Substituted Macrocycles and Related Methods of Treatment - Patent application

Abstract

The present invention provides compounds that are useful for treating 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 / 128,404, filed December 21, 2020, and U.S. Provisional Patent Application No. 63 / 190,937, filed May 20, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to substituted macrocyclic compounds, and in particular to substituted macrocyclic compounds that have agonist activity. [Background technology]

[0003] Orexins are neuropeptides synthesized and released by a subpopulation of neurons within the lateral hypothalamus and surrounding areas. Orexins consist of two subtypes, orexin A and orexin B. Orexin A and orexin B bind to orexin receptors (ORRs), 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, including maintenance of 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 modified 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 (ORR) knockout mice have suggested that the ORR plays a dominant role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999; Neuron, Vol. 38, 715-730, 2003). Therefore, orexin 2 receptor agonists may be therapeutic agents for narcolepsy or other disorders that present with excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0005] Compounds having agonistic activity at the orexin 2 receptor are hypothesized to be useful as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome, hypersomnia syndromes characterized by hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, 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; U.S. Patent Application Publication No. 20190040010; U.S. Patent Application Publication No. 20190031611; U.S. Patent Application Publication No. 20170226137). However, these compounds are unsatisfactory in terms of, for example, activity, pharmacokinetics, brain / central nervous system permeability, or safety. Therefore, the development of improved compounds with orexin 2 receptor agonist activity is desired. Summary of the Invention

[0007] The present invention aims to provide substituted macrocyclic compounds that have orexin 2 receptor agonist activity.

[0008] Thus, in a first aspect, the present invention provides compounds of formula IA: [ka] A compound represented by the formula: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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 absent; Z is (CR12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 wherein at least one of is C1-C3 alkyl substituted with hydroxyl; or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, a compound of Formula I: [ka] wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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-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; 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; Furthermore, 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; R10 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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 10Aryl, 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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 Provided herein are compounds of formula IA having the structure of formula I, or a pharmaceutically acceptable salt thereof, wherein one or more of:

[0010] Formula II-A: [ka] wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 2, 3, 4 or 5 when Y is not present; m is Y is NR 10 or when O, it is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13Also provided herein are compounds having the structure of Formula II-A, or pharmaceutically acceptable salts thereof, wherein one or more of:

[0011] In one embodiment, a compound of formula II: [ka] wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 2, 3, 4 or 5 when Y is not present; m is Y is NR 10 or when O, it is 1, 2, 3 or 4; Furthermore, 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 12and 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 Provided herein are compounds of formula II-A having the structure of formula II, wherein one or more of: is present; or a pharmaceutically acceptable salt thereof.

[0012] Also provided herein are pharmaceutical compositions comprising a compound of any of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In another aspect, provided herein are methods of treating narcolepsy in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, provided herein are methods of treating cataplexy in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein are compounds that are useful for treating narcolepsy or cataplexy in a subject, for example, compounds of Formula IA, Formula I, Formula II-A, or Formula II, or pharmaceutically acceptable salts thereof:

[0016] In a non-limiting aspect, these compounds can modulate the orexin 2 receptor. 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 agonists of the orexin 2 receptor.

[0017] 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, either individually or as part of a larger group, unless otherwise limited in specific instances.

[0018] 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 methods in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0019] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of its grammatical object. By way of example, "an" means one term or more than one element. Furthermore, the use of terms such as "including" and other forms such as "include," "includes," and "included" is not limiting.

[0020] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent with the context in which the term is used. When used herein when referring to a measurable value, such as an amount, duration, etc., the term "about" is meant to encompass the stated value and variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, and therefore variations are appropriate for practicing the methods of the present disclosure.

[0021] As used herein, "EC 50 " refers to the concentration of a compound required to achieve an effect that is 50% of the compound's maximal effect.

[0022] As used herein, the term "agonist" refers to a compound that, when contacted with a target of interest (e.g., the orexin 2 receptor), increases the magnitude of an activity or function of a given target compared to the magnitude of the activity or function observed in the absence of the agonist.

[0023] The terms "treat," "treated," "treating," or "treatment" include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment comprises contacting the orexin 2 receptor with an effective amount of a compound of the invention for a condition associated with narcolepsy or cataplexy.

[0024] As used herein, the terms "prevent" or "prevention" refer to the absence of development of a disorder or disease if it has not already occurred, or the absence of further development of a disorder or disease if it has already occurred. The ability to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

[0025] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include farm animals and pets, such as mammals such as sheep, cows, pigs, dogs, cats, and mice. Preferably, the patient, subject, or individual is human.

[0026] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. That 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. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0027] 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 a compound and is relatively non-toxic, that is, it may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components contained in the composition.

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety 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. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from 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 free base form of these compounds with a stoichiometric amount of the appropriate salt or acid in water, an organic solvent, or a mixture of water and an organic solvent. Generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred non-aqueous media. The term "pharmaceutically acceptable salt" is not limited to simple salts or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis-salts, such as bis-hydrochloride salts. 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.

[0029] As used herein, the terms "composition" or "pharmaceutical composition" refer to a mixture of at least one compound useful within the present invention and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0030] As used herein, "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the 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, including the compound useful within the invention, and not harmful to the patient. Some examples of materials that 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, ethylcellulose, and acetylcellulose; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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; saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0031] As used herein, "pharmaceutically acceptable carrier" 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 within the present invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in pharmaceutical compositions used in practicing 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.

[0032] As used herein, terms such as "alkyl," by themselves or as part of another substituent, mean, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C-C alkyl means an 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 C-C alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0033] 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 a fluorine, chlorine, or bromine atom, and more preferably a fluorine or chlorine atom.

[0034] As used herein, terms such as "alkylene" refer to divalent aliphatic hydrocarbyl groups having, for example, 1 to 4 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), isopropylene (-CHCH(CH)-), and the like.

[0035] 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.

[0036] 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.

[0037] As used herein, terms such as "alkoxy" refer to an -O-alkyl group, 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.

[0038] 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, which 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 in 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.

[0039] As used herein, the term "heterocyclyl" refers to 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. Such rings may be fused, where fusion is as defined above. Heterocyclyl also includes bicyclic structures which may be bridged or spirocyclic in nature, where each individual ring in 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), including, but not limited to, epoxydyl, 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, a term such as "heterocyclyl" may 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.

[0040] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring that contains one or more polyunsaturated rings and has the property of being aromatic, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0041] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system containing one, two, or three rings, which may be fused, as defined above. When rings are fused, one of the rings must be fully unsaturated, and one or more of the fused rings may be fully saturated, partially unsaturated, or fully unsaturated. Terms such as "aryl" include, but are not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term "aryl" refers to any of C6-C6 alkyl aryls. 10 May include aryl, C6-C8 aryl or C6 aryl (ie phenyl).

[0042] 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. Such rings may be fused, with fusion being as defined above. Examples of the term "heteroaryl" include, but are 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" may 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.

[0043] An aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded to the designated moiety through different ring atoms; if otherwise (i.e., shown or described without indication of a particular point of attachment), it is understood that all possible points, whether through a carbon atom or, for example, a trivalent nitrogen atom, are intended. For example, a term such as "pyridinyl" means 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, and a term such as "thiophenyl" means 2-thiophenyl or 3-thiophenyl.

[0044] As used herein, the term "substituted" means that an atom or group of atoms is substituted for a hydrogen as a substituent bonded to another group.

[0045] Compounds of the Invention Thus, in a first aspect, the present invention provides compounds of formula IA: [ka] A compound represented by the formula: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NRa R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 wherein at least one of is C1-C3 alkyl substituted with hydroxyl; or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, a compound of Formula I: [ka] wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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), 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R bare each independently H or unsubstituted C1-C3 alkyl; m is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 Provided herein are compounds of formula IA having the structure of formula I, or a pharmaceutically acceptable salt thereof, wherein one or more of:

[0047] In one embodiment of formula (I), (a)-(d): (a) at least one R is selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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, C1-C3 alkyl or C1-C3 alkoxyl; (c) E is C1 alkyl substituted with one or more halogen, C1-C3 alkyl, or C1-C3 alkoxyl; or (d)R 14 , R15 , R 16 , R 17 and R 18 at least one of which is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens.

[0048] In another embodiment of Formula (I), at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0049] In another embodiment of Formula (I), E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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.

[0050] In another embodiment of Formula (I), E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is trifluoromethyl. In another embodiment of Formula (I), E is methyl. In another embodiment of Formula (I), E is ethyl. In another embodiment of Formula (I), E is propyl. In another embodiment of Formula (I), E is isopropyl. In another embodiment of Formula (I), E is cyclopropyl. In another embodiment of Formula (I), E is tetrahydrofuranyl.

[0051] In another embodiment of Formula (I), R 14 , R 15 , R 16 , R 17 and R 18 At least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens.

[0052] In another embodiment of formula (I), R1, R2, R4, R5, R6, R7, R8, R9 and R 11 At least one of the is hydroxyl.

[0053] In another embodiment of Formula (I), R 12 and R 13 At least one of is a C1-C3 alkyl substituted with hydroxyl.

[0054] In another 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.

[0055] In another embodiment of Formula (I), Ring A is phenyl. In another embodiment of Formula (I), Ring A is pyridinyl. In another embodiment of Formula (I), Ring A is pyridazinyl.

[0056] In another embodiment of Formula (I), Ring A is pyrimidinyl. In another embodiment of Formula (I), Ring A is pyrazinyl. In another embodiment of Formula (I), Ring A is triazinyl.

[0057] 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), ring A is phenyl and Y is NR 10 In another embodiment of Formula (I), Ring A is phenyl and Y is O. In another embodiment of Formula (I), Ring A is phenyl and Y is absent. In another embodiment of Formula (I), Ring A is pyridinyl and Y is NR 10 In another embodiment of Formula (I), Ring A is pyridinyl and Y is O. In another embodiment of Formula (I), Ring A is pyridinyl and Y is absent. In another embodiment of Formula (I), Ring A is pyridazinyl and Y is NR 10 In another embodiment of Formula (I), Ring A is pyridazinyl and Y is O. In another embodiment of Formula (I), Ring A is pyridazinyl and Y is absent. In another embodiment of Formula (I), Ring A is pyrimidinyl and Y is NR 10 In another embodiment of Formula (I), Ring A is pyrimidinyl and Y is O. In another embodiment of Formula (I), Ring A is pyrimidinyl and Y is absent. In another embodiment of Formula (I), Ring A is pyrazinyl and Y is NR 10 In another embodiment of Formula (I), Ring A is pyrazinyl and Y is O. In another embodiment of Formula (I), Ring A is pyrazinyl and Y is absent. In another embodiment of Formula (I), Ring A is triazinyl and Y is NR 10 In another embodiment of Formula (I), ring A is triazinyl and Y is O. In another embodiment of Formula (I), ring A is triazinyl and Y is absent.

[0058] 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.

[0059] In another embodiment of Formula (I), V is CR3. In another embodiment of Formula (I), V is N.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] In another embodiment of Formula (I), E is 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 C2-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (I), E is C2-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 C2-C3 alkyl. In another embodiment of Formula (I), E is C2-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 C6-C 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 C1-C3 alkylene-(C6-C 10In another embodiment of formula (I), E is C1-C3 alkylene-(C6-C aryl) substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 10 In another embodiment of Formula (I), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (I), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0064] In another embodiment of Formula (I), E is an unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (I), E is a 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 8-10 membered heterocyclyl. In another embodiment of Formula (I), E is an 8-10 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 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- to 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.

[0065] In another embodiment of Formula (I), E is an unsubstituted 5-10 membered heteroaryl. In another embodiment of Formula (I), E is a 5-10 membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 5-6 membered heteroaryl. In another embodiment of Formula (I), E is a 5-6 membered heteroaryl 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 heteroaryl. In another embodiment of Formula (I), E is a 5 membered heteroaryl 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 heteroaryl. In another embodiment of Formula (I), E is a 6-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 8-membered heteroaryl. In another embodiment of Formula (I), E is an 8-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is an unsubstituted 10-membered heteroaryl. In another embodiment of Formula (I), E is a 10-membered heteroaryl 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 , 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), 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 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), and 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) 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), and 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 10Aryl 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 the 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 the 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 the 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 the 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, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is oxetanyl, wherein the oxetanyl 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 morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 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 16 is unsubstituted C1-C3 alkyl, and R 15is 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.

[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 not present and m is 1. In another embodiment of Formula (I), Y is not present and m is 2. In another embodiment of Formula (I), Y is not present and m is 3. In another embodiment of Formula (I), Y is not present and m is 4. In another embodiment of Formula (I), Y is not present and m is 1, 2 or 3. In another embodiment of Formula (I), Y is not present and m is 2, 3 or 4. In another embodiment of Formula (I), Y is not present and m is 1 or 2. In another embodiment of Formula (I), Y is not present 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), ring A is phenyl and n is 1. In another embodiment of Formula (I), ring A is phenyl and n is 2. In another embodiment of Formula (I), ring A is phenyl and n is 3. In another embodiment of Formula (I), ring A is pyridinyl and n is 1. In another embodiment of Formula (I), ring A is pyridinyl and n is 2. In another embodiment of Formula (I), ring A is pyridinyl and n is 3. In another embodiment of Formula (I), ring A is pyridazinyl and n is 1. In another embodiment of Formula (I), ring A is pyridazinyl and n is 2. In another embodiment of Formula (I), ring A is pyridazinyl and n is 3. In another embodiment of Formula (I), ring A is pyrimidinyl and n is 1. In another embodiment of Formula (I), ring A is pyrimidinyl and n is 2. In another embodiment of Formula (I), Ring A is pyrimidinyl and n is 3. In another embodiment of Formula (I), Ring A is pyrazinyl and n is 1. In another embodiment of Formula (I), Ring A is pyrazinyl and n is 2. In another embodiment of Formula (I), Ring A is pyrazinyl and n is 3. In another embodiment of Formula (I), Ring A is triazinyl and n is 1. In another embodiment of Formula (I), Ring A is triazinyl and n is 2. In another embodiment of Formula (I), Ring A is triazinyl and n is 3.

[0078] In another embodiment of Formula (I), ring A is phenyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is phenyl, n is 2, and Y is NR 10 In another embodiment of Formula (I), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of Formula (I), ring A is phenyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is phenyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is phenyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is phenyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is phenyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is phenyl, n is 3, and Y is absent.

[0079] In another embodiment of Formula (I), ring A is phenyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, n is 3, Y is not present, and m is 3 or 4.

[0080] In another embodiment of Formula (I), ring A is pyridinyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is pyridinyl, n is 2, and Y is NR 10 In another embodiment of Formula (I), ring A is pyridinyl, n is 3 and Y is NR 10 In another embodiment of Formula (I), ring A is pyridinyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, and Y is absent.

[0081] In another embodiment of Formula (I), ring A is pyridinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 3 and Y is NR 10and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridinyl, n is 3, Y is not present, and m is 3 or 4.

[0082] In another embodiment of Formula (I), ring A is pyridazinyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is pyridazinyl, n is 2 and Y is NR 10 In another embodiment of Formula (I), ring A is pyridazinyl, n is 3 and Y is NR10 In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, and Y is absent.

[0083] In another embodiment of Formula (I), ring A is pyridazinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyridazinyl, n is 3, Y is not present, and m is 3 or 4.

[0084] In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2 and Y is NR 10 In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3 and Y is NR 10 In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, and Y is absent.

[0085] In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3 and Y is NR 10and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrimidinyl, n is 3, Y is not present, and m is 3 or 4.

[0086] In another embodiment of Formula (I), ring A is pyrazinyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is pyrazinyl, n is 2 and Y is NR 10In another embodiment of Formula (I), ring A is pyrazinyl, n is 3 and Y is NR 10 In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, and Y is absent.

[0087] In another embodiment of Formula (I), ring A is pyrazinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), Ring A is pyrazinyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), Ring A is pyrazinyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), Ring A is pyrazinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), Ring A is pyrazinyl, n is 3 and Y is NR10 and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is pyrazinyl, n is 3, Y is not present, and m is 3 or 4.

[0088] In another embodiment of Formula (I), ring A is triazinyl, n is 1 and Y is NR 10 In another embodiment of Formula (I), ring A is triazinyl, n is 2 and Y is NR 10 In another embodiment of Formula (I), ring A is triazinyl, n is 3 and Y is NR 10 In another embodiment of Formula (I), ring A is triazinyl, n is 1, and Y is O. In another embodiment of Formula (I), ring A is triazinyl, n is 2, and Y is O. In another embodiment of Formula (I), ring A is triazinyl, n is 3, and Y is O. In another embodiment of Formula (I), ring A is triazinyl, n is 1, and Y is absent. In another embodiment of Formula (I), ring A is triazinyl, n is 2, and Y is absent. In another embodiment of Formula (I), ring A is triazinyl, n is 3, and Y is absent.

[0089] In another embodiment of Formula (I), ring A is triazinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 2 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 3 and Y is NR 10and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 1, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 2, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is not present, and m is 1 or 2. In another embodiment of Formula (I), ring A is triazinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (I), ring A is triazinyl, n is 3, Y is not present, and m is 3 or 4.

[0090] In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 3. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 3.

[0091] In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3.

[0092] In another embodiment of Formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (I), ring A is phenyl, 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), ring A is phenyl, 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), ring A is phenyl, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, 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), ring A is phenyl, 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), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4. In another embodiment of Formula (I), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0093] In another embodiment of Formula (I), p is 0, R1, R2, R4, and R5 are each H. In another embodiment of Formula (I), p is 0, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (I), p is 0, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (I), p is 0, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R 11 are H, and R 12 and R 13 are H respectively.

[0094] In another embodiment of Formula (I), p is 1, R1, R2, R4, and R5 are each H. In another embodiment of Formula (I), p is 1, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (I), p is 1, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (I), p is 1, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R 11are H, and R 12 and R 13 are H respectively.

[0095] In another embodiment of Formula (I), p is 2, R1, R2, R4, and R5 are each H. In another embodiment of Formula (I), p is 2, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (I), p is 2, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (I), p is 2, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R 11 are H, and R 12 and R 13 are H respectively.

[0096] In another embodiment of Formula (I), p is 1, 2, 3, or 4, and R is fluorine. In another embodiment of Formula (I), p is 1, 2, 3, or 4, and R is deuterium. In another embodiment of Formula (I), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of Formula (I), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of Formula (I), p is 1, and R is unsubstituted C1-C3 alkyl. In another embodiment of Formula (I), p is 1, and R is methyl. In another embodiment of Formula (I), p is 1 or 2, and each R is methyl. In another embodiment of Formula (I), p is 1 and R is C1-C3 alkyl substituted with one or more halogens. In another embodiment of Formula (I), p is 1 and R is CF3. In another embodiment of Formula (I), p is 1 or 2 and each R is CF3.

[0097] 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 the is deuterium.

[0098] 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 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 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 R18 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 is H and m is 1.

[0099] Each of the embodiments described herein with respect to compounds of formula I also applies to compounds of formula IA.

[0100] Formula II-A: [ka] wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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-C10 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R b are each independently H or unsubstituted C1-C3 alkyl; m is 2, 3, 4 or 5 when Y is not present; m is Y is NR 10 or when O, it is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NRa R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 Also provided herein are compounds having the structure of Formula II-A, or pharmaceutically acceptable salts thereof, wherein one or more of:

[0101] In one embodiment, a compound of formula II: [ka] wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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), 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 absent; Z is (CR 12 R 13 ) m and; each R is independently selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; p is 0, 1, 2, 3 or 4; R a and R bare each independently H or unsubstituted C1-C3 alkyl; m is 2, 3, 4 or 5 when Y is not present; m is Y is NR 10 or when O, it is 1, 2, 3 or 4; Furthermore, 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 are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; However, (a) to (f): (a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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; (c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; (d)R 14 , R 15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 at least one of is hydroxyl; or (f)R 12 and R 13 Provided herein are compounds of formula II-A having the structure of formula II, wherein one or more of: is present; or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment of formula (II), (a)-(d): (a) at least one R is selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium; (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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, C1-C3 alkyl or C1-C3 alkoxyl; (c) E is C1 alkyl substituted with one or more halogen, C1-C3 alkyl, or C1-C3 alkoxyl; or (d)R 14 , R15 , R 16 , R 17 and R 18 at least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens.

[0103] In another embodiment of Formula (II), at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0104] In another embodiment of Formula (II), E is NR a R b , C1-C3 alkylene-NR a R b , C2-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), and C1-C3 alkylene-NR a R b , C2-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.

[0105] In another embodiment of Formula (II), E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is trifluoromethyl. In another embodiment of Formula (II), E is methyl. In another embodiment of Formula (II), E is ethyl. In another embodiment of Formula (II), E is propyl. In another embodiment of Formula (II), E is isopropyl. In another embodiment of Formula (II), E is cyclopropyl. In another embodiment of Formula (II), E is tetrahydrofuranyl.

[0106] In another embodiment of Formula (II), R 14 , R 15 , R 16 , R 17 and R 18 At least one of is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens.

[0107] In another embodiment of Formula (II), R1, R2, R4, R5, R6, R7, R8, R9 and R 11 At least one of the is hydroxyl.

[0108] In another embodiment of Formula (II), R 12 and R 13 At least one of is a C1-C3 alkyl substituted with hydroxyl.

[0109] In another 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.

[0110] In another embodiment of Formula (II), Ring A is phenyl. In another embodiment of Formula (II), Ring A is pyridinyl. In another embodiment of Formula (II), Ring A is pyridazinyl. In another embodiment of Formula (II), Ring A is pyrimidinyl. In another embodiment of Formula (II), Ring A is pyrazinyl. In another embodiment of Formula (II), Ring A is triazinyl.

[0111] In another embodiment of Formula (II), Y is NR 10 In another embodiment of Formula (II), Y is O. In another embodiment of Formula (II), Y is absent. In another embodiment of Formula (II), Ring A is phenyl and Y is NR 10 In another embodiment of Formula (II), Ring A is phenyl and Y is O. In another embodiment of Formula (II), Ring A is phenyl and Y is absent. In another embodiment of Formula (II), Ring A is pyridinyl and Y is NR 10 In another embodiment of Formula (II), Ring A is pyridinyl and Y is O. In another embodiment of Formula (II), Ring A is pyridinyl and Y is absent. In another embodiment of Formula (II), Ring A is pyridazinyl and Y is NR 10 In another embodiment of Formula (II), Ring A is pyridazinyl and Y is O. In another embodiment of Formula (I), Ring A is pyridazinyl and Y is absent. In another embodiment of Formula (II), Ring A is pyrimidinyl and Y is NR 10 In another embodiment of Formula (II), Ring A is pyrimidinyl and Y is O. In another embodiment of Formula (II), Ring A is pyrimidinyl and Y is absent. In another embodiment of Formula (II), Ring A is pyrazinyl and Y is NR 10 In another embodiment of Formula (II), Ring A is pyrazinyl and Y is O. In another embodiment of Formula (II), Ring A is pyrazinyl and Y is absent. In another embodiment of Formula (II), Ring A is triazinyl and Y is NR 10 In another embodiment of Formula (II), ring A is triazinyl and Y is O. In another embodiment of Formula (II), ring A is triazinyl and Y is absent.

[0112] 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.

[0113] In another embodiment of Formula (II), V is CR3. In another embodiment of Formula (II), V is N.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] In another embodiment of Formula (II), E is NR a R b In another embodiment of formula (II), E is C1-C3 alkylene-NRa R b In another embodiment of Formula (II), E is unsubstituted C2-C3 alkyl, unsubstituted C2-C4 alkenyl, or unsubstituted C2-C4 alkynyl. In another embodiment of Formula (II), E is C2-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 C2-C3 alkyl. In another embodiment of Formula (II), E is C2-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 alkoxy. 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 alkoxy. 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 C-C aryl substituted with one or more halogen, hydroxyl, C-C alkyl, or C-C 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-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 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.

[0118] In another embodiment of Formula (II), E is an unsubstituted 4-10 membered heterocyclyl. In another embodiment of Formula (II), E is a 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 8-10 membered heterocyclyl. In another embodiment of Formula (II), E is an 8-10 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 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- to 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.

[0119] 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. In another embodiment of Formula (II), E is an unsubstituted 5-6 membered heteroaryl. In another embodiment of Formula (II), E is a 5-6 membered heteroaryl 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 heteroaryl. In another embodiment of Formula (II), E is a 5 membered heteroaryl 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 heteroaryl. In another embodiment of Formula (II), E is a 6-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 8-membered heteroaryl. In another embodiment of Formula (II), E is an 8-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is an unsubstituted 10-membered heteroaryl. In another embodiment of Formula (II), E is a 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0120] In another embodiment of Formula (II), E is 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), and C1-C3 alkylene-NR a Rb , 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.

[0121] 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), and 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) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0122] 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), and 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-C10 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.

[0123] 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.

[0124] 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.

[0125] In another embodiment of Formula (II), E is methyl, wherein the 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 the 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 the 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 the 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, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (II), E is oxetanyl, wherein the oxetanyl 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 morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0126] 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), R 16 is unsubstituted C1-C3 alkyl, and R15 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.

[0127] 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 5. 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.

[0128] 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.

[0129] In another embodiment of Formula (II), Y is not present and m is 2. In another embodiment of Formula (II), Y is not present and m is 3. In another embodiment of Formula (II), Y is not present and m is 4. In another embodiment of Formula (II), Y is not present and m is 2, 3, or 4. In another embodiment of Formula (II), Y is not present and m is 3 or 4.

[0130] 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.

[0131] In another embodiment of Formula (II), ring A is phenyl and n is 1. In another embodiment of Formula (II), ring A is phenyl and n is 2. In another embodiment of Formula (II), ring A is phenyl and n is 3. In another embodiment of Formula (II), ring A is pyridinyl and n is 1. In another embodiment of Formula (II), ring A is pyridinyl and n is 2. In another embodiment of Formula (II), ring A is pyridinyl and n is 3. In another embodiment of Formula (II), ring A is pyridazinyl and n is 1. In another embodiment of Formula (II), ring A is pyridazinyl and n is 2. In another embodiment of Formula (II), ring A is pyridazinyl and n is 3. In another embodiment of Formula (II), ring A is pyrimidinyl and n is 1. In another embodiment of Formula (II), ring A is pyrimidinyl and n is 2. In another embodiment of Formula (II), Ring A is pyrimidinyl and n is 3. In another embodiment of Formula (II), Ring A is pyrazinyl and n is 1. In another embodiment of Formula (II), Ring A is pyrazinyl and n is 2. In another embodiment of Formula (II), Ring A is pyrazinyl and n is 3. In another embodiment of Formula (II), Ring A is triazinyl and n is 1. In another embodiment of Formula (II), Ring A is triazinyl and n is 2. In another embodiment of Formula (II), Ring A is triazinyl and n is 3.

[0132] In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is NR 10 In another embodiment of Formula (II), ring A is phenyl, n is 2, and Y is NR 10 In another embodiment of Formula (II), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is phenyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is phenyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is phenyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is phenyl, n is 3, and Y is absent.

[0133] In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is phenyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is phenyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 3 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, n is 3, Y is not present, and m is 3 or 4.

[0134] In another embodiment of Formula (II), ring A is pyridinyl, n is 1 and Y is NR 10 In another embodiment of Formula (II), ring A is pyridinyl, n is 2, and Y is NR 10 In another embodiment of Formula (II), ring A is pyridinyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), ring A is pyridinyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, and Y is absent.

[0135] In another embodiment of Formula (II), ring A is pyridinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyridinyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyridinyl, n is 3, and Y is NR 10and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyridinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridinyl, n is 3, Y is not present, and m is 3 or 4.

[0136] In another embodiment of Formula (II), ring A is pyridazinyl, n is 1 and Y is NR 10 In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, and Y is NR 10In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, and Y is absent.

[0137] In another embodiment of Formula (II), ring A is pyridazinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyridazinyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyridazinyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyridazinyl, n is 2 and Y is NR 10and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyridazinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyridazinyl, n is 3, Y is not present, and m is 3 or 4.

[0138] In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1 and Y is NR 10 In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, and Y is NR 10 In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, and Y is absent.

[0139] In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyrimidinyl, n is 2, and Y is NR10 and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyrimidinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrimidinyl, n is 3, Y is not present, and m is 3 or 4.

[0140] In another embodiment of Formula (II), Ring A is pyrazinyl, n is 1 and Y is NR 10In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, and Y is NR 10 In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, and Y is absent.

[0141] In another embodiment of Formula (II), Ring A is pyrazinyl, n is 1 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyrazinyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), Ring A is pyrazinyl, n is 3 and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyrazinyl, n is 2 and Y is NR10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is pyrazinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is pyrazinyl, n is 3, Y is not present, and m is 3 or 4.

[0142] In another embodiment of Formula (II), ring A is triazinyl, n is 1 and Y is NR 10 In another embodiment of Formula (II), ring A is triazinyl, n is 2, and Y is NR 10 In another embodiment of Formula (II), ring A is triazinyl, n is 3, and Y is NR 10 In another embodiment of Formula (II), ring A is triazinyl, n is 1, and Y is O. In another embodiment of Formula (II), ring A is triazinyl, n is 2, and Y is O. In another embodiment of Formula (II), ring A is triazinyl, n is 3, and Y is O. In another embodiment of Formula (II), ring A is triazinyl, n is 1, and Y is absent. In another embodiment of Formula (II), ring A is triazinyl, n is 2, and Y is absent. In another embodiment of Formula (II), ring A is triazinyl, n is 3, and Y is absent.

[0143] In another embodiment of Formula (II), ring A is triazinyl, n is 1 and Y is NR 10and m is 1 or 2. In another embodiment of Formula (II), Ring A is triazinyl, n is 2, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is triazinyl, n is 3, and Y is NR 10 and m is 1 or 2. In another embodiment of Formula (II), ring A is triazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is triazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is triazinyl, n is 1, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is triazinyl, n is 2, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is triazinyl, n is 1, and Y is not present, and m is 2. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is not present, and m is 2. In another embodiment of Formula (II), ring A is triazinyl, n is 1, and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is triazinyl, n is 2 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), Ring A is triazinyl, n is 3 and Y is NR 10 and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 1, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 2, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is not present, and m is 3 or 4. In another embodiment of Formula (II), ring A is triazinyl, n is 3, Y is not present, and m is 3 or 4.

[0144] In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 3. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 3.

[0145] In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3.

[0146] In another embodiment of Formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (II), ring A is phenyl, 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), ring A is phenyl, 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), ring A is phenyl, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, p is 0, 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), ring A is phenyl, T is CRR, W is CRR, V is CR, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CRR, W is CRR, V is CR, Y is O, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, T is CRR, W is CRR, V is CR, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, T is CRR, W is CRR, V is CR, Y is O, n is 2, and m is 3 or 4.In another embodiment of Formula (II), ring A is phenyl, T is CRR, W is CRR, V is CR, Y is O, n is 3, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CRR, W is CRR, V is CR, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CRR, W is CRR, V is CR, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (II), ring A is phenyl, p is 0, T is CRR, W is CRR, V is CR, Y is O, n is 3, and m is 3 or 4.

[0147] In another embodiment of Formula (II), p is 0, R1, R2, R4, and R5 are each H. In another embodiment of Formula (II), p is 0, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (II), p is 0, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (II), p is 0, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R 11 are H, and R 12 and R 13 are H respectively.

[0148] In another embodiment of Formula (II), p is 1, R1, R2, R4, and R5 are each H. In another embodiment of Formula (II), p is 1, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (II), p is 1, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (II), p is 1, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R11 are H, and R 12 and R 13 are H respectively.

[0149] In another embodiment of Formula (II), p is 2, R1, R2, R4, and R5 are each H. In another embodiment of Formula (II), p is 2, R1, R2, R4, and R5 are each H, and R3 is H. In another embodiment of Formula (II), p is 2, R1, R2, R4, and R5 are each H, R3 is H, and R6, R7, R8, R9, and R 11 are each H. In another embodiment of Formula (II), p is 2, R1, R2, R4 and R5 are each H, R3 is H, and R6, R7, R8, R9 and R 11 are H, and R 12 and R 13 are H respectively.

[0150] In another embodiment of Formula (II), p is 1, 2, 3, or 4, and R is fluorine. In another embodiment of Formula (II), p is 1, 2, 3, or 4, and R is deuterium. In another embodiment of Formula (II), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of Formula (II), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of Formula (II), p is 1, and R is unsubstituted C1-C3 alkyl. In another embodiment of Formula (II), p is 1, and R is methyl. In another embodiment of Formula (II), p is 1 or 2, and each R is methyl. In another embodiment of Formula (II), p is 1 and R is C1-C3 alkyl substituted with one or more halogens. In another embodiment of Formula (II), p is 1 and R is CF3. In another embodiment of Formula (II), p is 1 or 2 and each R is CF3.

[0151] 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 the is deuterium.

[0152] 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 2. 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. 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 2. 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 , R17 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 is H and m is 2.

[0153] Each of the embodiments described herein with respect to compounds of formula II also applies to compounds of formula II-A.

[0154] According to Formula IA, Formula II-A or Formula II herein, Ring A is pyridinyl and the position of the pyridinyl N atom is designated as shown below: [ka] .

[0155] Further, according to Formula IA, Formula II-A or Formula II herein, Ring A is pyridazinyl, and the position of the pyridazinyl N atom is designated as shown below: [ka] .

[0156] Further, according to formula IA, formula II-A or formula II herein, ring A is pyrimidinyl, and the position of the pyrimidinyl N atom is designated as shown below: [ka] .

[0157] Further, according to formula IA, formula II-A or formula II herein, ring A is pyrazinyl, and the position of the pyrazinyl N atom is designated as shown below: [ka] .

[0158] Further, according to formula IA, formula II-A or formula II herein, ring A is triazinyl and the position of the triazinyl N atom is designated as shown below: [ka] .

[0159] All other variations described in Formula IA, Formula I, Formula II-A, or Formula II are as described above.

[0160] Certain embodiments of the compounds of Formula IA, Formula I, Formula II-A, Formula II, or pharmaceutically acceptable salts thereof are shown in Table 1. The compounds of Formula IA, Formula I, Formula II-A, Formula II, or pharmaceutically acceptable salts thereof, and the compounds of Table 1, or pharmaceutically acceptable salts thereof, may be collectively or individually referred to as "compounds of the invention" or "compounds provided herein." [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0161] The disclosed compounds have one or more stereocenters, and each stereocenter can independently exist in either the R or S configuration. In one embodiment, the compounds described herein exist in optically active or racemic forms. It is understood that the compounds described herein encompass racemates, optically active forms, regioisomers, and stereoisomers, or combinations thereof, that possess the therapeutically useful properties described herein.

[0162] Preparation of optically active forms can be carried out in any suitable manner, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis of optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In one embodiment, a mixture of two or more isomers is utilized as the disclosed compounds described herein. In another embodiment, pure isomers are utilized 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 compounds and their isomers can be carried out by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0163] In one embodiment, the disclosed compounds can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0164] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from that typically 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 higher mass isotopes, such as deuterium, confers greater metabolic stability (e.g., increased in vivo half-life or reduced required dose). In another embodiment, the compounds described herein are 2 H (i.e., deuterium) isotope.

[0165] 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 Topography (PET) studies for examining receptor occupancy on substrates. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriate isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0166] Certain compounds described herein and other compounds encompassed by one or more of the formulae described herein and having different substituents can be synthesized using the techniques and materials described herein, for example, 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 4th 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. Ed., (Wiley 1999), all of which are incorporated herein by reference for their disclosures. The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein.

[0167] The compounds described herein are synthesized using any suitable procedure, starting from compounds available from commercial sources, or prepared using the procedures described herein.

[0168] 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 comprising 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.

[0169] 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 thereof.

[0170] In one embodiment, the compounds of the present invention may be used to treat narcolepsy in a subject. In one embodiment, the compounds of the present invention may be used to treat cataplexy in a subject. In one embodiment, the compounds of the present invention may be used to treat hypersomnia in a subject.

[0171] Orexin 2 receptors are important in a wide range of biological functions, suggesting that they play a role in a wide variety of disease processes in humans or other species. The compounds of the present invention are useful for treating, preventing, or ameliorating the risk of one or more of the following symptoms or diseases among various neurological and psychiatric disorders associated with altered sleep / wake function: Namely, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome, hypersomnia syndrome characterized by hypersomnia (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, Mobius 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 encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinaemic obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity), obesity), hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications of anesthesia, sleep disorders, excessive daytime sleepiness, insomnia, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep clusters, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disordersdisorder, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, dusk dementia, sundowning symptoms, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, cardiac arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, coronary artery disease, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Fröhlich syndrome, growth hormone deficiency, normal mutant short stature stature), Turner syndrome, children with acute lymphoblastic leukemia, Syndrome X, reproductive hormone abnormalities, sexual and reproductive dysfunction such as decreased fertility, infertility, decreased male gonadal function, and hirsutism in both men and women, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux disease, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, risk of secondary outcomes of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and a reduced risk of left ventricular hypertrophy, migraines, headaches, and neuropathic conditions. Pain, Parkinson's disease, psychiatric disorders, autoimmune encephalitis, cancer-related fatigue (such as 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 flushes, night sweats, reproductive / urinary system disorders, disorders related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorderacute neurological and psychiatric disorders such as separation anxiety disorder, social anxiety disorder, anxiety disorders, cerebral defects following cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, nerve damage due to hypoglycemia, Huntington's chorea, 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 disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Gilles de la Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder These include 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).

[0172] In particular, the compounds of the present invention are hypothesized to be useful as therapeutic or preventive agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome, hypersomnia syndromes characterized by hypersomnia (e.g., 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, disorders of consciousness such as coma, side effects and complications of anesthesia, and the like, or as anesthesia reversal agents.

[0173] 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.

[0174] In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy type 1. In another embodiment, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy type 2. 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.

[0175] In another embodiment, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for the treatment of hypersomnia in Parkinson's disease.

[0176] In another embodiment, the compounds of the invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for the treatment of hypersomnia. In another embodiment, the compounds of the invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for the treatment of excessive daytime sleepiness associated with Parkinson's disease.

[0177] In another embodiment, the compounds of the invention have orexin 2 receptor agonist activity and are useful as agents for the prevention or treatment of excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy.

[0178] In another embodiment, the present invention provides a method of treating narcolepsy in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0179] In another embodiment, the present invention provides a method of treating narcolepsy type 1 in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0180] In another embodiment, the present invention provides a method of treating type 2 narcolepsy in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0181] In another embodiment, the present invention provides a method of treating narcolepsy and excessive daytime sleepiness in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0182] In another embodiment, the present invention provides a method for treating cataplexy, narcolepsy, and excessive daytime sleepiness in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0183] In another embodiment, the present invention provides a method of treating narcolepsy and cataplexy in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0184] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0185] In another embodiment, the present invention provides a method of treating idiopathic hypersomnia in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0186] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and idiopathic hypersomnia in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0187] In another embodiment, the present invention provides a method of treating obstructive sleep apnea in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0188] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject, comprising administering to a subject in need thereof a compound of Formula IA, Formula I, Formula II-A, or Formula II, or a pharmaceutically acceptable salt thereof.

[0189] 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.

[0190] Each of the embodiments described herein with respect to the use of compounds of formula I also applies to compounds of formula IA. Each of the embodiments described herein with respect to the use of compounds of formula II also applies to compounds of formula II-A.

[0191] In any of the compositions or methods described herein, the compound of Formula IA, Formula I, Formula II-A, Formula II, or a pharmaceutically acceptable salt thereof is present and / or administered in a therapeutically effective amount.

[0192] Administration / Dosage / Formulation In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of the present invention in association with a pharmaceutically acceptable carrier.

[0193] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to provide 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.

[0194] In particular, the selected dose will vary depending on a variety of factors including the activity of the particular compound employed, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or substances 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 well known in the medical arts.

[0195] A medical practitioner (e.g., a physician or veterinarian) skilled in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start administration of the pharmaceutical composition to administer a level of the disclosed compound lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0196] In certain embodiments, it is particularly advantageous to formulate the compound into a unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically discrete unit suitable as a unitary dose for the patient to be treated, each unit containing a predetermined amount of the disclosed compound calculated to produce a desired therapeutic effect together with the necessary pharmaceutical vehicle.The unit dosage form of the present invention is dictated by and directly varies according to (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of the technology of mixing / formulating such disclosed compound to treat narcolepsy or cataplexy in patients.

[0197] In one embodiment, the compounds of the present invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, a pharmaceutical composition of the present invention comprises a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0198] In some embodiments, the dosage of the disclosed compounds is from 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, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg.

[0199] Routes of administration of any of the compositions of the present invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the present invention may be formulated for administration by any suitable route, such as oral or parenteral administration, including, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., vaginal and perivaginal), (trans)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0200] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, lozenges, 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 and aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It is understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

[0201] For oral administration, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gelcaps are particularly suitable. Compositions intended for oral administration may be prepared according to any method known in the art, and may 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 cornstarch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or delay the release of the active ingredient. Formulations for oral administration may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0202] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous injection or infusion, or for administration as a bolus or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles may be used, optionally containing other processing agents such as suspending, stabilizing, or dispersing agents.

[0203] 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 this invention and are encompassed by the appended claims. For example, variations in reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents, using art-recognized substitutions and no more than routine experimentation, are within the scope of this application.

[0204] Whenever values and ranges are provided herein, it is understood that all values and ranges encompassed by those values and ranges are meant to be encompassed within the scope of the present invention. Additionally, all values within those ranges and upper or lower limits of value ranges are also contemplated by this application.

[0205] The following examples further illustrate aspects of the present invention, but do not limit the teachings or disclosure of the present invention as set forth herein.

[0206] 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 those in the art.

[0207] General Procedure Liquid chromatography mass spectroscopy (LCMS) data were acquired using LabSolutions software on a Shimadzu LCMS-2020. Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scatter (ES) ionization sources.

[0208] Nuclear magnetic resonance (NMR) data were acquired using Topspin 3.5pI7 or Topspin 4.1.1 on a Bruker AVANCE III HD or Bruker AVANCE NEO instrument.1 H NMR chemical shift values are reported in parts per million downfield from tetramethylsilane and were recorded on a 300 or 400 MHz spectrometer unless otherwise indicated. Chemical shift values are referenced to residual peaks of the deuterated solvent and are expressed in parts per million (δ).

[0209] Example 1: Synthesis Procedure The synthetic procedures for preparing the compounds of the present invention are readily available to those skilled in the art.Unless otherwise specified, starting materials are generally obtained from commercial sources.Synthetic procedures for related compounds can be found, for example, in U.S. Patent Application No. 17 / 104,993 and PCT Application No. PCT / US20 / 62320, both of which were filed on November 25, 2020, and are expressly incorporated herein by reference.

[0210] The following abbreviations are 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 PE = petroleum ether EtOAc = ethyl acetate DMF = dimethylformamide TFA = trifluoroacetic acid LiOH = lithium hydroxide min=minutes hr=hour NaH = sodium hydride Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) DMSO = dimethyl sulfoxide i-PrOH = isopropanol Pd / C = palladium on carbon XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine Boc = tert-butyloxycarbonyl Ms = methanesulfonyl Bn = benzyl Et = ethyl Cbz = carboxybenzyl PMB = para-methoxybenzyl DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene NBS = N-bromosuccinimide Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DMAP = 4-(dimethylamino)pyridine NCS = N-chlorosuccinimide DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone LDA = lithium diisopropylamide TfO = trifluoromethanesulfonate KHMDS = potassium bis(trimethylsilyl)amide solution KOAc = potassium acetate XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Et3N or TEA = triethylamine TMSOTf = trimethylsilyl trifluoromethanesulfonate

[0211] Scheme 1 [ka] Example 1.1 [ka] A 5 L four-necked round-bottom flask purged with and maintained under an inert atmosphere of nitrogen was charged with 4-[2-(benzyloxy)phenyl]cyclohexan-1-one (210 g, 749 mmol, 1.00 equiv.) in tetrahydrofuran (2.1 L). L-Selectride (1 mol / L in THF) (1123 mL, 5257 mmol, 1.50 equiv.) was then added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 4 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted with ethyl acetate, and the organic phase was washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 to 1:5) to afford 137 g (64%) of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol as a solid.

number

[0212] [ka] A 2 L, four-necked, round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with NaH (60 wt%, 26.9 g, 2.00 equiv.) in tetrahydrofuran (200 mL). Then, a solution of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol (95 g, 336 mmol, 1.00 equiv.) in THF (200 mL) was added dropwise with stirring at 50–55°C. After stirring for 2 h, a solution of 3-bromo-2-(bromomethyl)pyridine (143.5 g, 571 mmol, 1.70 equiv.) in THF (550 mL) was added dropwise with stirring at 50–55°C. The resulting solution was stirred at 50–55°C for 14 h. The reaction mixture was cooled. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 to 1:2) to give 94 g (62%) of 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine as a solid.

number

[0213] [ka] A 2 L, four-necked, round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with Xantphos (10.7 g, 18 mmol, 0.10 equiv.), CsCO (84 g, 258 mmol, 1.39 equiv.), 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine (84 g, 185 mmol, 1.00 equiv.), Pd(dba) (8.5 g, 9 mmol, 0.05 equiv.), and tert-butyl carbamate (26 g, 222 mmol, 1.20 equiv.) in dioxane (840 mL). The resulting solution was stirred at 100 °C for 5 h. The solids were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 to 1:4) to give 74 g (82%) of tert-butyl-N-[2-([[1s,4S)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid.

[0214] [ka] A 2 L three-necked round-bottom flask was charged with tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (74 g, 151 mmol, 1.00 equiv.) and Pd / C (7.4 g, 10 wt %) in ethyl alcohol (740 mL), followed by flushing with hydrogen gas. The resulting solution was stirred at room temperature for 14 h. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 to 1:2) to give 51.36 g (85%) of tert-butyl N-[2-([[(1s,4s)-4-[2-(hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid.

number

[0215] [ka] A 250 mL round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (8 g, 20.075 mmol, 1 equiv.), KCO (13.97 g, 100.35 mmol, 5 equiv.), acetone (120 mL), and ethyl bromoacetate (5.03 g, 30.119 mmol, 1.5 equiv.). The resulting solution was stirred at 50 °C for 24 h. The solids were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:2) to give ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (8.7 g, 89.43%) as a yellow oil.

number

[0216] [ka] To a stirred mixture of ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (7.89 g, 16.268 mmol, 1 equiv.) in MeOH (142 mL) and AcOH (15.8 mL) was added PtO (1.85 g, 8.142 mmol, 0.50 equiv.) at room temperature under a hydrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was concentrated under reduced pressure. The reaction was quenched with saturated NaHCO (aq.) at 0 °C. The resulting mixture was extracted with CHCl (3 × 500 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a cis- and trans-diastereomeric mixture (7 g, 88.7%) as a solid. The crude product was purified by preparative TLC (DCM / MeOH=20:1) to give a cis-racemic mixture (4.1 g) and a trans-racemic mixture (1.7 g) of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate.

number

[0217] [ka] A 500 mL round-bottom flask purged with nitrogen and maintained under a nitrogen atmosphere was charged with a cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g, 8.356 mmol, 1 equiv), MeOH (30 mL), THF (60 mL), HO (30 mL), and lithium hydroxide (83 mg, 3.465 mmol, 5 equiv). The reaction was stirred at room temperature for 2 h. The reaction was concentrated and the residue was purified by reverse phase flash using the following conditions, followed by lyophilization to give 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (2.35 g, 60.8%) as a solid.

number

[0218] [ka] To a 2000 mL round-bottom flask was added 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (100 mg, 0.216 mmol, 1 equiv.), MeCN (36 mL), DMF (9 mL), HATU (124 mg, 0.326 mmol, 1.51 equiv.) and DIPEA (56 mg, 0.436 mmol, 2.02 equiv.) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. LCMS showed complete conversion. The resulting mixture was concentrated. The crude product was purified by tert-butyl((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 The (-yl)carbamate was used directly in the next step without purification.

number

[0219] [ka] In a 500 mL round bottom flask purged with nitrogen and maintained under an inert atmosphere of nitrogen, the crude mixture of tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 The resulting solution was stirred at 25° C. for 1 hour. LCMS showed complete conversion. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give (2-yl)carbamate (2 g, 4.499 mmol, 1 equiv.), DCM (120 mL), and TFA (40 mL). The resulting solution was stirred at 25° C. for 1 hour. LCMS showed complete conversion. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 32.1 g (800 mg, 51.6%) of -amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one were obtained.

number

[0220] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3To a stirred mixture of 1,4-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (100 mg, 1.0 equiv., 0.3 mmol) and DIEA (112 mg, 3.0 equiv., 0.9 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (81 mg, 2.0 equiv., 0.6 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC and chiral HPLC to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)cyclohexanacyclooctaphane-5 3 -yl)cyclopropanesulfonamide (55 mg, 41%) was obtained.

number

[0221] Example 1.2 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a stirred mixture of N-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (100 mg, 1.0 equiv., 0.3 mmol) and DBU (132 mg, 3.0 equiv., 0.9 mmol) in dichloromethane (20 mL) was added propane-2-sulfonyl chloride (82 mg, 2.0 equiv., 0.6 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography and chiral HPLC to give N-((2)-dichloromethane as a solid. 1 S, 2 4 S, 5 2R, 5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)cyclohexanacyclooctaphane-5 3 -yl)propane-2-sulfonamide (50 mg, 37%) was obtained.

number

[0222] Example 1.3 [ka] tert-Butyl tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a stirred mixture of tert-butyl(2-yl)carbamate (1.5 g, 1.0 equiv., 3.3 mmol) in MeCN (50 mL) and THF (50 mL) was added NBS (1.2 g, 2.0 equiv., 6.7 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was recrystallized from PE / EtOAc (10:1, 30 mL) to give tert-butyl(2-yl)carbamate as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Bromo-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)carbamate (2.0 g, 90.5%) was obtained.

number

[0223] [ka] tert-Butyl(2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Bromo-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a stirred mixture of MeB(OH) (0.23 g, 2.0 equiv., 3.8 mmol), and Pd(dppf)Cl (0.14 g, 0.1 equiv., 0.2 mmol) in 1,4-dioxane (100 mL) and HO (10 mL) was added KCO (0.79 g, 3.0 equiv., 5.7 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give tert-butyl ((2-yl)carbamate as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)carbamate (525 mg, 41.9%) was obtained.

number

[0224] [ka] tert-Butyl ((2 1 S, 2 4 S, 5 2 R, 5 3 S)-1 5 -Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3To a solution of (2-yl)carbamate (1.0 g, 1.0 equiv., 2.2 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (1.24 g, 5.0 equiv., 10.9 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The resulting mixture was diluted with dichloromethane (50 mL). The combined organic layers were washed with NaHCO3 (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 5 440 mg (51.0%) of 4,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one was obtained.

number

[0225] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 5 To a solution of 2-methyl-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (220 mg, 1.0 equiv., 0.61 mmol), DMAP (15 mg, 0.2 equiv., 0.12 mmol), and DIEA (238 mg, 3.0 equiv., 1.8 mmol) in dichloromethane (20 mL) was added cyclopropanesulfonyl chloride (173 mg, 2.0 equiv., 1.2 mmol). After stirring at 25°C under a nitrogen atmosphere for 4 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC and chiral preparative HPLC to give N-((2 1 S,2 4 S,5 2 R,53 S)-1 5 -Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)cyclopropanesulfonamide (89.5 mg, 33%) was obtained.

number

[0226] Example 1.4 [ka] To a stirred mixture of benzyl 2-hydroxyacetate (21.9 g, 5.0 equiv, 131.6 mmol) in DMF (100 mL) at 0° C. was added NaH (60%, 5.26 g, 5.0 equiv, 131.6 mmol) in several portions.

[0227] The resulting mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. 3-Bromo-2-fluoro-4-methylpyridine (5.00 g, 1.0 equiv., 26.314 mmol) was added to the above mixture at room temperature, and the resulting mixture was stirred at 80°C for an additional 2 hours. The reaction was quenched at 0°C by the addition of saturated NH4Cl(aq) (500 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give benzyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (7.3 g, 83.0%) as an oil.

number

[0228] [ka] 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 (5.00 g, 1.0 equivalent, 3.51 mmol) and benzyl To a solution of 2-((3-bromo-4-methylpyridin-2-yl)oxyacetate (1.41 g, 1.2 equiv., 4.21 mmol) in 1,4-dioxane (20 mL) and water (5.0 mL) was added Na2CO3 (1.12 g, 3.0 equiv., 10.5 mmol) and Pd(dppf)Cl2 (385 mg, 0.15 equiv., 0.53 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The crude was purified by reverse-phase flash chromatography to give benzyl (2R,3S)-2-(((4-(2-(2-(benzyloxy)-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (2.0 g, 80.0%) as an oil.

[0229] [ka] To a solution of benzyl (2R,3S)-2-(((4-(2-(2-(benzyloxy)-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (2.00 g, 1.0 equivalent, 2.86 mmol) in i-PrOH (30 mL) was added Pd / C (152 mg, 0.5 equivalent, 1.43 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated under a hydrogen atmosphere at room temperature using a hydrogen balloon for 15 hours. The mixture was filtered through a CELITE® (Imerys Minerals California Inc., San Jose, CA) pad and concentrated under reduced pressure to give the crude product. The crude was purified by reverse-phase flash chromatography to give 2-((3-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetic acid (950 mg, 69.9%) as a solid.

number

[0230] [ka] To a stirred mixture of 2-((3-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetic acid (900 mg, 1.0 equiv., 1.89 mmol) and DIEA (734 mg, 3.0 equiv., 5.68 mmol) in MeCN (400 mL) was added HATU (1.08 g, 1.5 equiv., 2.84 mmol) at 25° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give tert-butyl((5 2 R,5 3 S,E)-1 4-Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-5 3 -yl)carbamate (650 mg, 75.1%) was obtained.

number

[0231] [ka] tert-Butyl ((5 2 R,5 3 S,E)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-5 3 To a solution of tert-butyl((2-yl)carbamate (1.2 g, 1.0 equiv., 2.6 mmol) in MeOH (200 mL) and acetic acid (20.0 mL) was added Pd / C (0.56 g, 10 wt%, 0.2 equiv., 0.52 mmol). The reaction mixture was stirred under a hydrogen atmosphere for 5 days. The crude was purified by reverse-phase flash chromatography to give tert-butyl((2-yl)carbamate) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)carbamate (500 mg, 41.0%) was obtained.

number

[0232] [ka] tert-Butyl ((21 S,2 4 S,5 2 R,5 3 S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 A solution of (400 mg, 1.0 equiv., 0.87 mmol) methyl-(2-methyl-yl)carbamate in 15 mL of DCM and 3 mL of TFA was added. The reaction mixture was stirred at 25° C. under a nitrogen atmosphere for 1 hour. The resulting mixture was extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO.

[0233] After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give ((2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4 1,4-Dimethyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (230 mg, 73.5%) was obtained.

number

[0234] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4To a solution of 5-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (50 mg, 1.0 equiv., 0.14 mmol) and DBU (170 mg, 8.0 equiv., 1.12 mmol) in DCM (6 mL) was added dropwise a stirred solution of propane-2-sulfonyl chloride (99 mg, 5.0 equiv., 0.70 mmol) in DCM (0.4 mL) at 25°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 4 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 The crude product was purified by preparative chiral HPLC to give the pure enantiomers.

number

[0235] Example 1.5 [ka] N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a stirred solution of N-((2-yl)cyclopropanesulfonamide (100 mg, 1.0 equiv., 0.2 mmol) in MeCN (5 mL) and THF (5 mL) was added NCS (59 mg, 2.0 equiv., 0.4 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give N-((2-yl)cyclopropanesulfonamide as a solid.1 S,2 4 S,5 2 R,5 3 S)-1 5 -Chloro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)cyclopropanesulfonamide (64.6 mg, 60%) was obtained.

number

[0236] Example 1.6 [ka] To a stirred solution of 1-tert-butyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (1.12 g, 1.0 equiv., 4.35 mmol) and DMPU (1.92 g, 3.5 equiv., 15.0 mmol) in THF (30 mL) was added LDA (5.19 mL, 8.8 equiv., 48.4 mmol) dropwise over 5 minutes at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for an additional 1.5 hours. To the above mixture was added a solution of 1-(benzyloxy)-2-[4-(chloromethoxy)cyclohexyl]-3-methylbenzene (1.58 g, 1.1 equiv., 4.57 mmol) in THF (5 mL) dropwise over 5 minutes at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 minutes, followed by stirring at room temperature for an additional 3 hours. The reaction was quenched with water, and the mixture was extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give 1-(tert-butyl) 3-ethyl 5-((((1s,4s)-4-(2-(benzyloxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-4-oxopyrrolidine-1,3-dicarboxylate (2.25 g, 91.4%) as an oil.

number

[0237] [ka] A solution of 1-(tert-butyl) 3-ethyl 5-((((1s,4s)-4-(2-(benzyloxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-4-oxopyrrolidine-1,3-dicarboxylate (2.0 g, 3.54 mmol) in DMSO (10 mL) and water (1 mL) was stirred at 125° C. for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give tert-butyl 2-((((1s,4s)-4-(2- (benzyloxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-3-oxopyrrolidine-1-carboxylate (1.83 g, 100%) was obtained.

number

[0238] [ka] A mixture of EtOH (25 mL), tert-butyl 2-[([4-[2-(benzyloxy)-6-methylphenyl]cyclohexyl]oxy)methyl]-3-oxopyrrolidine-1-carboxylate (1.78 g, 1.0 equiv., 3.61 mmol) and Pd / C (1.19 g, 3.1 equiv., 0.011 mmol) was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give tert-butyl 2-((((1s,4s)-4-(2-hydroxy-6-methylphenyl)cyclohexyl)oxy)methyl)-3-oxopyrrolidine-1-carboxylate (1.48 g, 100%) as a solid.

number

[0239] [ka] To a stirred mixture of 2-((((1s,4s)-4-(2-hydroxy-6-methylphenyl)cyclohexyl)oxy)methyl)-3-oxopyrrolidine-1-carboxylate (1.27 g, 1.0 equiv., 3.15 mmol) and KPO (5.34 g, 8.0 equiv., 25.2 mmol) in MeCN (25 mL) was added tert-butyl 2-bromoacetate (3.68 g, 6.0 equiv., 18.9 mmol) dropwise over 2 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 5 hours. The reaction mixture was purified by reverse-phase flash chromatography to give tert-butyl 2-((((1s,4s)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-3-oxopyrrolidine-1-carboxylate (1.57 g, 84%) as an oil.

number

[0240] [ka] To a stirred mixture of tert-butyl 2-((((1s,4s)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-3-oxopyrrolidine-1-carboxylate (1.34 g, 1.0 equiv., 2.59 mmol), (4-methoxyphenyl)methanamine (2.13 g, 6.0 equiv., 15.5 mmol), and MgSO (623 mg, 2.0 equiv., 5.18 mmol) in DCM (40 mL) was added sodium triacetoxyborohydride (4.39 g, 8.0 equiv., 20.7 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give tert-butyl (2R,3S)-2-((((1s,4S)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.7 g, 99%) as an oil.

number

[0241] [ka] To a stirred mixture of tert-butyl (2R,3S)-2-((((1s,4S)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)-6-methylphenyl)cyclohexyl)oxy)methyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.66 g, 1.0 equiv., 2.60 mmol) in DCM (10 mL) was added TFA (5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 hours and concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give 2-(2-((1S,4s)-4-(((2R,3S)-3-((4-methoxybenzyl)amino)pyrrolidin-2-yl)methoxy)cyclohexyl)-3-methylphenoxy)acetic acid (1.52 g, 95%) as an oil.

[0242] To the above mixture and diisopropylethylamine (4.07 g, 10.0 equiv., 31.5 mmol) in DCM (30 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (3.01 g, 3.0 equiv., 9.45 mmol) dropwise over 2 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 1.5 hours. The crude was purified by reverse-phase flash chromatography to give (2) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((4-Methoxybenzyl)amino)-16-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (0.77 g, 45%) was obtained.

number

[0243] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a stirred mixture of -((4-methoxybenzyl)amino)-16-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (236 mg, 1.0 equiv., 0.51 mmol) and Pd / C (270 mg, 5.0 equiv., 2.54 mmol) in i-PrOH (20 mL) was added ammonium formate (801 mg, 25.0 equiv., 12.7 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 85°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give ((2 1 S,2 4 S,5 2 R,5 3S)-5 3 -amino-16-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (169 mg, 96%) was obtained.

number

[0244] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a stirred mixture of 1,4-amino-16-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (155 mg, 1.0 equiv., 0.45 mmol) and DIEA (116 mg, 2.0 equiv., 0.90 mmol) in dichloromethane (15 mL) was added MsCl (77.3 mg, 1.5 equiv., 0.68 mmol) dropwise over 2 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-16-Methyl-6-oxo-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (126 mg, 65.9%) was obtained.

number

[0245] Example 1.7 [ka] To a stirred solution of ethyl 2-hydroxyacetate (5.42 g, 1.3 equiv., 52.0 mmol) in DMF (150 mL) was added sodium hydroxide (3.20 g, 60 wt%, 2.0 equiv., 80.0 mmol) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes. To the above mixture was added 5-bromo-4-chloro-6-methylpyrimidine (8.30 g, 1.0 equiv., 40.0 mmol) and potassium fluoride (2.32 g, 1.0 equiv., 40.0 mmol) at room temperature. The resulting mixture was stirred at 80° C. for an additional 30 minutes. The reaction was quenched by the addition of saturated aqueous sodium chloride at 0° C. The resulting mixture was diluted with ethyl acetate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give ethyl 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)acetate (8.02 g, 72.9%) as a solid.

number

[0246] [ka] To a solution of ethyl 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)acetate (3.30 g, 1.2 equiv., 12.0 mmol) and 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 (5.70 g, 1.0 equiv., 10.0 mmol) in 1,4-dioxane (60 mL) and HO (15 mL) was added Pd(dppf)Cl (0.73 g, 0.1 equiv., 1.00 mmol) and NaCO (3.20 g, 3.0 equiv., 30.0 mmol).

[0247] After stirring at 80°C under a nitrogen atmosphere for 2 hours, the resulting mixture was diluted with HO (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL) and 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-(4-(2-ethoxy-2-oxoethoxy)-6-methylpyridin-5-yl)cyclohex-3-en-1-yl)oxy)methyl)piperidine-1-carboxylate (5.40 g, 85.0%) as a solid.

number

[0248] [ka] To a solution of (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(((4-(4-(2-(ethoxy-2-oxoethoxy)-6-methylpyrimidin-5-yl)cyclohex-3-en-1-yl)oxy)methyl)piperidine-1-carboxylate (5.7 g, 1.0 equivalent, 8.9 mmol) in 2-propanol (210 mL) was added palladium (0.95 g, 10 wt%, 0.1 equivalent, 0.89 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 4 hours, filtered through a Celite pad, and concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification.

[0249] [ka] To a solution of ethyl 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-6-methylpyrimidin-4-yl)oxy)acetate (4.5 g, 1.0 equiv., 8.9 mmol) in THF (24 mL) and HO (8.0 mL) was added LiOH (0.32 g, 1.5 equiv., 13 mmol). The resulting mixture was stirred at 25 °C for 1 h, and the resulting mixture was acidified to pH = 5 and subsequently concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-6-methylpyrimidin-4-yl)oxy)acetic acid (3.5 g, 82%) as a solid.

number

[0250] [ka] To a stirred mixture of HATU (2.6 g, 1.5 equiv., 6.9 mmol) and DIEA (1.8 g, 3.0 equiv., 14 mmol) in acetonitrile (1.1 L) was added a solution of 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-6-methylpyrimidin-4-yl)oxy)acetic acid (2.2 g, 1.0 equiv., 4.6 mmol) in DMF (25 mL) dropwise over 5 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude was purified by reverse-phase flash chromatography to give tert-butyl((5 2 R,5 3 S,E)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-53 -yl)carbamate (1.8 g, 85%) was obtained.

number

[0251] [ka] tert-Butyl ((5 2 R,5 3 S,E)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-5 3 To a solution of tert-butyl((2-yl)carbamate (500 mg, 1.0 equiv., 1.09 mmol) in MeOH (90 mL) and AcOH (10 mL) was added Pd / C (580 mg, 10 wt%, 0.5 equiv., 0.55 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 7 days, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give tert-butyl((2-yl)carbamate) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)carbamate (310 mg, 62%) was obtained.

number

[0252] [ka] tert-Butyl ((2 1 S,2 4 S,52 R,5 3 S)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 To a solution of (2-yl)carbamate (430 mg, 1.0 equiv., 0.93 mmol) in dichloromethane (15 mL) was added TFA (0.5 mL). The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 1,4-Diamino-16-methyl-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (299 mg, 89.0%) was obtained.

number

[0253] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a solution of N-amino-16-methyl-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (45 mg, 1.0 equiv., 0.12 mmol) in DCM (2 mL) was added DIEA (81 mg, 5.0 equiv., 0.62 mmol) and methanesulfonyl chloride (43 mg, 3.0 equiv., 0.37 mmol). The resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,53 S)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 35 mg (62.0%) of (4-yl)methanesulfonamide was obtained. The racemic product was purified by chiral preparative HPLC to give the pure enantiomers.

number

[0254] Example 1.8 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6 To a stirred solution of 2-methyl-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (287.00 mg, 1.0 equiv., 0.801 mmol) and TEA (243.0 mg, 3.0 equiv., 2.40 mmol) in dichloromethane (10 mL) was added MsCl (137.6 mg, 1.5 equiv., 1.20 mmol) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (260 mg, 74.4%) was obtained.

number

[0255] Example 1.9 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a stirred solution of 1,1,1-trifluoro-N-((2-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (100 mg, 1.0 equiv., 0.30 mmol) in dichloromethane (10 mL) was added EtN (176 mg, 6.0 equiv., 1.74 mmol) and trifluoromethanesulfonyl chloride (196 mg, 4.0 equiv., 1.16 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40° C. for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to give 1,1,1-trifluoro-N-((2-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (75.0 mg, 54.2%) was obtained.

number

[0256] Example 1.10 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 3 ,1 5To a stirred mixture of 1,4-difluoro-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (500.0 mg, 1.0 equiv., 1.365 mmol) and DBU (1039 mg, 5.0 equiv., 6.823 mmol) in DCM (40 mL) was added propane-2-sulfonyl chloride (574 mg, 3.0 equiv., 4.026 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from DCM / MeOH (1:10 mL) to give N-(((2 1 S,2 4 S,5 2 R,5 3 S)-1 3 ,1 5 -Difluoro-6-oxo-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)propane-2-sulfonamide (500 mg, 77.5%) was obtained.

number

[0257] Example 1.11 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 3To a stirred solution of 1,2-methyl-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (740.0 mg, 1.0 equiv., 2.06 mmol) and TEA (1040 mg, 5.0 equiv., 10.3 mmol) in dichloromethane (40.0 mL) was added MsCl (709.4 mg, 3.0 equiv., 6.193 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give N-((2 1 S, 24S, 52R, 53S)-1 3 -Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (450 mg, 49.9%) was obtained.

number

[0258] Example 1.12 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a solution of N-amino-3,8-dioxa-1(2,3)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (50 mg, 1.0 equiv., 144.33 μmol) and cyclopropanesulfonyl chloride (30.5 mg, 1.5 equiv., 216.5 μmol) in DCM (2 mL) was added DIPEA (37.4 mg, 2.0 equiv., 288.7 μmol) and DMAP (3.6 mg, 0.2 equiv., 28.87 μmol). The resulting mixture was stirred at 25° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-1(2,3)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)cyclopropanesulfonamide (55 mg, 80%) was obtained.

number

[0259] Example 1.13 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a solution of N-amino-3,8-dioxa-1(2,3)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (50 mg, 1.0 equiv., 144.33 μmol) and propane-2-sulfonyl chloride (30.9 mg, 1.5 equiv., 216.49 μmol) in DCM (5 mL) was added DIPEA (37.4 mg, 2.0 equiv., 288.7 μmol) and DMAP (3.6 mg, 0.2 equiv., 28.87 μmol). The resulting mixture was stirred at 25° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-1(2,3)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)propane-2-sulfonamide (35 mg, 51%) was obtained.

number

[0260] Example 1.14 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6 To a solution of 1,2-methyl-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (760 mg, 1.0 equiv., 2.11 mmol) in DCM (30 mL) was added DMAP (25.8 mg, 0.1 equiv., 210.8 μmol), DIEA (1.47 mL, 4.0 equiv., 8.43 mmol), and cyclopropanesulfonyl chloride (889.2 mg, 3.0 equiv., 6.33 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)cyclopropanesulfonamide (990 mg, 93.8%) was obtained.

number

[0261] Example 1.15 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3To a solution of 1,1,1-trifluoro-N-(2,1)-amino-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphan-6-one (1.5 g, 1.0 equiv., 4.35 mmol) in DCM (30 mL) was added TEA (1.32 g, 3.0 equiv., 13.0 mmol) at room temperature. The solution was cooled to -50 °C, and then TfO (1.84 g, 1.5 equiv., 6.51 mmol) was added dropwise to the solution. The resulting solution was stirred at -50 °C for 30 min. The resulting mixture was quenched with saturated aqueous NaHCO and diluted with 20 mL of water. The mixture was then extracted with ethyl acetate (3 × 100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1,1,1-trifluoro-N-(2,1)-amino-3,8-dioxa-1(2,1)-pyridina-5(2,1)-piperidina-2(2,1)-cyclohexanacyclooctaphan-6-one as a solid. 1 S, 2 4 S, 5 2 R, 5 3 S)-6-Oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (1.68 g, 81.0%) was obtained.

number

[0262] Example 1.16 [ka] To a stirred mixture of (2R,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (20.0 g, 1.0 equiv., 86.5 mmol) and KCO (19.1 g, 1.6 equiv., 138.0 mmol) in DMF (300 mL) was added MeI (14.9 g, 1.2 equiv., 104.7 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure to give 1-tert-butyl 2-methyl(2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (21.0 g, 99.0%) as an oil.

number

[0263] [ka] A mixture of 1-tert-butyl 2-methyl(2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (21.0 g, 1.0 equivalent, 85.6 mmol) and 4 N HCl in 1,4-dioxane (300.0 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours. The precipitated solid was collected by filtration and washed with ethyl ether to give methyl (2R,3R)-3-hydroxypyrrolidine-2-carboxylate hydrochloride (14.4 g, 92.6%).

number

[0264] [ka] To a stirred solution of methyl (2R,3R)-3-hydroxypyrrolidine-2-carboxylate hydrochloride (14.40 g, 1.0 equiv., 79.3 mmol) and DIEA (25.6 g, 2.5 equiv., 198.0 mmol) in DCM (300.0 mL) was added benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.8 g, 1.0 equiv., 79.3 mmol) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was diluted with dichloromethane (300 mL). The resulting mixture was washed with 2N aqueous HCl (500 mL*3). The resulting organic layer was washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-benzyl 2-methyl (2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (18 g, 81.3%) as a solid.

number

[0265] [ka] To a stirred solution of 1-benzyl 2-methyl(2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (18.0 g, 1.0 equiv., 64.4 mmol) and benzyl bromide (16.5 g, 1.5 equiv., 96.7 mmol) in DCM (360.0 mL) was added AgO (44.8 g, 3.0 equiv., 193.3 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 days with tin foil to protect from light. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-benzyl 2-methyl(2R,3R)-3-(benzyloxy)pyrrolidine-1,2-dicarboxylate (17.2 g, 72.2%) as an oil.

number

[0266] [ka] To a stirred solution of 1-benzyl 2-methyl(2R,3R)-3-(benzyloxy)pyrrolidine-1,2-dicarboxylate (17.2 g, 1.0 equiv., 46.6 mmol) in THF (400 mL) was added NaBH (17.6 g, 10 equiv., 465.6 mmol) and LiCl (19.7 g, 10 equiv., 465.6 mmol) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The mixture was cooled to 0° C. The reaction was quenched by adding saturated NH Cl (aq.) at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl (2S,3R)-3-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (15 g, 94.4%) as an oily substance.

number

[0267] [ka] To a stirred solution of (COCl)2 (6.69 g, 1.2 equiv., 52.7 mmol) in DCM (300 mL) was added dropwise a solution of DMSO (8.24 g, 2.4 equiv., 105.4 mmol) in DCM (50.0 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 1.5 hours. A solution of benzyl (2S,3R)-3-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (15.0 g, 1.0 equiv., 43.9 mmol) in DCM (50.0 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour, followed by the dropwise addition of TEA (22.2 g, 5.0 equiv., 219.7 mmol). The mixture was stirred at −78° C. for 1 hour, and the reaction mixture was allowed to warm to room temperature.

[0268] The reaction was quenched by adding water. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure.

[0269] The residue was purified by silica gel column chromatography to give benzyl (2R,3R)-3-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (13.8 g, 80.7%) as an oily substance.

number

[0270] [ka] In a three-necked round-bottom flask, tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)silane (9.90 g, 1.0 equiv., 29.5 mmol) in DCM (200 mL) was added to benzyl (2R,3R)-3-(benzyloxy)-2-formylpyrrolidine-1-carboxylate (10.0 g, 1.0 equiv., 29.5 mmol), which had been dried under high vacuum for 1 hour, under a N atmosphere. The mixture was cooled to -78 °C. TMSOTf (7.20 g, 1.1 equivalents, 32.4 mmol) in DCM (20 mL) was added dropwise to the mixture at −78° C., followed by the dropwise addition of a solution of triethylsilane (6.17 g, 1.8 equivalents, 53.0 mmol) in DCM (20 mL) at −78° C. The resulting reaction solution was stirred at −78° C. for 0.5 hours. It was then warmed to 20° C. and stirred for 0.5 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The resulting organic phase was dried over anhydrous magnesium sulfate. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (10.0 g, 62.0%) as an oil.

number

[0271] [ka] To a stirred solution of 3-bromo-2-fluoro-4-methylpyridine (10 g, 1.0 equiv., 53 mol) in DMF (150 mL) was added sodium methyl 2-hydroxyacetate (27 g, 5.0 equiv., 0.26 mol) and cesium carbonate (26 g, 1.5 equiv., 79 mol). The mixture was stirred at 60 °C under a nitrogen atmosphere for 4 h. The mixture was filtered, and the resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with water (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give ethyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (11 g, 40 mmol, 76%) as a solid.

number

[0272] [ka] To a solution of benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (20 g, 1.0 equiv., 37 mmol) and ethyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (11 g, 1.1 equiv., 40 mmol) in 1,4-dioxane (400 mL) and HO (100 mL) was added NaCO (12 g, 3.0 equiv., 0.11 mol) and Pd(dppf)Cl (2.7 g, 0.1 equiv., 3.7 mmol) under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was extracted with ethyl acetate (3*300 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(2-(2-ethoxy-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (16 g, 26 mmol, 71%) as an oil.

number

[0273] [ka] To a solution of benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(2-(2-ethoxy-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (16 g, 1.0 equiv., 26 mmol) in i-PrOH (500 mL) was added Pd / C (0.28 g, 0.1 equiv., 2.6 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 5 hours under a hydrogen atmosphere using a hydrogen balloon. The resulting mixture was then filtered through a CELITE® pad and concentrated under reduced pressure to give the crude product. The mixture was concentrated under reduced pressure to give ethyl 2-((3-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetate (11 g, 23 mmol, 88%) as a solid. The crude product was used directly in the next step without further purification.

number

[0274] [ka] To a stirred mixture of ethyl 2-((3-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetate (11 g, 1.0 equiv., 23 mmol) in MeOH (150 mL) was added a solution of lithium hydroxide (1.6 g, 3.0 equiv., 69 mmol) in HO (75 mL). The resulting mixture was stirred at 25 °C for 2 h. The mixture was adjusted to pH 5-6. The crude was purified by reverse-phase flash chromatography to give 2-((3-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetic acid (9.5 g, 21 mmol, 92%) as an oil.

number

[0275] [ka] To a stirred mixture of HATU (12 g, 1.5 equiv., 31 mmol) and diisopropylethylamine (8.1 g, 3.0 equiv., 63 mmol) in acetonitrile (200 mL) was added a solution of 2-((3-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-4-methylpyridin-2-yl)oxy)acetic acid (9.5 g, 1.0 equiv., 21 mmol). The resulting mixture was stirred at 25 °C for 2 h. The crude was purified by reverse-phase flash chromatography to give (5) as a solid. 2 S,5 3 R,E)-5 3 -(Benzyloxy)-14-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphane-2 1 -en-6-one (5.6 g, 13 mmol, 61%) was obtained.

number

[0276] [ka] ((5 2 S,5 3 R,E)-5 3 -(Benzyloxy)-14-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphane-2 1To a solution of 2-en-6-one (5.6 g, 1.0 equiv., 13 mmol) in MeOH (300 mL) was added Pd / C (1.4 g, 1.0 equiv., 13 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 5 days, filtered through a Celite® pad, and concentrated under reduced pressure to give the crude product. Subsequently, the crude product was added to Pd / C (0.01 g, 5 wt%) under a nitrogen atmosphere. The resulting mixture was hydrogenated at 50° C. for 24 hours under 6 atm, filtered through a Celite® pad, and concentrated under reduced pressure to give the crude product. The crude was purified by reverse-phase flash chromatography to give ((2 1 R,2 4 R,5 2 S,5 3 R)-5 3 -Hydroxy-14-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolizina-2(1,4)-cyclohexanacyclooctaphan-6-one (2.9 g, 8.4 mmol, 63%) was obtained.

number

[0277] [ka] (2 1 R,2 4 R,5 2 S,5 3 R)-5 3To a stirred mixture of 1-hydroxy-14-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphan-6-one (2.9 g, 1.0 equiv., 8.4 mmol) in dichloromethane (15 mL) was added tosyl-Cl (2.4 g, 1.5 equiv., 13 mmol), triethylamine (3.5 mL, 3.0 equiv., 25 mmol), and 4-dimethylaminopyridine (0.20 g, 0.2 equiv., 1.7 mmol). The resulting mixture was stirred at 40° C. for 16 h. The reaction was monitored by LCMS. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give (2) as a solid. 1 R,2 4 R,5 2 S,5 3 R)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphane-5 3 To give 3.4 g (6.8 mmol, 81%) of 4-methyl-4-ylbenzenesulfonate.

number

[0278] [ka] (2 1 R,2 4 R,5 2 S,5 3 R)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphane-5 3To a stirred solution of 2-yl-4-methylbenzenesulfonate (3.4 g, 1.0 equiv., 6.8 mmol) in DMF (30 mL) was added tetrabutylammonium azide (5.8 g, 3.0 equiv., 20 mmol). The resulting mixture was stirred at 80° C. for 16 h. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give (2) as an oil. 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Azide-1 4 -Methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolizina-2(1,4)-cyclohexanacyclooctaphan-6-one (1.6 g, 4.3 mmol, 63%) was obtained.

number

[0279] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a solution of 1.6 g (1.0 equivalent, 4.3 mmol) of 14-azido-14-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphan-6-one in 100 mL of methanol was added Pd / C (4.6 g, 10 wt%, 4.3 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated using a hydrogen balloon under a hydrogen atmosphere at room temperature for 16 hours. The crude was purified by reverse-phase flash chromatography to give ((2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 41,4-Dimethyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolizina-2(1,4)-cyclohexanacyclooctaphan-6-one (905 mg, 2.62 mmol, 61%) was obtained.

number

[0280] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4 To a solution of 1,1,1-trifluoro-N-(2-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphan-6-one (10 mg, 1.0 equiv., 29 μmol) in dichloromethane (2 mL) was added trifluoromethanesulfonic anhydride (9.8 mg, 1.2 equiv., 35 μmol) and triethylamine (8.8 mg, 3.0 equiv., 87 μmol). The resulting mixture was stirred at −50° C. for 0.5 h. The resulting mixture was extracted with NH4HCO3. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1,1,1-trifluoro-N-(2-methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphan-6-one as a solid. 1 S,2 4 S,5 2 R,5 3 S)-14-Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-pyrrolina-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (4.4 mg, 9.2 μmol, 32%) was obtained.

number

[0281] Example 1.17 [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 t-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 minutes. 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 adding 10 L of saturated 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 obtain 3-bromo-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridine (962.0 g, 80.0%) as an oily substance.

[0282] [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) was added Pd(dba) (134.2 g, 0.05 equiv., 0.15 mol), Xantphos (169.6 g, 0.10 equiv., 0.29 mol), and CsCO (2395 g, 2.5 equiv., 7.3 mol) under a nitrogen atmosphere. The resulting solution was stirred at 100 °C for 20 h. The solid was filtered off. 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.

[0283] [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 equiv., 1.7 mmol) in methanol (6.0 L) and acetic acid (600 mL) was added PtO (77.26 g, 0.20 equiv., 340.2 mmol). The mixture was hydrogenated under 20 atm of hydrogen at room temperature. 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.

[0284] [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 at room temperature overnight. The reaction was then quenched by adding 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 oily substance.

[0285] [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 equivalent, 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. The reaction was then quenched by adding 6 L of ice water. 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 a 5:1 ratio of EtO to EA (10 mL / g) to give benzyl racemic-(cis)-3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (108.7 g, 28.2%) as a solid, and the filtrate was concentrated in vacuo to give benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (64.0 g) as an oil.

number

[0286] [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) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 3 hours, followed by the addition of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (27.9 g, 1.2 equiv., 78.2 mmol) in THF (100 mL) and stirring at −78° C. for 2 hours. The resulting mixture was stirred at −78° C. for 2 hours. The mixture was added dropwise to 200 mL of saturated 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.

[0287] [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 equivalent, 0.59 mol) and bis(pinacolato)diboron (180 g, 1.2 equivalent, 0.71 mol) in 1,4-dioxane (3.5 L) was added Pd(dppf)Cl (24.1 g, 0.05 equivalent, 29.5 mmol) and potassium acetate (116 g, 2.0 equivalent, 1.18 mol) under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. 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-phase 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.

number

[0288] [ka] 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 (500.0 mg, 1.0 equiv., 0.876 mmol), benzyl 2-(2-bromo-3-fluorophenyl)-2-methylpropional A mixture of Pd(dppf)Cl₂·CHCl₂ (142.8 mg, 0.2 equiv., 0.175 mmol), and KCO₃ (302.8 mg, 2.5 equiv., 2.19 mmol) in 1,4-dioxane (8.0 mL) and HO (2.0 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL) and dried over anhydrous NaSO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give benzyl 2-[[(4-[2-[2-(benzyloxy)-2-oxoethoxy]-6-fluorophenyl]cyclohex-3-en-1-yl)oxy]methyl]-3-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (470 mg, 76.3%) as an oil.

number

[0289] [ka] A mixture of i-PrOH (6.0 mL), benzyl 2-[[(4-[2-[2-(benzyloxy)-2-oxoethoxy]-6-fluorophenyl]cyclohex-3-en-1-yl)oxy]methyl]-3-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (100.0 mg, 1.0 equivalent, 0.142 mmol) and Pd / C (30.3 mg, 2.0 equivalent, 0.285 mmol) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The resulting mixture was filtered, and the filter cake was washed with i-PrOH (3 × 3 mL). The filtrate was concentrated under reduced pressure to give 2-[4-([3-[(tert-butoxycarbonyl)amino]piperidin-2-yl]methoxy)cyclohex-1-en-1-yl]-3-fluorophenoxyacetic acid (58.0 mg, 85.2%) as a solid.

number

[0290] [ka] To a solution of 2-[4-([3-[(tert-butoxycarbonyl)amino]piperidin-2-yl]methoxy)cyclohex-1-en-1-yl]-3-fluorophenoxyacetic acid (53.0 mg, 1.0 equivalent, 0.11 mmol) and diisopropylethylamine (43 mg, 3.0 equivalent, 0.33 mmol) in acetonitrile (53 mL) was added HATU (63.0 mg, 1.5 equivalent, 0.17 mmol). After stirring at room temperature for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give tert-butyl((5 2 R,5 3 S,E)-1 6 -Fluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-5 3 -yl)carbamate (36.0 mg, 71%) was obtained.

number

[0291] [ka] tert-Butyl ((5 2 R,5 3 S,E)-1 6 -Fluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-2 1 -En-5 3 A mixture of tert-butyl((2-yl)carbamate (30.0 mg, 1.0 equiv., 65 μmol) and Pd / C (6.9 mg, 1 equiv., 65 μmol) in MeOH (6 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The resulting mixture was filtered, and the filter cake was subsequently washed with MeOH (3×3 mL). The filtrate was concentrated under reduced pressure to give tert-butyl((2-yl)carbamate) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Fluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)carbamate (28.0 mg, 93%) was obtained.

number

[0292] [ka] tert-Butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Fluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3A mixture of (2-yl)carbamate (28.0 mg, 1.0 equivalent, 61 μmol) in TFA (1.25 mL) and dichloromethane (5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6 -Fluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (20.0 mg, 91%) was obtained.

number

[0293] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6 To a solution of 2.00 g (1.0 equiv., 5.52 mmol) of 1-fluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one and diisopropylethylamine (1.44 mL, 1.5 equiv., 8.28 mmol) in dichloromethane (80 mL) was added TfO (1.21 mL, 1.3 equiv., 7.17 mmol) in dichloromethane (0.2 mL) dropwise at −40° C. The resulting mixture was stirred at −40° C. for 2 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude was triturated with ethyl acetate (50 mL) and finally dried under high vacuum to give 1,1,1-trifluoro-N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6-Fluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 3-yl)methanesulfonamide (2.2 g, 4.2 mmol, 75%). The isomeric mixture was purified by chiral preparative HPLC to give the pure enantiomers as white solids.

number

[0294] Example 1.18 [ka] N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a solution of N-((2-yl)methanesulfonamide (4.00 g, 1.0 equiv., 9.0 mmol) in MeCN (40 mL) and THF (40 mL) was added N-bromosuccinimide (3.37 g, 2.0 equiv., 0.02 mol). The resulting mixture was stirred at 25° C. for 18 h. The reaction was quenched by adding saturated aqueous sodium chloride solution at 0° C. The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography to give N-((2-yl)methanesulfonamide) as a solid. 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Bromo-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (4.7 g, 9.4 mmol, 100%) was obtained.

number

[0295] [ka] N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Bromo-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a solution of N-((2-yl)methanesulfonamide (2.50 g, 1.0 equivalent, 4.99 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.90 g, 1.5 equivalent, 7.48 mmol) in 1,4-dioxane (50 mL) was added KOAc (1.47 g, 3.0 equivalent, 15.0 mmol), Pd2(dba)3 (457 mg, 0.1 equivalent, 499 μmol), and XPhos (475 mg, 0.2 equivalent, 997 μmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3.5 hours. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude was purified by flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (2.2 g, 4.0 mmol, 80%) was obtained.

number

[0296] [ka] N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a stirred mixture of N-((2-yl)methanesulfonamide (2.20 g, 1.0 equiv., 4.01 mmol) in 1,4-dioxane (25 mL) was added hydrogen peroxide (30 wt%, 20 equiv., 80.2 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 4 h. The resulting mixture was stirred at 25 °C for 4 h. The reaction was quenched by adding saturated NaHSO3 at 0 °C. The resulting mixture was extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Hydroxy-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (1.2 g, 2.7 mmol, 68%) was obtained.

number

[0297] Example 1.19 [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3To a stirred mixture of 1,4-amino-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (1.4 g, 1.0 equiv., 4.2 mmol) and TEA (0.89 mL, 1.5 equiv., 6.4 mmol) in DCM (20 mL) was added trifluoromethanesulfonic anhydride (1.4 g, 1.2 equiv., 5.1 mmol) in DCM (5 mL) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 40 min. The reaction was quenched by the addition of NaHCO (aq.) at 0° C. The resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give 1,1,1-trifluoro-N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (1.5 g, 3.2 mmol, 77%) was obtained.

number

[0298] Example 1.20 [ka] To a stirred solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.0 g, 1.5 equiv., 0.03 mol) and DMPU (7.0 mL, 3.0 equiv., 0.05 mol) in THF (50 mL) was added n-butyllithium (2.0 g, 1.5 equiv., 0.03 mol) in portions at −78 °C under a N atmosphere. To the above mixture was added 1-(benzyloxy)-2-((1s,4s)-4-(chloromethoxy)cyclohexyl)benzene (6.0 g, 1.0 equiv., 0.02 mol) in portions over 3 h at −78 °C. The resulting mixture was stirred at −78 °C for an additional 4 h. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography to give (2S,5R)-2-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.6 g, 12 mmol, 60%) as an oil.

number

[0299] [ka] To a solution of (2S,5R)-2-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine, 2,5-dihydropyrazine (5.2 g, 1.0 equiv., 10 mmol) in acetonitrile (72 mL) was added HCl (30%) (72 mL), and the resulting mixture was stirred at 40° C. for 2 hours. The crude was purified by reverse-phase flash chromatography to give methyl O-((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serinate, HCl (3.8 g, 90%) as an oil.

[0300] [ka] To a solution of methyl O-((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl-L-serinate, HCl (3.8 g, 1.0 equiv., 9.0 mmol) and NaHCO3 (aq) (40 mL) in THF (40 mL) was added benzyl carbonochloridate (1.9 g, 1.2 equiv., 11 mmol). The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was extracted with dichloromethane (3 * 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography to give methyl N-((benzyloxy)carbonyl)-O-((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serinate (3.23 g, 69%) as an oil.

number

[0301] [ka] To a stirred mixture of methyl N-((benzyloxy)carbonyl)-O-((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serinate (3.0 g, 1.0 equiv., 6 mmol) in diethyl ether (150 mL) was added LiAlH (0.3 g, 1.5 equiv., 9 mmol) under a nitrogen atmosphere at −20 °C. The resulting mixture was stirred at −20 °C for 18 h. To the above mixture was added THF at −20 °C. The resulting mixture was stirred for an additional 10 min at −20 °C. The reaction was quenched by adding NaSO·10H O at −20 °C. The resulting mixture was stirred for an additional 10 min. The resulting mixture was filtered and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography to give benzyl ((R)-1-(((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxypropan-2-yl)carbamate (2.1 g, 70%) as an oil.

number

[0302] [ka] To a solution of benzyl ((R)-1-(((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxypropan-2-yl)carbamate (1.9 g, 1.0 equiv., 3.9 mmol) in dichloromethane (80 mL) was added Dess-Martin periodinane (2.0 g, 1.2 equiv., 4.7 mmol). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was diluted with dichloromethane (3 × 20 mL). The crude was purified by flash chromatography to give tert-butyl ((S)-1-(((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-oxopropan-2-yl)carbamate (1.4 g, 3.1 mmol, 80%) as a solid.

number

[0303] [ka] To a stirred mixture of lithium diisopropylethylamide (0.91 g, 2.5 equiv., 8.5 mmol) in THF (2 mL) was added dropwise a solution of propan-2-one (0.20 g, 1.0 equiv., 3.4 mmol) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. To the above mixture was added dropwise a solution of benzyl ((S)-1-oxo-3-(((1s,4R)-4-phenylcyclohexyl)oxy)propan-2-yl)carbamate (1.3 g, 1.0 equiv., 3.4 mmol) in THF (2 mL) under a nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for an additional 1 hour. The reaction was warmed to room temperature and quenched with saturated NH4Cl (5 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography to give benzyl ((2S)-1-(((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxy-5-oxohexan-2-yl)carbamate (500 mg, 916 μmol, 27%) as an oil.

number

[0304] [ka] To a solution of benzyl ((2S)-1-(((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxy-5-oxohexan-2-yl)carbamate (0.5 g, 1.0 equivalent, 0.9 mmol) in i-PrOH (50 mL) was added Pd / C (0.3 g, 10 wt%, 0.3 equivalent, 0.3 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature, filtered through a Celite® pad, and concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification.

number

[0305] [ka] To a solution of (2S,3R)-2-((((1s,4R)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methyl-3,4-dihydro-2H-pyrrol-3-ol (0.5 g, 1.0 equiv., 2 mmol) in i-PrOH (30 mL) was added NaBH(OAc) (2.0 equiv., 1.8 mmol). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification.

number

[0306] [ka] To a solution of (2S,3R)-2-((((1s,4R)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-ol (500 mg, 1.0 equiv., 1.64 mmol) and NaHCO3 (aq) (10 mL) in acetonitrile (30 mL) was added di-tert-butyl dicarbonate (536 mg, 1.5 equiv., 2.46 mmol). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by reverse-phase flash chromatography to give tert-butyl (2R,3R)-3-hydroxy-2-((((1s,4S)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (210 mg, 518 μmol, 31.6%) as a solid.

number

[0307] [ka] To a solution of tert-butyl (2S,3R)-3-hydroxy-2-((((1s,4R)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (210 mg, 1.0 equiv., 518 μmol) and tert-butyl 2-bromoacetate (121 mg, 1.2 equiv., 621 μmol) in acetonitrile (5 mL) was added KCO (143 mg, 2.0 equiv., 1.04 mmol). The resulting mixture was stirred at 25 °C for 3 days. The residue was purified by preparative TLC to give tert-butyl (2S,3R)-2-((((1s,4R)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)phenyl)cyclohexyl)oxy)methyl)-3-hydroxy-5-methylpyrrolidine-1-carboxylate (195 mg, 375 μmol, 72.5%) as a semisolid.

number

[0308] [ka] To a solution of tert-butyl (2S,3R)-2-((((1s,4R)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)phenyl)cyclohexyl)oxy)methyl)-3-hydroxy-5-methylpyrrolidine-1-carboxylate (190 mg, 1.0 equiv., 366 μmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (310 mg, 2.0 equiv., 731 μmol). The resulting mixture was stirred at 25 °C for 2 h. The residue was purified by preparative TLC to give tert-butyl (2S)-2-((((1s,4R)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)phenyl)cyclohexyl)oxy)methyl)-5-methyl-3-oxopyrrolidine-1-carboxylate (130 mg, 251 μmol, 68.7%) as a solid.

number

[0309] [ka] To a solution of tert-butyl (2S)-2-((((1s,4R)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)phenyl)cyclohexyl)oxy)methyl)-5-methyl-3-oxopyrrolidine-1-carboxylate (120 mg, 1.0 equiv., 232 μmol) in dichloromethane (8 mL) was added triethylamine (4 mL). The resulting mixture was stirred at 25° C. for 3.5 hours. The crude product was used directly in the next step without further purification.

number

[0310] [ka] To a solution of 2-(2-((1R,4s)-4-(((2S)-5-methyl-3-oxopyrrolidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (100 mg, 1.0 equiv., 277 μmol) and HATU (158 mg, 1.5 equiv., 415 μmol) in acetonitrile (50 mL) was added DIEA (145 μL, 3.0 equiv., 830 μmol). The resulting mixture was stirred at 25° C. for 1 h. Two peaks could be detected by LCMS. The residue was purified by preparative TLC to give (2 1 R,2 4 R,5 2 S)-5 5 -Methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 ,6-dione (30 mg, 87 μmol, 32%) was obtained.

number

[0311] [ka] (2 1 R,2 4 R,5 2 S)-5 5 -Methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 To a solution of 2,6-dione (25 mg, 1.0 equiv., 73 μmol) and MgSO (1.8 mg, 0.2 equiv., 15 μmol) in dichloromethane (1 mL) was added (4-methoxyphenyl)methanamine (12 mg, 1.2 equiv., 87 μmol) and sodium triacetoxyborohydride (31 mg, 2.0 equiv., 0.15 mmol). The resulting mixture was stirred at 25°C for 12 hours. The residue was purified by preparative TLC to give (2 1 S,2 4 S,52 R,5 3 S)-5 3 -((4-methoxybenzyl)amino)-5 5 1,4-Dimethyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (28 mg, 60 μmol, 83%) was obtained.

number

[0312] [ka] (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((4-methoxybenzyl)amino)-5 5 To a solution of 2-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (28.0 mg, 1.0 equiv., 60.3 μmol) and ammonium formate (114 mg, 90.1 μL, 30.0 equiv., 1.81 mmol) in 2-propanol (1.5 mL) was added dry Pd / C (64.1 mg, 10 wt%, 1.0 equiv., 60.3 μmol) under a N atmosphere. The resulting mixture was stirred at 85 °C for 2 h. The crude product was used directly in the next step without further purification.

number

[0313] [ka] (2 1 S,2 4 S,5 2 R,5 3 S, 5 5 R)-5 3 -amino-5 5To a solution of 1-methyl-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (15 mg, 1.0 equiv., 44 μmol) in dichloromethane (1 mL), DIEA (17 mg, 23 μL, 3.0 equiv., 0.13 mmol) and methanesulfonic anhydride (15 mg, 2.0 equiv., 87 μmol) were added at room temperature. The resulting mixture was stirred at 20°C for 1 hour. The residue was purified by preparative TLC to give N-((2 1 S,2 4 S,5 2 R,5 3 S,5 5 R)-5 5 -Methyl-6-oxo-3,8-dioxa-5(2,1)-pyrrolizina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide (3.0 mg, 7.0 μmol, 16%) was obtained.

number

[0314] Example 2: Human OX2R IP1 assay T-Rex CHO cells stably overexpressing the human orexin 2 receptor (OX2R) were induced overnight with 1 μg / mL doxycycline in a T225 flask. 24 hours after induction, cells were detached with Accutase and plated at 30,000 cells / well in a 384-well proxy plate. Cells were then treated with different test compounds in 1x stimulation buffer (pH 7.4) containing 10 mM HEPES, 1 mM CaCl2, 0.5 mM MgCl2, 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl for 1 hour at 37°C. After incubation, the reaction was terminated by the addition of cell lysis buffer and a detection mix consisting of IP1-d2 and anti-IP1-cryptate diluted in 1x stimulation buffer. The plate was allowed to incubate at room temperature for 1 hour and then read on an ENVISION® multimode plate reader to measure inositol phosphates.

[0315] Cisbio IP1 is a cell-based functional assay that quantifies the accumulation of inositol phosphate (IP), a metabolite released as a result of orexin 2 receptor activation via the phospholipase C-Gq signaling pathway. This is a competitive immunoassay in which IP1 produced by cells upon receptor activation competes with an IP1 analog conjugated to a d2 fluorophore (acceptor) for binding to an anti-IP1 monoclonal antibody labeled with a Eu cryptate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0316] EC reported in Table 2 50 Values were obtained using the human OX2R IP1 assay described above. Data are the mean EC 50 Values are ± SEM. Reference Compound A is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-piperidine-1-carboxylate (Example 5 of PCT Publication No. WO2017 / 135306). Reference Compound B is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (Example 483 of PCT Publication No. WO2019 / 027058). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

[0317] Example 3: MDCK-MDR1 permeability assay Bidirectional permeability (e.g., apical to basolateral and basolateral to apical) of test compounds in MDCK-MDR1 cells was assessed using MDCK-MDR1 cells seeded in Solvo PreadyPort™ MDCK 96-well plates. Upon receiving plates from ReadyCell (Barcelona, Spain), they were processed according to the PreadyPort™ user manual.

[0318] For apical to basolateral (A→B) permeability, 80 μL of test compound (3 μM) co-administered with LY (Lucifer Yellow) (100 μM) in HBSS (Hank's Balanced Salt Solution) assay buffer was added to the donor side (A), and 250 μL of HBSS buffer was added to the receiver side (B). For basolateral to apical (B→A) permeability, 255 μL of test compound (3 μM) in HBSS assay buffer was added to the donor side (B), and 75 μL of HBSS buffer containing LY (100 μM) was added to the receiver side (A).

[0319] The plate was placed in an incubator set at 37°C. After 10 minutes of preheating, a 5 μL aliquot was removed from the donor compartment and set aside as the dosing solution. The MDCK-MDR1 incubation plate was returned to the incubator for 2 hours of incubation at 37°C. After the 2-hour incubation, 25 μL and 5 μL aliquots were removed from the receiver and donor sides, respectively. The 5 μL aliquots removed from the donor side (before and after the 2-hour incubation) were diluted with 20 μL of HBSS buffer. All samples were mixed with 150 μL of acetonitrile and 200 μL of water containing an internal standard (IS) and analyzed by LC-MS / MS.

[0320] The following formula: P app = dQ / dt × 1 / A × C0, During the ceremony: dQ / dt: Amount of substance transferred during the incubation time (nmol / s) A: Insert area (0.14 cm for PreadyPort™ MDR1-96) 2 ) C0: initial concentration (nmol / mL) of the product applied to the luminal (A → B) or basolateral (B → A) compartment. Apparent permeation (P app ) was calculated.

[0321] P app (from the outside of the basement membrane to the luminal side) app The efflux ratio (ER) was determined by dividing the luminal to basolateral ratio (LUMINAL to LAMINAL). This is a general measure of the involvement of active processes. An ER of >2 is considered positive for active transport.

[0322] The following formula: Recovery rate =

number

[0323] The data reported in Table 3 were obtained by the MDCK-MDR1 permeability assay described above. [Table 3-1] [Table 3-2] [Table 3-3]

[0324] Example 4: Hepatocyte stability assay Cryopreserved hepatocytes from male Sprague-Dawley rats and hepatocytes from a pool of 50 human hepatocytes of various genders were used to assess in vitro metabolic stability. 6 Incubation mixtures were prepared in a 48-well plate by mixing 250 μL of pre-warmed KHB (Krebs-Henseleit buffer) containing hepatocytes at 10 cells / mL with 250 μL of pre-warmed KHB buffer containing 2 μM test compound, resulting in a final concentration of 1 μM test compound (0.1% DMSO) and 1x 10% DMSO. 6A total of 100 cells / mL of hepatocytes was obtained. The reaction mixture was incubated at 37°C. 50 μL aliquots of the incubation mixture were removed at time points (0, 15, 30, 60, 120, and 240 min) and transferred to a 96-well plate containing 300 μL of ice-cold acetonitrile (containing 30 ng / mL labetalol and 10 ng / mL naltrexone-d3 as internal standards) and immediately placed on ice to terminate the reaction. Samples were centrifuged and transferred to a 96-well plate for liquid chromatography with tandem mass spectrometry (LC-MS / MS) analysis to monitor the depletion of test compounds.

[0325] The peak area ratio (analyte / IS) at time zero was assumed to be 100%, and the data were calculated as percent remaining by dividing the peak area ratio remaining by the peak area ratio at time zero. The data were fitted to a first-order degradation model to determine the half-life. The slope of the line was determined from a plot of the log(ln) peak area versus time. The half-life (T) was then calculated using the following equation: 1 / 2 ) and intrinsic clearance (CL int ) was calculated. Elimination rate constant (k) = (-slope) Half-life (T 1 / 2 ) min=0.693 / k Intrinsic clearance (CLint) (mL / min / million cells) = (V × 0.693) / T1 / 2 V = incubation volume mL / cell count

[0326] In vitro T in mL / min / kg using the formula shown below 1 / 2 The in vitro intrinsic clearance (CL int,hep ) was converted to

number

[0327] The following equation was fitted from the well-stirred model:

number

[0328] The extraction ratio (ER) was calculated by dividing the hepatic blood flow by the hepatic clearance of the compound. The data reported in Table 5 were obtained using the human hepatocyte stability assay described above. [Table 5-1] [Table 5-2] [Table 5-3]

[0329] Example 5: Evaluation of wakefulness promotion in Sprague-Dawley rats Adult male Sprague-Dawley rats were evaluated for wakefulness promotion using electroencephalography (EEG) and electromyography (EMG). All rats (Charles River Laboratories, Raleigh, NC, USA) were intraperitoneally implanted with a telemetry device (F50-EEE, Data Sciences International Inc., MN, USA) under isoflurane anesthesia. For EEG, stainless steel screws were implanted in the frontal and parietal cortices, and a reference screw was placed in the cerebellum. For EMG, electrodes were placed in the neck muscles. After surgery, rats were given carprofen and allowed to recover for 7–10 days. Rats were habituated to the laboratory for 7 days and maintained on a 12-h light-dark cycle.

[0330] EEG and EMG data were recorded using a DSI telemetry system and Ponemah software (Data Sciences International Inc., MN, USA). Sleep-wake stages were scored in 10-second periods both manually and using the supervised machine learning software platform Somnivore. After processing, recordings were visually inspected as needed.

[0331] All test compounds were dissolved in 5% DMSO and suspended in 95% saline with 0.5% methylcellulose and 0.5% Tween. In a crossover design, they were administered at a dose volume of 3.33 mL / kg body weight during the inactive light cycle at zeitgeber time 5 (ZT5). Unless otherwise specified, all compounds were administered orally. Recordings for each rat began immediately after dosing and continued for up to 6 hours after dosing.

[0332] Two key endpoints included wakefulness time and cortical activation time. Wakefulness time was derived from sleep-wake stage analysis. Cortical activation time was based on the duration of elevation of frontal gamma neural oscillatory activity (30-100 Hz) relative to pre-treatment baseline, an important function of wakefulness. Mean cortical activation time was calculated relative to the vehicle treatment period of 6 hours post-dose. Results are shown in Table 6 below. [Table 6]

[0333] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Compound of formula IA: 【Chemistry 1A】 wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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- to 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- to 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-(5-10 membered heteroaryl) is unsubstituted or is 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 O; Z is (CR １２ R １３ ) ｍ and Each R is halogen, deuterium, hydroxyl, cyano, unsubstituted C １ -C ３ Alkyl and C substituted with one or more halogens or deuterium １ -C ３ independently selected from the group consisting of alkyl; p is 0, 1, 2, 3 or 4; R ａ and R ｂ are each independently H or unsubstituted C １ -C ３ is alkyl; m is 1; 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 form a single bond together with the carbon atom to which they are attached; 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 atom to which they are attached, C ３ -C ５ Forming a cycloalkyl; Or alternatively, R ３ and R ４ together with the carbon atom 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; Each R １２ and R １３ H, halogen, deuterium, unsubstituted C １ -C ３ C substituted with alkyl and hydroxyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; R １４ , R １５ and R １６ are H, unsubstituted C, １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; Each R １７ and R １８ is H, unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; However, (a) to (f): (a) at least one R is hydroxyl, cyano, unsubstituted C １ -C ３ Alkyl and C substituted with one or more halogens or deuterium １ -C ３ selected from the group consisting of alkyl; (b) E is NR ａ R ｂ , C １ -C ３ Alkylene -NR ａ R ｂ , C ２ -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- to 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- to 10-membered heteroaryl or C １ -C ３ alkylene-(5-10 membered heteroaryl), １ -C ３ Alkylene -NR ａ R ｂ , C ２ -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- to 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- to 10-membered heteroaryl or C １ -C ３ Alkylene-(5- to 10-membered heteroaryl) is unsubstituted or is substituted with one or more of halogen, hydroxyl, C １ -C ３ Alkyl or C １ -C ３ alkoxy substituted; (c) E is one or more of halogen, hydroxyl, C １ -C ３ Alkyl or C １ -C ３ Alkoxyl-substituted C １ is alkyl; (d) R １４ , R １５ , R １６ , R １７ and R １８ At least one of the groups is unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ is alkyl; (e) R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １１ is hydroxyl; or (f) R １２ and R １３ At least one of the C is substituted with hydroxyl. １ -C ３ Alkyl or a pharma- ceutically acceptable salt thereof, wherein one or more of:

2. The compound of claim 1, wherein the compound of formula IA, or a pharma- ceutically acceptable salt thereof, is a compound of formula I, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】

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

4. 3. The compound of claim 1 or claim 2, wherein n is 2.

5. The compound according to any one of claims 1 to 4, wherein Ring A is phenyl.

6. The compound according to any one of claims 1 to 4, wherein Ring A is pyridinyl.

7. T is CR １ R ２ The compound according to any one of claims 1 to 6,

8. The compound according to any one of claims 1 to 6, wherein T is O.

9. W is CR ４ R ５ The compound according to any one of claims 1 to 8,

10. The compound according to any one of claims 1 to 8, wherein W is O.

11. V is CR ３ The compound according to any one of claims 1 to 10,

12. T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 1 to 6,

13. Ring A is phenyl and T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 1 to 4,

14. Ring A is pyridinyl and T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 1 to 4,

15. The compound or a pharma- ceutically acceptable salt thereof is 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 3. The compound of claim 2 selected from the group consisting of:

16. Compound of formula II-A: 【Chemistry 3A】 wherein Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is 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- to 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- to 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-(5-10 membered heteroaryl) is unsubstituted or is 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 Each R is halogen, deuterium, hydroxyl, cyano, unsubstituted C １ -C ３ Alkyl and C substituted with one or more halogens or deuterium １ -C ３ independently selected from the group consisting of alkyl; p is 0, 1, 2, 3 or 4; R ａ and R ｂ are each independently H or unsubstituted C １ -C ３ is alkyl; When Y is absent, m is 2, 3, 4 or 5; Y is NR １０ or O, m is 1, 2, 3 or 4; 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 form a single bond together with the carbon atom to which they are attached; 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 atom to which they are attached, C ３ -C ５ Forming a cycloalkyl; Or alternatively, R ３ and R ４ together with the carbon atom 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 is 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 H, halogen, deuterium, unsubstituted C １ -C ３ C substituted with alkyl and hydroxyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; R １４ , R １５ and R １６ are H, unsubstituted C, １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; Each R １７ and R １８ is H, unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ independently selected from the group consisting of alkyl; However, (a) to (f): (a) at least one R is hydroxyl, cyano, unsubstituted C １ -C ３ Alkyl and C substituted with one or more halogens or deuterium １ -C ３ selected from the group consisting of alkyl; (b) E is NR ａ R ｂ , C １ -C ３ Alkylene -NR ａ R ｂ , C ２ -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- to 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- to 10-membered heteroaryl or C １ -C ３ alkylene-(5-10 membered heteroaryl), １ -C ３ Alkylene -NR ａ R ｂ , C ２ -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- to 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- to 10-membered heteroaryl or C １ -C ３ Alkylene-(5- to 10-membered heteroaryl) is unsubstituted or is substituted with one or more of halogen, hydroxyl, C １ -C ３ Alkyl or C １ -C ３ alkoxy substituted; (c) E is one or more of halogen, hydroxyl, C １ -C ３ Alkyl or C １ -C ３ Alkoxyl-substituted C １ is alkyl; (d) R １４ , R １５ , R １６ , R １７ and R １８ At least one of the groups is unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens １ -C ３ is alkyl; (e) R １ , R ２ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １１ is hydroxyl; or (f) R １２ and R １３ At least one of the C is substituted with hydroxyl. １ -C ３ Alkyl or a pharma- ceutically acceptable salt thereof, wherein one or more of:

17. The compound of claim 16, wherein the compound of formula II-A, or a pharma- ceutically acceptable salt thereof, is a compound of formula II, or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】

18. 18. The compound of claim 16 or claim 17, wherein n is 1.

19. 18. The compound of claim 16 or claim 17, wherein n is 2.

20. The compound according to any one of claims 16 to 19, wherein Ring A is phenyl.

21. The compound according to any one of claims 16 to 19, wherein Ring A is pyridinyl.

22. T is CR １ R ２ The compound according to any one of claims 16 to 21,

23. The compound according to any one of claims 16 to 21, wherein T is O.

24. W is CR ４ R ５ The compound according to any one of claims 16 to 23,

25. The compound of any one of claims 16 to 23, wherein W is O.

26. V is CR ３ The compound according to any one of claims 16 to 25,

27. T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 16 to 21,

28. Ring A is phenyl and T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 16 to 19,

29. Ring A is pyridinyl and T is CR １ R ２ and W is CR ４ R ５ and V is CR ３ The compound according to any one of claims 16 to 19,

30. The compound or a pharma- ceutically acceptable salt thereof is 【Chemistry 4-1】 【Chemistry 4-2】 18. The compound of claim 17, selected from the group consisting of:

31. The compound of claim 30, 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

32. The compound comprising: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

33. The compound comprising: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

34. The compound comprising: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

35. The compound comprising: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

36. The compound comprising: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

37. The compound comprising: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

38. 38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

39. Use of a compound according to any one of claims 1 to 37 or a pharma- ceutically acceptable salt thereof, or a composition according to claim 38, for the manufacture of a medicament for treating narcolepsy in a subject.

40. Use of a compound according to any one of claims 1 to 37 or a pharma- ceutically acceptable salt thereof, or a composition according to claim 38, for the manufacture of a medicament for treating cataplexy in a subject.

41. A compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, or a composition according to claim 38, for use in the treatment of narcolepsy in a subject in need thereof.

42. A compound according to any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, or a composition according to claim 38, for use in treating cataplexy in a subject in need thereof.

Images