (IV), m is 1. In another embodiment of Formula (IV), m is 2. In another embodiment of Formula (IV), m is 3. In another embodiment of Formula (IV), m is 4. In another embodiment of Formula (IV), m is 1, 2 or 3. In another embodiment of Formula (IV), m is 2, 3 or 4. In another embodiment of Formula (IV), m is 1 or 2. In another embodiment of Formula (IV), m is 3 or 4.

[0182] In another embodiment of Formula (IV), Y is O and m is 1. In another embodiment of Formula (IV), Y is O and m is 2. In another embodiment of Formula (IV), Y is O and m is 3. In another embodiment of Formula (IV), Y is O and m is 4. In another embodiment of Formula (IV), Y is O and m is 1, 2 or 3. In another embodiment of Formula (IV), Y is O and m is 2, 3 or 4. In another embodiment of Formula (IV), Y is O and m is 1 or 2. In another embodiment of Formula (IV), Y is O and m is 3 or 4.

[0183] In another embodiment of Formula (IV), Y is absent and m is 2. In another embodiment of Formula (IV), Y is absent and m is 3. In another embodiment of Formula (IV), Y is absent and m is 4. In another embodiment of Formula (IV), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (IV), Y is absent and m is 2 or 3. In another embodiment of Formula (IV), Y is absent and m is 3 or 4.

[0184] In another embodiment of formula (IV), Y is NR 10 and m is 1. In another embodiment of formula (IV), Y is NR 10 and m is 2. In another embodiment of formula (IV), Y is NR 10 and m is 3. In another embodiment of formula (IV), Y is NR 10 and m is 4. In another embodiment of formula (IV), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (IV), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (IV), Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), Y is NR 10 and m is 3 or 4.

[0185] In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (IV), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (IV), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (IV), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (IV), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (IV), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0186] In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0187] In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0188] In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0189] In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10and m is 3 or 4. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (IV), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0190] In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (IV), the fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (IV), the fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (IV), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0191] In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (IV), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0192] In another embodiment of Formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of formula (IV), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0193] In another embodiment of Formula (IV), R1, R2, R4 and R5 are each H. In another embodiment of Formula (IV), R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of Formula (IV), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are each H. In another embodiment of formula (IV), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0194] In another embodiment of Formula (IV), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (IV), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (IV), R6, R7, R8, R9, and R 11 In another embodiment of formula (IV), one or more of R, R, R, R and R are fluorine. 11 In another embodiment of formula (IV), one or more of R 12 and R 13 In another embodiment of formula (IV), one or more of R 12 and R 13 One or more of is deuterium.

[0195] In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 2. In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18is H. In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 2. In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 2.

[0196] Each of the embodiments described herein with respect to compounds of formula IV also applies to compounds of formula IV-A.

[0197] Formula VA: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0198] In another embodiment, a compound of formula V: [ka] Provided herein are compounds of formula VA having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NRa R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0199] In one embodiment of Formula (V), n is 1. In another embodiment of Formula (V), n is 2. In another embodiment of Formula (V), n is 3.

[0200] In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (V), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (V), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (V), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (V), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (V), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (V), fused ring A is 6 membered heteroaryl.

[0201] In another embodiment of Formula (V), fused ring A is cyclopentyl. In another embodiment of Formula (V), fused ring A is cyclopentenyl. In another embodiment of Formula (V), fused ring A is cyclohexyl. In another embodiment of Formula (V), fused ring A is cyclohexenyl. In another embodiment of Formula (V), fused ring A is pyrrolyl. In another embodiment of Formula (V), fused ring A is pyrazolyl. In another embodiment of Formula (V), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (V), fused ring A is imidazolyl. In another embodiment of Formula (V), fused ring A is isoxazolyl. In another embodiment of Formula (V), fused ring A is tetrahydropyranyl. In another embodiment of Formula (V), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (V), fused ring A is dihydropyranyl. In another embodiment of formula (V), fused ring A is dihydrofuranyl.

[0202] In another embodiment of formula (V), Y is NR 10 In another embodiment of Formula (V), Y is O. In another embodiment of Formula (V), Y is absent. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl and Y is NR 10 In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (V), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (V), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (V), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (V), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0203] In another embodiment of Formula (V), T is CR1R2. In another embodiment of Formula (V), T is O. In another embodiment of Formula (V), W is CR4R5. In another embodiment of Formula (V), W is O. In another embodiment of Formula (V), T is CR1R2 and W is CR4R5. In another embodiment of Formula (V), T is O and W is CR4R5. In another embodiment of Formula (V), T is CR1R2 and W is O.

[0204] In another embodiment of Formula (V), V is CR3. In another embodiment of Formula (V), V is N.

[0205] In another embodiment of Formula (V), T is CR1R2 and V is CR3. In another embodiment of Formula (V), T is O and V is CR3. In another embodiment of Formula (V), T is CR1R2 and V is N. In another embodiment of Formula (V), T is O and V is N.

[0206] In another embodiment of Formula (V), W is CR4R5 and V is CR3. In another embodiment of Formula (V), W is O and V is CR3. In another embodiment of Formula (V), W is CR4R5 and V is N. In another embodiment of Formula (V), W is O and V is N.

[0207] In another embodiment of Formula (V), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (V), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (V), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (V), T is CR1R2, W is O and V is N. In another embodiment of Formula (V), T is O, W is CR4R5 and V is CR3.

[0208] In another embodiment of Formula (V), E is H. In another embodiment of Formula (V), E is hydroxyl. In another embodiment of Formula (V), E is NR a R bIn another embodiment of formula (V), E is C(=O)NR a R b In another embodiment of formula (V), E is C1-C3 alkylene-NR a R b In another embodiment of Formula (V), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (V), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (V), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (V), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (V), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (V), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (V), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is an unsubstituted C6-C 10 In another embodiment of formula (V), E is a C6-C aryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.10 In another embodiment of formula (V), E is unsubstituted C1-C3 alkylene-(C6-C 10 In another embodiment of formula (V), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (V), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (V), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0209] In another embodiment of Formula (V), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (V), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (V), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (V), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (V), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (V), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0210] In another embodiment of formula (V), E is NR a R b , C(=O)NR a R b, C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0211] In another embodiment of formula (V), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0212] In another embodiment of formula (V), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0213] In another embodiment of formula (V), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0214] In another embodiment of Formula (V), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0215] In another embodiment of Formula (V), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is methyl. In another embodiment of Formula (V), E is trifluoromethyl. In another embodiment of Formula (V), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (V), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (V), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (V), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0216] In another embodiment of formula (V), R 14 is H. In another embodiment of formula (V), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (V), R 15 and R 16 are each H. In another embodiment of formula (V), R 15 is unsubstituted C1-C3 alkyl, and R 16 is H. In another embodiment of formula (V), R 16is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (V), each R 17 and R 18 is H. In another embodiment of formula (V), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (V), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (V), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (V), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0217] In another embodiment of Formula (V), m is 1. In another embodiment of Formula (V), m is 2. In another embodiment of Formula (V), m is 3. In another embodiment of Formula (V), m is 4. In another embodiment of Formula (V), m is 1, 2 or 3. In another embodiment of Formula (V), m is 2, 3 or 4. In another embodiment of Formula (V), m is 1 or 2. In another embodiment of Formula (V), m is 3 or 4.

[0218] In another embodiment of Formula (V), Y is O and m is 1. In another embodiment of Formula (V), Y is O and m is 2. In another embodiment of Formula (V), Y is O and m is 3. In another embodiment of Formula (V), Y is O and m is 4. In another embodiment of Formula (V), Y is O and m is 1, 2 or 3. In another embodiment of Formula (V), Y is O and m is 2, 3 or 4. In another embodiment of Formula (V), Y is O and m is 1 or 2. In another embodiment of Formula (V), Y is O and m is 3 or 4.

[0219] In another embodiment of Formula (V), Y is absent and m is 2. In another embodiment of Formula (V), Y is absent and m is 3. In another embodiment of Formula (V), Y is absent and m is 4. In another embodiment of Formula (V), Y is absent and m is 5. In another embodiment of Formula (V), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (V), Y is absent and m is 2 or 3. In another embodiment of Formula (V), Y is absent and m is 4 or 5.

[0220] In another embodiment of formula (V), Y is NR 10 and m is 1. In another embodiment of formula (V), Y is NR 10 and m is 2. In another embodiment of formula (V), Y is NR 10 and m is 3. In another embodiment of formula (V), Y is NR 10 and m is 4. In another embodiment of formula (V), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (V), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (V), Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), Y is NR 10 and m is 3 or 4.

[0221] In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (V), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (V), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (V), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (V), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (V), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0222] In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0223] In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0224] In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0225] In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10and m is 3 or 4. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (V), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0226] In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0227] In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (V), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (V), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0228] In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0229] In another embodiment of Formula (V), R1, R2, R4 and R5 are each H. In another embodiment of Formula (V), R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of Formula (V), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are each H. In another embodiment of Formula (V), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0230] In another embodiment of Formula (V), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (V), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (V), R6, R7, R8, R9, and R 11 In another embodiment of formula (V), one or more of R, R, R, R and R are fluorine. 11 In another embodiment of formula (V), one or more of R 12 and R 13 In another embodiment of formula (V), one or more of R 12 and R 13 One or more of is deuterium.

[0231] In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 2. In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18is H. In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 2. In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 2.

[0232] Each of the embodiments described herein with respect to compounds of formula V also applies to compounds of formula VA.

[0233] Formula VI-A: [ka] Also provided herein is a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10 or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20 are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0234] In another embodiment, a compound of formula VI: [ka] Provided herein is a compound of formula VI-A having the structure: Fused ring A is C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium; [ka] is a single or double bond; J and L are each independently C or N; M is N or CR 19 and; Q is N or CR 20 and; G is C(=O) or S(=O)2; n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NRa R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, and C1-C3 alkylene-(5-10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; R a and R b are each independently H or unsubstituted C1-C3 alkyl; when Y is absent, m is 2, 3, 4, or 5; or Y is NR 10or when O, m is 1, 2, 3 or 4; and further: R1, R2, R4 and R5 are each independently selected from the group consisting of H, hydroxyl, halogen and deuterium; or alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond; R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl; R6, R7, R8, R9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 are independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; R 19 and R 20are each independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0235] In one embodiment of Formula (VI), n is 1. In another embodiment of Formula (VI), n is 2. In another embodiment of Formula (VI), n is 3.

[0236] In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl. In another embodiment of Formula (VI), fused ring A is C4-C6 cycloalkyl. In another embodiment of Formula (VI), fused ring A is C4-C5 cycloalkyl. In another embodiment of Formula (VI), fused ring A is 4-7 membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5-6 membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5 membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 6 membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5-8 membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 5-6 membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 5 membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 6 membered heteroaryl.

[0237] In another embodiment of Formula (VI), fused ring A is cyclopentyl. In another embodiment of Formula (VI), fused ring A is cyclopentenyl. In another embodiment of Formula (VI), fused ring A is cyclohexyl. In another embodiment of Formula (VI), fused ring A is cyclohexenyl. In another embodiment of Formula (VI), fused ring A is pyrrolyl. In another embodiment of Formula (VI), fused ring A is pyrazolyl. In another embodiment of Formula (VI), fused ring A is 1-methylpyrazolyl. In another embodiment of Formula (VI), fused ring A is imidazolyl. In another embodiment of Formula (VI), fused ring A is isoxazolyl. In another embodiment of Formula (VI), fused ring A is tetrahydropyranyl. In another embodiment of Formula (VI), fused ring A is tetrahydrofuranyl. In another embodiment of Formula (VI), fused ring A is dihydropyranyl. In another embodiment of formula (VI), fused ring A is dihydrofuranyl.

[0238] In another embodiment of formula (VI), Y is NR 10 In another embodiment of Formula (VI), Y is O. In another embodiment of Formula (VI), Y is absent. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl and Y is NR 10 In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl and Y is O. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl and Y is absent. In another embodiment of Formula (VI), fused ring A is a C4-C8 cycloalkyl and Y is NR 10 In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl and Y is absent. In another embodiment of Formula (VI), fused ring A is 4-7 membered heterocyclyl and Y is NR 10 In another embodiment of Formula (VI), fused ring A is a 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (VI), fused ring A is a 4- to 7-membered heterocyclyl and Y is absent.

[0239] In another embodiment of Formula (VI), T is CR1R2. In another embodiment of Formula (VI), T is O. In another embodiment of Formula (VI), W is CR4R5. In another embodiment of Formula (VI), W is O. In another embodiment of Formula (VI), T is CR1R2 and W is CR4R5. In another embodiment of Formula (VI), T is O and W is CR4R5. In another embodiment of Formula (VI), T is CR1R2 and W is O.

[0240] In another embodiment of formula (VI), V is CR3. In another embodiment of formula (VI), V is N.

[0241] In another embodiment of Formula (VI), T is CR1R2 and V is CR3. In another embodiment of Formula (VI), T is O and V is CR3. In another embodiment of Formula (VI), T is CR1R2 and V is N. In another embodiment of Formula (VI), T is O and V is N.

[0242] In another embodiment of Formula (VI), W is CR4R5 and V is CR3. In another embodiment of Formula (VI), W is O and V is CR3. In another embodiment of Formula (VI), W is CR4R5 and V is N. In another embodiment of Formula (VI), W is O and V is N.

[0243] In another embodiment of Formula (VI), T is CR1R2, W is CR4R5 and V is CR3. In another embodiment of Formula (VI), T is CR1R2, W is O and V is CR3. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5 and V is N. In another embodiment of Formula (VI), T is CR1R2, W is O and V is N. In another embodiment of Formula (VI), T is O, W is CR4R5 and V is CR3.

[0244] In another embodiment of Formula (VI), E is H. In another embodiment of Formula (VI), E is hydroxyl. In another embodiment of Formula (VI), E is NR a Rb In another embodiment of formula (VI), E is C(=O)NR a R b In another embodiment of formula (VI), E is C1-C3 alkylene-NR a R b In another embodiment of Formula (VI), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (VI), E is C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3 alkyl. In another embodiment of Formula (VI), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of Formula (VI), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of Formula (VI), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (VI), E is 4-10 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3 alkylene-(4-10 membered heterocyclyl). In another embodiment of Formula (VI), E is a C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is an unsubstituted C6-C 10In another embodiment of formula (VI), E is a C6-C aryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of formula (VI), E is unsubstituted C1-C3 alkylene-(C6-C 10 In another embodiment of formula (VI), E is C1-C3 alkylene-(C6-C3 aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (VI), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (VI), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0245] In another embodiment of Formula (VI), E is an unsubstituted 4-7 membered heterocyclyl. In another embodiment of Formula (VI), E is a 4-7 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is an unsubstituted 4-6 membered heterocyclyl. In another embodiment of Formula (VI), E is a 4-6 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is an unsubstituted 4 membered heterocyclyl. In another embodiment of Formula (VI), E is a 4 membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is an unsubstituted 5 membered heterocyclyl. In another embodiment of Formula (VI), E is a 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is an unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (VI), E is a 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0246] In another embodiment of formula (VI), E is NR a R b , C(=O)NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkylene -NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0247] In another embodiment of formula (VI), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0248] In another embodiment of formula (VI), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 Aryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0249] In another embodiment of formula (VI), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0250] In another embodiment of formula (VI), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0251] In another embodiment of Formula (VI), E is methyl, wherein methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is methyl. In another embodiment of Formula (VI), E is trifluoromethyl. In another embodiment of Formula (VI), E is dioxanyl, wherein dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is tetrahydropyranyl, wherein tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is tetrahydrofuranyl, wherein tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (VI), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (VI), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl. In another embodiment of Formula (VI), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C alkoxyl.

[0252] In another embodiment of formula (VI), R 14 is H. In another embodiment of formula (VI), R 14 is unsubstituted C1-C3 alkyl. In another embodiment of formula (VI), R 15 and R 16 are each H. In another embodiment of formula (VI), R 15 is unsubstituted C1-C3 alkyl, and R 16 is H. In another embodiment of formula (VI), R 16 is unsubstituted C1-C3 alkyl, and R 15 is H. In another embodiment of formula (VI), each R 17 and R 18 is H. In another embodiment of formula (VI), R 17 is unsubstituted C1-C3 alkyl, and R 18 is H. In another embodiment of formula (VI), R 18 is unsubstituted C1-C3 alkyl, and R 17 is H. In another embodiment of formula (VI), R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl and the others are each H. In another embodiment of formula (VI), R 14 , R 15 , R 16 , R 17 and R 18 Each of is H.

[0253] In another embodiment of Formula (VI), m is 1. In another embodiment of Formula (VI), m is 2. In another embodiment of Formula (VI), m is 3. In another embodiment of Formula (VI), m is 4. In another embodiment of Formula (VI), m is 1, 2 or 3. In another embodiment of Formula (VI), m is 2, 3 or 4. In another embodiment of Formula (VI), m is 1 or 2. In another embodiment of Formula (VI), m is 3 or 4.

[0254] In another embodiment of Formula (VI), Y is O and m is 1. In another embodiment of Formula (VI), Y is O and m is 2. In another embodiment of Formula (VI), Y is O and m is 3. In another embodiment of Formula (VI), Y is O and m is 4. In another embodiment of Formula (VI), Y is O and m is 1, 2 or 3. In another embodiment of Formula (VI), Y is O and m is 2, 3 or 4. In another embodiment of Formula (VI), Y is O and m is 1 or 2. In another embodiment of Formula (VI), Y is O and m is 3 or 4.

[0255] In another embodiment of Formula (VI), Y is absent and m is 2. In another embodiment of Formula (VI), Y is absent and m is 3. In another embodiment of Formula (VI), Y is absent and m is 4. In another embodiment of Formula (VI), Y is absent and m is 2, 3 or 4. In another embodiment of Formula (VI), Y is absent and m is 2 or 3. In another embodiment of Formula (VI), Y is absent and m is 4 or 5.

[0256] In another embodiment of formula (VI), Y is NR 10 and m is 1. In another embodiment of formula (VI), Y is NR 10 and m is 2. In another embodiment of formula (VI), Y is NR 10 and m is 3. In another embodiment of formula (VI), Y is NR 10 and m is 4. In another embodiment of formula (VI), Y is NR 10 and m is 1, 2 or 3. In another embodiment of formula (VI), Y is NR 10 and m is 2, 3 or 4. In another embodiment of formula (VI), Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), Y is NR 10 and m is 3 or 4.

[0257] In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl and n is 1. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl and n is 2. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl and n is 3. In another embodiment of Formula (VI), fused ring A is 4-7 membered heterocyclyl and n is 1. In another embodiment of Formula (VI), fused ring A is 4-7 membered heterocyclyl and n is 2. In another embodiment of Formula (VI), fused ring A is 4-7 membered heterocyclyl and n is 3. In another embodiment of Formula (VI), fused ring A is 5-8 membered heteroaryl and n is 1. In another embodiment of Formula (VI), fused ring A is 5-8 membered heteroaryl and n is 2. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl and n is 3.

[0258] In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is absent.

[0259] In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 3, and Y is absent.

[0260] In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1 and Y is NR 10 In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is absent.

[0261] In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, and Y is NR 10and m is 3 or 4. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is C4-C8 cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (VI), fused ring A is C4-C8 cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

[0262] In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 4-7 membered heterocyclyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 4- to 7-membered heterocyclyl, n is 3, Y is absent, and m is 3 or 4.

[0263] In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (VI), fused ring A is a 5-8 membered heteroaryl, n is 3, Y is absent, and m is 3 or 4.

[0264] In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (VI), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0265] In another embodiment of Formula (VI), R1, R2, R4, and R5 are each H. In another embodiment of Formula (VI), R1, R2, R4, and R5 are each H; R3 is H. In another embodiment of Formula (VI), R1, R2, R4, and R5 are each H; R3 is H; R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (VI), R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 are H and R respectively. 12 and R 13 are H respectively.

[0266] In another embodiment of Formula (VI), one or more of R1, R2, R4, and R5 is fluorine. In another embodiment of Formula (VI), one or more of R1, R2, R4, and R5 is deuterium. In another embodiment of Formula (VI), R6, R7, R8, R9, and R 11 In another embodiment of formula (VI), one or more of R, R, R, R and R are fluorine. 11 In another embodiment of formula (VI), one or more of R 12 and R 13 In another embodiment of formula (VI), one or more of R 12 and R 13 One or more of is deuterium.

[0267] In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 2. In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18is H. In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 is H and m is 2. In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is H. In another embodiment of formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of is H and m is 2.

[0268] Each of the embodiments described herein with respect to compounds of formula VI also applies to compounds of formula VI-A.

[0269] Certain embodiments of compounds of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof, are set forth below in Table 1. Compounds of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof, and compounds of Table 1, or a pharmaceutically acceptable salt thereof, are sometimes referred to herein, collectively or individually, as "compounds of the invention" or "compounds provided herein." [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0270] The disclosed compounds have one or more stereocenters, and each stereocenter can independently exist in either R or S configuration.In one embodiment, the compounds described herein exist in optically active form or racemic form.It is understood that the compounds described herein include racemic, optically active, positional isomers and stereoisomeric forms, or their combinations that have the therapeutically useful properties described herein.

[0271] Preparation of optically active forms can be achieved in any suitable manner, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In one embodiment, a mixture of two or more isomers is used as the disclosed compounds described herein. In another embodiment, a pure isomer is used as the disclosed compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, or separation of a mixture of enantiomers or diastereomers. Resolution of the compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0272] In one aspect, the disclosed compounds can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0273] The compounds described herein also include isotopically labeled compounds, in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P and 35 In one embodiment, isotopically labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isomers, such as deuterium, provides greater metabolic stability (e.g., increased in vivo half-life or reduced administration requirements). In another embodiment, the compounds described herein are 2 Contains the H (i.e., deuterium) isotope.

[0274] In yet another embodiment, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, is useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs a suitable isotopically labeled reagent in place of an otherwise used unlabeled reagent.

[0275] Certain compounds described herein, and other compounds encompassed by one or more of the formulas described herein with different substituents, can be synthesized using the techniques and materials described herein, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001) and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), all of which are incorporated by reference for such disclosures. The general methods for the preparation of the compounds described herein are modified using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein.

[0276] The compounds described herein are synthesized using any suitable procedure beginning with compounds available from commercial sources or prepared using the procedures described herein.

[0277] Treatment method The compounds of the present invention can be used in a method for treating a disease or condition in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutical composition containing a compound of the present invention. In one embodiment of the methods described herein, the subject is a human. In one aspect, the compounds provided herein are useful for treating a disease or condition by acting as agonists of the orexin-2 receptor.

[0278] The compounds of the present invention may be used to treat a disease or condition selected from the group consisting of narcolepsy, cataplexy, or hypersomnia in a subject in need of such treatment.

[0279] In one embodiment, the compounds of the present invention can be used to treat narcolepsy in a subject. In one embodiment, the compounds of the present invention can be used to treat cataplexy in a subject. In one embodiment, the compounds of the present invention can be used to treat hypersomnia in a subject.

[0280] Orexin-2 receptor is important in a wide range of biological functions.This suggests that orexin-2 receptor plays a role in various disease processes in humans or other species.The compounds of the present invention are useful for treating, preventing or ameliorating one or more of the following symptoms or the risk of diseases of various neurological and psychiatric diseases associated with changes in sleep / wake function: The present invention may include, but is not limited to, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome, hypersomnolence syndrome characterized by excessive sleepiness (e.g., in subjects with Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple system atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, or Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinism-induced obesity, hyperplasmic obesity, pituitary hypoplasia, hypocalcemia ... Hypothyroid obesity, hypoplastic (hypoplasmic) obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, infantile obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple or central obesity), insulin resistance syndrome, Alzheimer's disease, disturbances of consciousness such as coma, side effects and complications due to anesthesia, sleep disturbances, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's dusk), sundowning phenomenon, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive eating disorder, obesity-related disorders, high blood pressure, diabetes, increased plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction,Congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, polycystic ovarian disease, craniopharingioma, Prader-Willi syndrome, Froelich syndrome, growth hormone deficiency, normal mutant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, sexual and reproductive dysfunction such as subfertility, infertility, male hypogonadism, and female hirsutism, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, and obesity-hypoventilation syndrome (Pickwickian syndrome). ), respiratory disorders such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, risk of secondary consequences of obesity, e.g., reduced risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, autoimmune encephalitis, cancer-related fatigue (e.g., excessive daytime sleepiness or fatigue related to cancer and / or chemotherapy), cancer-related nausea and vomiting, corticobasal degeneration, Huntington's disease, neuromyelitis optica, nociception, progressive supranuclear palsy, schizophrenia, systemic lupus erythematosus traumatic brain injury, hot flashes, night sweats, disorders of the reproductive / urinary system, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neurological injury, Huntington's chorea disease, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorders, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced tremor-paresis syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy,and traumatic brain injury (TBI).

[0281] In particular, the compounds of the present invention are useful as therapeutic or prophylactic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome, hypersomnolence syndrome characterized by excessive sleepiness (e.g., in Parkinson's disease, Guillain-Barré syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbances of consciousness such as coma, side effects and complications of anesthesia, etc., or anesthetic antagonists.

[0282] In one embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for narcolepsy.

[0283] In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for type 1 narcolepsy. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for type 2 narcolepsy. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy and excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy and cataplexy. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for idiopathic hypersomnia. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for obstructive sleep apnea.

[0284] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for hypersomnia in Parkinson's disease.

[0285] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for excessive sleepiness. In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for excessive daytime sleepiness associated with Parkinson's disease.

[0286] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy.

[0287] In another aspect, the present invention provides a method of treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0288] In another aspect, the present invention provides a method of treating narcolepsy type 1 in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0289] In another aspect, the present invention provides a method of treating narcolepsy type 2 in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0290] In another aspect, the present invention provides a method of treating narcolepsy and excessive daytime sleepiness in a subject in need of such treatment, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0291] In another aspect, the present invention provides a method of treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject in need of such treatment, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof.

[0292] In another aspect, the present invention provides a method of treating narcolepsy and cataplexy in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0293] In another aspect, the invention provides a method of treating excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0294] In another aspect, the present invention provides a method of treating idiopathic hypersomnia in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0295] In another aspect, the present invention provides a method of treating excessive daytime sleepiness and idiopathic hypersomnia in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0296] In another aspect, the present invention provides a method of treating obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0297] In another aspect, the present invention provides a method of treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of Formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof.

[0298] In any of the methods described herein, the subject is administered a compound of Formula I. In any of the methods described herein, the subject is administered a compound of Formula II. In any of the methods described herein, the subject is administered a compound of Formula III. In any of the methods described herein, the subject is administered a compound of Formula IV. In any of the methods described herein, the subject is administered a compound of Formula V. In any of the methods described herein, the subject is administered a compound of Formula VI.

[0299] Each of the embodiments described herein with respect to the use of a compound of formula I also applies to a compound of formula IA. Each of the embodiments described herein with respect to the use of a compound of formula II also applies to a compound of formula II-A. Each of the embodiments described herein with respect to the use of a compound of formula III also applies to a compound of formula III-A. Each of the embodiments described herein with respect to the use of a compound of formula IV also applies to a compound of formula IV-A. Each of the embodiments described herein with respect to the use of a compound of formula V also applies to a compound of formula VA. Each of the embodiments described herein with respect to the use of a compound of formula VI also applies to a compound of formula VI-A.

[0300] In any of the compositions or methods described herein, the compound of formula IA, I, II-A, II, III-A, III, IV-A, IV, VA, V, VI-A or VI, or a pharmaceutically acceptable salt thereof, is present and / or administered in a therapeutically effective amount.

[0301] Administration / Dosage / Formulation In another aspect, provided herein are pharmaceutical compositions comprising at least one compound of the present invention in association with a pharmaceutically acceptable carrier.

[0302] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0303] In particular, the selected dose level will depend on a variety of factors such as the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors known in the medical arts.

[0304] A medical doctor, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can begin administering the pharmaceutical composition to administer the disclosed compounds at levels lower than needed to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0305] In certain embodiments, it is particularly advantageous to formulate compound in unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage refers to a physically separate unit that is adapted to be a unit dose for the patient to be treated; each unit contains a predetermined amount of disclosed compound that is calculated to produce desired therapeutic effect in association with required pharmaceutical vehicle.The unit dosage form of the present invention is determined by and directly depends on (a) the specific characteristics of disclosed compound and the specific therapeutic effect achieved, and (b) the limitations inherent in the field of compound / formulation of such disclosed compound for treating narcolepsy or cataplexy in patients.

[0306] In one embodiment, the compounds of the present invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0307] In some embodiments, the dosage of the disclosed compounds is about 1 mg to about 1,000 mg. In some embodiments, the dosage of the disclosed compounds used in the compositions described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg, or less than about 10 mg. For example, the dosage is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.

[0308] The administration route of any of the compositions of the present invention can be oral, nasal, rectal, vaginal, parenteral, buccal, sublingual or topical.The compounds for use in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., transvaginal and perivaginal), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.In one embodiment, the preferred administration route is oral.

[0309] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions useful in the present invention are not limited to the particular formulations and compositions described herein.

[0310] For oral application, tablets, dragees, liquids, drops, suppositories or capsules, caplets and gel caps are particularly suitable.The composition intended for oral use can be prepared according to any method known in the art, and such composition can contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for tablet manufacture.Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate.Tablets can be uncoated or can be coated by known techniques for scientific precision or to delay the release of active ingredients.Preparations for oral use can also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert diluent.

[0311] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, optionally containing other formulatory agents such as suspending, stabilizing, or dispersing agents, can be used.

[0312] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims appended hereto. It should be understood that modifications using no more than routine experimentation with art-recognized variations in reaction conditions, including, but not limited to, reaction time, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, are within the scope of this application.

[0313] Whenever values ​​and ranges are provided herein, it is understood that all values ​​and ranges subsumed within those values ​​and ranges are intended to be encompassed within the scope of the present invention. Furthermore, all values ​​subsumed within those ranges, as well as the upper or lower limits of a range of values, are also contemplated by this application.

[0314] The following examples further illustrate aspects of the present invention, but are in no way a limitation of the inventive technology or disclosure described herein. [Example]

[0315] Example The present invention is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology and immunology, which are within the skill of the art.

[0316] General Procedure Example 1: Synthetic Procedure The synthetic procedures for preparing the compounds of the present invention are readily available to those skilled in the art.Unless otherwise indicated, starting materials are generally obtained from commercial suppliers.Synthetic procedures for other macrocyclic compounds can be found, for example, in U.S. Application No. 17 / 104,993 and PCT Application No. PCT / US20 / 62320, both filed on November 25, 2020, U.S. Provisional Application No. 63 / 128,404, filed on December 21, 2020, and U.S. Provisional Application No. 63 / 179,616, filed on April 26, 2021, all of which are expressly incorporated herein by reference.

[0317] The following abbreviations may be used in the synthetic examples below: AcOH = acetic acid DCM = dichloromethane MsCl = methanesulfonyl chloride MeOH = methanol THF = tetrahydrofuran EtOH = ethanol PtO2 = platinum dioxide HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DIPEA or DIEA = N,N-diisopropylethylamine t Bu = tert-butyl ACN or MeCN = acetonitrile EtOAc = ethyl acetate DMF = dimethylformamide TFA = trifluoroacetic acid LiOH = lithium hydroxide min=minutes hr=hour Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(O) DMSO = dimethyl sulfoxide i-PrOH = isopropanol Pd / C = palladium on carbon XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Boc = tert-butyloxycarbonyl Ms = methanesulfonyl Bn = benzyl Et = ethyl Cbz = carboxybenzyl Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) TfO = trifluoromethanesulfonate KHMDS = potassium bis(trimethylsilyl)amide solution Et3N or TEA = triethylamine.

[0318] Example 1.1 [ka] To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (753.0 g, 1.0 equiv., 4.8 mol) in THF (10 L) was added potassium tert-butoxide (534.3 g, 1.3 equiv., 4.8 mol) in portions at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 0 °C for 30 min. To this was added a solution of 3-bromo-2-(bromomethyl)pyridine (919.0 g, 1.0 equiv., 4.8 mol) in THF (1.0 L) dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 L of sat. NH4Cl (aq.). The resulting solution was extracted with 3 × 1 L of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3-bromo-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridine (962.0 g, 80.0%) as an oil.

[0319] [ka] To a stirred solution of 3-bromo-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridine (962.0 g, 1.0 equiv., 2.9 mol) and tert-butyl carbamate (686.7 g, 2.0 equiv., 5.9 mol) in dioxane (10.0 L) under a nitrogen atmosphere, Pd2(dba)3 (134.2 g, 0.05 equiv., 0.15 mol), XantPhos (169.6 g, 0.10 equiv., 0.29 mol), and Cs2CO3 (2395 g, 2.5 equiv., 7.3 mol) were added. The resulting solution was stirred at 100 °C for 20 h. The solids were removed by filtration. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column to give tert-butyl N-[2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridin-3-yl]carbamate (620.0 g, 58.0%) as a solid.

[0320] [ka] To a stirred solution of tert-butyl N-[2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridin-3-yl]carbamate (620.0 g, 1.0 equivalent, 1.7 mmol) in methanol (6.0 L) and acetic acid (600 mL) was added PtO (77.26 g, 0.20 equivalent, 340.2 mmol). The mixture was hydrogenated at room temperature under 20 atm of hydrogen. The resulting solution was stirred at room temperature overnight. The solids were filtered off. The resulting mixture was concentrated in vacuo to give tert-butyl N-[2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidin-3-yl]carbamate (620.0 g, 99.9%) as an oil.

[0321] [ka] To a stirred mixture of tert-butyl N-[2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidin-3-yl]carbamate (620.0 g, 1.0 equiv., 1.7 mmol) in DCM (6.0 L) was added N-(benzyloxycarbonyloxy)succinimide (845.9 g, 1.2 equiv., 2.0 mol) and DIEA (648.9 g, 3.0 equiv., 5.0 mol) at room temperature. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 5 L of water / ice. The resulting mixture was extracted with 2×2 L of DCM. The mixture was dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl 3-[(tert-butoxycarbonyl)amino]-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidine-1-carboxylate (422.0 g, 50.0%) as an oil.

[0322] [ka] To a stirred solution of benzyl 3-[(tert-butoxycarbonyl)amino]-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidine-1-carboxylate (422.0 g, 1.0 equiv., 0.84 mol) in acetic acid (280 mL) was added water (140 mL) at room temperature. The resulting solution was stirred at 30° C. for 12 hours. The mixture was cooled to 10° C. Then, 6 L of ice water was added to quench the reaction. The resulting solution was stirred at 10° C. for 1 hour. The precipitated solid was collected by filtration. The crude product was purified by three recrystallizations from diethyl ether:ethyl acetate = 5:1 (10 mL / g) to give benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (108.7 g, 28.2%) as a solid. LCMS (ESI): m / z [M+H] + = 461; 1 H-NMR (300MHz, DMSO-d6) δ 7.38 - 7.26 (m, 5H), 6.97 - 6.95 (m, 1H), 5.06 (brs, 2H), 4.60 (brs, 1H), 3.92 - 3.81 (m, 1H), 3.76 - 3.42 (m, 4H), 2.95 - 2.72 (m, 1H), 2.39 - 2.23 (s, 2H), 2.18 - 2.05 (m, 2H), 1.93 - 1.80 (m, 4H), 1.73 - 1.48 (m, 3H), 1.39 - 1.36 (m, 10H).

[0323] [ka] To a stirred solution of benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (30.0 g, 1.0 equiv., 65.1 mmol) in THF (300 mL) was added KHMDS (78.2 mL, 1.2 equiv., 78.2 mmol) at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 3 hours, and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (27.9 g, 1.2 equiv., 78.2 mmol) in THF (100 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 2 hours. The mixture was added dropwise to 200 mL of sat. NH4Cl (aq.) at 0° C. The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (41.0 g, crude) as an oil.

[0324] [ka] To a solution of benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (350 g, 1.0 equiv., 0.59 mol) and bis(pinacolato)diboron (180 g, 1.2 equiv., 0.71 mol) in 1,4-dioxane (3.5 L) was added Pd(dppf)Cl.CHCl (24.1 g, 0.05 equiv., 29.5 mmol) and potassium acetate (116 g, 2.0 equiv., 1.18 mol) under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by reverse flash chromatography to give benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (90.8 g, 26.2%) as a solid. LCMS (ESI): m / z [M+H] + = 571; 1 H-NMR (300MHz, DMSO-d6): δ7.41-7.24 (m, 5H), 6.91 (brs, 1H), 6.30 (brs, 1H), 5.08...

Claims

1. Formula IA, II-A, III-A, IV-A, VA or VI-A: 【Chemistry 1-1】 【Chemistry 1-2】 【Chemistry 1-3】 (In the formula: The fused ring A is C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl, where C 4 -C 8 Cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl may be unsubstituted or substituted with one or more of halogen, deuterium, hydroxyl, cyano, C 1 -C 3 Alkoxy, unsubstituted C 1 -C 3 Alkyl and C substituted with one or more halogens or deuterium 1 -C 3 substituted with alkyl; 【Chemistry 2】 is a single bond or a double bond; J and L are each independently C or N; M is N or CR 19 and Q is N or CR 20 and G is C(=O) or S(=O) 2 and n is 1, 2 or 3; E is H, hydroxyl, NR a R b , C(=O)NR a R b , C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4-10 membered heterocyclyl, C 1 -C 3 Alkylene-(4-10 membered heterocyclyl), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5-10 membered heteroaryl and C 1 -C 3 alkylene-(5-10 membered heteroaryl), 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4-10 membered heterocyclyl, C 1 -C 3 Alkylene-(4-10 membered heterocyclyl), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5-10 membered heteroaryl or C 1 -C 3 Alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more of halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 alkoxy substituted; T is CR 1 R 2 or O; W is CR 4 R 5 or O; U is CR 6 R 7 and X is CR 8 R 9 and V is CR 3 or N; Y is NR 10 , O or absent; Z is (CR 12 R 13 ) m and R a and R b each independently represents H or unsubstituted C 1 -C 3 is alkyl; As for m: (i) for formula IA, II-A or III-A, m is 1, 2, 3 or 4; (ii) in the case of formula IV-A, VA or VI-A, when Y is NR 10 or O, m is 1, 2, 3 or 4; or (iii) for formula IV-A, VA or VI-A, when Y is absent, m is 2, 3, 4 or 5; and additionally: R 1 , R 2 , R 4 and R 5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; or alternatively, R 2 and R 5 together with the carbon atom to which they are attached form a single bond; R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl and cyano; or alternatively, R 3 and R 1 together with the carbon atoms to which they are attached, C 3 -C 5 Forming a cycloalkyl; or alternatively, R 3 and R 4 together with the carbon atoms to which they are attached, C 3 -C 5 Forming a cycloalkyl; R 6 , R 7 , R 8 , R 9 and R 11 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 H, unsubstituted C 1 -C 3 C substituted with alkyl and one or more halogens 1 -C 3 selected from the group consisting of alkyl; Each R 12 and R 13 are independently H, halogen, deuterium, or unsubstituted C 1 -C 3 C substituted with alkyl and hydroxyl or one or more halogens 1 -C 3 selected from the group consisting of alkyl; R 14 , R 15 and R 16 each independently represents H, unsubstituted C 1 -C 3 C substituted with alkyl or one or more halogens 1 -C 3 selected from the group consisting of alkyl; Each R 17 and R 18 are independently H, unsubstituted C 1 -C 3 C substituted with alkyl or one or more halogens 1 -C 3 selected from the group consisting of alkyl; R 19 and R 20 are each independently H, halogen, deuterium, hydroxyl, cyano, or unsubstituted C 1 -C 3 C substituted with alkyl and one or more halogens or deuterium 1 -C 3 alkyl) or a pharma- ceutically acceptable salt thereof.

2. A compound of formula IA, II-A, III-A, IV-A, VA or VI-A, or a pharma- ceutically acceptable salt thereof, having formula I, II, III, IV, V or VI: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 or a pharma- ceutically acceptable salt thereof. (i) n is 1 or 2, (ii) Y is O, absent or NR 10 ; (iii) T is CR1R2 or O; (iv) W is CR4R5 or O; (v) V is CR3; and / or (vi) E is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl); C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 The compound of claim 1 or 2, wherein the C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5-10 membered heteroaryl or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl.

4. E is C 1 -C 3 Alkyl, C 3 -C 8 cycloalkyl and 4- to 10-membered heterocyclyl; 1 -C 3 Alkyl, C 3 -C 8 Cycloalkyl or 4- to 10-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 The compound of claim 3 which is substituted with alkoxyl.

5. T is CR 1 R 2 and W is CR 4 R 5 and V is CR 3 3. The compound according to claim 1 or 2,

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

7. The compound of claim 6, wherein m is 2. 【Request 8】 【Chemical 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 2. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

9. 10. A pharmaceutical composition comprising a compound according to claim 1, 2 or 8, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

10. 13. Use of a compound according to claim 1, 2 or 8, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for narcolepsy.

11. 13. Use of a compound according to claim 1, 2 or 8, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for cataplexy.

12. 10. A compound according to claim 1, 2 or 8, or a pharma- ceutically acceptable salt thereof, for use in the treatment of narcolepsy in a subject in need thereof.

13. 10. A compound as claimed in claim 1, 2 or 8, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cataplexy in a subject in need thereof.

14. Use of the composition of claim 9 in the manufacture of a medicament for narcolepsy.

15. Use of the composition of claim 9 in the manufacture of a medicament for cataplexy.

16. The composition of claim 9 for use in treating narcolepsy in a subject in need thereof.

17. The composition of claim 9 for use in treating cataplexy in a subject in need of such treatment.

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