Substituted macrocyclic compounds and related therapeutic methods

Abstract

The present invention provides compounds useful for treating narcolepsy and cataplexy in a subject in need thereof. Also provided herein are related pharmaceutical compositions and methods.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 128,404, filed Dec. 21, 2020, and U.S. Provisional Application No. 63 / 190,937, filed May 20, 2021. The entire contents of the above applications are incorporated herein by reference. Technical Field

[0003] The present invention relates to substituted macrocyclic compounds, particularly substituted macrocyclic compounds having agonist activity. Background Art

[0004] Orexin is a neuropeptide synthesized and released by a subset of neurons in the lateral hypothalamus and its surrounding regions. It consists of two subtypes: orexin A and orexin B. Orexin A and orexin B bind to orexin receptors. Orexin receptors are G protein-coupled receptors that are preferentially expressed in the brain. There are two subtypes of orexin receptors (type 1 and type 2) (Cell, Vol. 92, 573-585, 1998). It is well known that the activation of orexin receptors is important for a variety of functions of the central nervous system, such as maintaining wakefulness, energy balance, reward processing, and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0005] Narcolepsy is a neurological disorder that causes excessive daytime sleepiness, sudden-onset muscle paralysis (cataplexy), and sleep pattern disturbances (Mahoney et al., Nature Reviews Neuroscience, 2019). Narcolepsy is known to be caused by the degeneration of orexin neurons. The symptoms of narcolepsy can be modeled in transgenic mice engineered to have orexin neuron degeneration, and the symptoms can be reversed by intracerebroventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies on orexin-2 receptor knockout mice have shown that the orexin-2 receptor plays a preferential role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999, Neuron, Vol. 38, 715-730, 2003). Therefore, orexin-2 receptor agonists can be drugs for treating narcolepsy or other diseases that present with excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0006] Compounds having agonist activity at the orexin-2 receptor are considered as new therapeutic agents for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbance of consciousness such as coma, narcolepsy syndrome, somnolence syndrome characterized by hypersomnia (such as 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, etc. (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; WO2015 / 048091; WO 2015 / 147240).

[0007] Some compounds having orexin-2 receptor agonist activity have been reported (U.S. Pat. No. 8,258,163; WO 2015 / 088000; WO 2014 / 198880; Journal of Medicinal Chemistry, Vol.58, pages 7931-7937; US 20190040010; US 20190031611; US 20170226137). However, these compounds are considered not satisfactory, for example, in terms of activity, pharmacokinetics, permeability to the brain / central nervous system or safety, and improved compounds having orexin-2 receptor agonist activity need to be developed. Summary of the Invention

[0008] The object of the present invention is to provide substituted macrocyclic compounds having orexin-2 receptor agonist activity.

[0009] Therefore, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein:

[0012] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0013] n is 1, 2 or 3;

[0014] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0015] T is CR1R2 or O;

[0016] W is CR4R5 or O;

[0017] U is CR6R7;

[0018] X is CR8R9;

[0019] V is CR3 or N;

[0020] Y is NR 10 , O or absent;

[0021] Z is (CR 12 R 13 ) m ;

[0022] Each R is independently selected from halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted by one or more halogens or deuterium;

[0023] p is 0, 1, 2, 3 or 4;

[0024] R a and R b are each independently H or an unsubstituted C1-C3 alkyl group;

[0025] m is 1, 2, 3 or 4;

[0026] Furthermore, wherein:

[0027] R1, R2, R4 and R5 are each independently selected from H, hydroxyl, halogen and deuterium;

[0028] Or, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0029] R3 is selected from H, halogen, hydroxyl and cyano;

[0030] Or, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl group;

[0031] Or, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl group;

[0032] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxyl, halogen and deuterium;

[0033] R 10 is selected from H, an unsubstituted C1-C3 alkyl group and a C1-C3 alkyl group substituted with one or more halogens;

[0034] Each R 12 and R 13 are independently selected from H, halogen, deuterium, an unsubstituted C1-C3 alkyl group and a C1-C3 alkyl group substituted with hydroxyl or one or more halogens;

[0035] R 14 、R 15 and R 16 are each independently selected from H, an unsubstituted C1-C3 alkyl group or a C1-C3 alkyl group substituted with one or more halogens;

[0036] Each R 17 and R 18 are independently selected from H, an unsubstituted C1-C3 alkyl group and a C1-C3 alkyl group substituted with one or more halogens;

[0037] Provided that one or more of (a)-(f) are present:

[0038] (a) At least one R is selected from the group consisting of hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0039] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl or C1-C3 alkoxy;

[0040] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl or C1-C3 alkoxy;

[0041] (d) At least one of R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0042] (e) At least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is hydroxy; or

[0043] (f) At least one of R 12 and R 13 is C1-C3 alkyl substituted with hydroxy.

[0044] In one embodiment, provided herein is a compound of Formula I-A having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0045]

[0046] Wherein:

[0047] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0048] n is 1, 2 or 3;

[0049] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0050] T is CR1R2 or O;

[0051] W is CR4R5 or O;

[0052] U is CR6R7;

[0053] X is CR8R9;

[0054] V is CR3 or N;

[0055] Y is NR 10 , O or absent;

[0056] Z is (CR 12 R 13 ) m ;

[0057] Each R is independently selected from halogen, deuterium, hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuteriums;

[0058] p is 0, 1, 2, 3, or 4;

[0059] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0060] m is 1, 2, 3, or 4;

[0061] Further, wherein:

[0062] R1, R2, R4, and R5 are each independently selected from H, hydroxy, halogen, and deuterium;

[0063] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0064] R3 is selected from H, halogen, hydroxy, and cyano;

[0065] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0066] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0067] R6, R7, R8, R9, and R 11 are each independently selected from H, hydroxy, halogen, and deuterium;

[0068] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0069] Each R 12 and R 13 are independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxy or one or more halogens;

[0070] R 14 、R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0071] Each R 17 and R 18 are independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0072] Provided that one or more of (a)-(f) are present:

[0073] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0074] (b) 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0075] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0076] (d) At least one of R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens;

[0077] (e) At least one of R1, R2, R4, R5, R6, R7, R8, R9, and R 11 is hydroxy; or

[0078] (f) At least one of R 12 and R 13 is C1-C3 alkyl substituted with hydroxy.

[0079] The present invention also provides a compound having the structure of Formula II-A or a pharmaceutically acceptable salt thereof:

[0080]

[0081] Wherein:

[0082] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0083] n is 1, 2 or 3;

[0084] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0085] T is CR1R2 or O;

[0086] W is CR4R5 or O;

[0087] U is CR6R7;

[0088] X is CR8R9;

[0089] V is CR3 or N;

[0090] Y is NR 10 , O or absent;

[0091] Z is (CR 12 R 13 ) m ;

[0092] Each R is independently selected from halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0093] p is 0, 1, 2, 3 or 4;

[0094] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0095] When Y is absent, m is 2, 3, 4 or 5; or

[0096] When Y is NR 10 or O, m is 1, 2, 3 or 4;

[0097] Furthermore, wherein:

[0098] R1, R2, R4 and R5 are each independently selected from H, hydroxyl, halogen and deuterium;

[0099] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0100] R3 is selected from H, halogen, hydroxyl and cyano;

[0101] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0102] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0103] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxyl, halogen and deuterium;

[0104] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0105] Each R 12 and R 13 are independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens;

[0106] R 14 , R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0107] Each R 17 and R 18Independently selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0108] Provided that one or more of (a)-(f) are present:

[0109] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0110] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), where 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0111] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0112] (d) At least one of R 14 , R 15 , R 16 , R 17 , and R 18 is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens;

[0113] (e) At least one of R1, R2, R4, R5, R6, R7, R8, R9, and R 11 is hydroxy; or

[0114] (f) R 12 and R13 at least one of which is a C1-C3 alkyl group substituted with a hydroxyl group.

[0115] In one embodiment, provided herein is a compound of Formula II-A having the structure of Formula II or a pharmaceutically acceptable salt thereof:

[0116]

[0117] wherein:

[0118] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0119] n is 1, 2 or 3;

[0120] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups;

[0121] T is CR1R2 or O;

[0122] W is CR4R5 or O;

[0123] U is CR6R7;

[0124] X is CR8R9;

[0125] V is CR3 or N;

[0126] Y is NR 10 , O or absent;

[0127] Z is (CR 12 R 13 ) m ;

[0128] Each R is independently selected from halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0129] p is 0, 1, 2, 3 or 4;

[0130] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0131] When Y is absent, m is 2, 3, 4 or 5; or

[0132] When Y is NR 10 or O, m is 1, 2, 3 or 4;

[0133] Furthermore, wherein:

[0134] R1, R2, R4 and R5 are each independently selected from H, hydroxyl, halogen and deuterium;

[0135] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0136] R3 is selected from H, halogen, hydroxyl and cyano;

[0137] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0138] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0139] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxyl, halogen and deuterium;

[0140] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0141] Each R 12 and R 13 are independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens;

[0142] R 14 、R 15 and R 16Each is independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0143] Each R 17 and R 18 are independently selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0144] Provided that one or more of (a)-(f) are present:

[0145] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0146] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0147] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0148] (d) At least one of R 14 , R 15 , R 16 , R 17 and R 18 is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens;

[0149] (e)At least one of R1, R2, R4, R5, R6, R7, R8, R9, and R 11 is a hydroxyl group; or

[0150] (f)At least one of R 12 and R 13 is a C1-C3 alkyl group substituted with a hydroxyl group.

[0151] The present invention also provides a pharmaceutical composition comprising a compound of formula I-A, I, II-A, or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] In another aspect, the present invention provides a method for treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A, or II, or a pharmaceutically acceptable salt thereof.

[0153] In another aspect, the present invention provides a method for treating cataplexy in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A, or II, or a pharmaceutically acceptable salt thereof. Detailed Description

[0154] The compounds provided herein, such as compounds of formula I-A, I, II-A, or II, or pharmaceutically acceptable salts thereof, are useful for treating narcolepsy or cataplexy in a subject.

[0155] In a non-limiting aspect, these compounds can modulate the orexin-2 receptor. In certain embodiments, the compounds provided herein are believed to be orexin-2 agonists. Thus, in one aspect, the compounds provided herein contribute to the treatment of narcolepsy in a subject by acting as agonists of the orexin-2 receptor.

[0156] Definition

[0157] The definitions of various terms used to describe the present invention are listed below. These definitions apply to the terms used in this specification and claims, unless otherwise limited in a particular instance either individually or as part of a larger group.

[0158] 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. In general, the terms and laboratory procedures used herein in cell culture, molecular genetics, organic chemistry, and polypeptide chemistry are well known and commonly employed in the art.

[0159] As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, "element" refers to one element or more than one element. In addition, the use of the term "including" and other forms such as "include", "includes", and "included" is not restrictive.

[0160] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. For measurable values referred to herein, such as amounts, lengths of time, etc., the term "about" means including variations of ±, ±±, including, including ±, ±±, including, and ±± including, ±± including, and ±± including ± compared to the specified value, as such variations are appropriate for performing the disclosed methods.

[0161] As used herein, the term "herein" 50 "refers to the concentration of a compound required to achieve 50% of the maximum observed effect of the compound.

[0162] As used herein, the term "agonist" refers to a compound that, when it contacts a target of interest (e.g., orexin-2 receptor), results in an increase in a certain activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.

[0163] The term "treatment" includes reducing or alleviating at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes contacting an effective amount of a compound of the present invention with an orexin-2 receptor to treat a disease associated with narcolepsy or cataplexy.

[0164] As used herein, the term "prevent" or "prevention" means that a disorder or disease does not occur if it has not occurred; if a disorder or disease has already occurred, it does not occur further. In addition, the ability of a person to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

[0165] As used herein, the terms "patient", "individual", or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and murine mammals. Preferably, the patient, individual, or subject is a human.

[0166] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to a dosage of a drug that is non-toxic but sufficient to provide the desired biological result. This result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by a person of ordinary skill in the art through routine experimentation.

[0167] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not destroy the biological activity or properties of a compound and is relatively non-toxic, i.e., can be administered to an individual without causing adverse biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0168] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base molecule 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; base salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound, such as those formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic molecule by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with the corresponding base or acid in water or an organic solvent, or a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to single salts or 1:1 salts. For example, "pharmaceutically acceptable salt" also includes double salts, such as dihydrochloride salts. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference.

[0169] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous injection, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0170] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound useful in the present invention within or to a patient, so that it can perform its intended function. Typically, such a construct is carried or transported from one organ or part of the body to another. Each carrier must be "acceptable," i.e., compatible with the other ingredients of the formulation, including the compound useful in the present invention, and not injurious 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0171] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, etc., that are physiologically acceptable to the patient and compatible with the activity of the compound useful in the present invention. Supplementary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can also include pharmaceutically acceptable salts of the compound useful in the present invention. Other additional ingredients that can be included in the pharmaceutical compositions used in the practice of the present invention are known in the art, for example, as described in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa), which is incorporated herein by reference.

[0172] As used herein, unless otherwise specified, the term "alkyl," by itself or as part of another substituent, refers to a straight-chain or branched-chain hydrocarbon having the designated number of carbon atoms (i.e., C 1-6 alkyl refers to an alkyl having 1 to 6 carbon atoms), including straight-chain and branched-chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0173] As used herein, unless otherwise specified, the term "halogen" or "halo", alone or as part of another substituent, refers to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0174] As used herein, the term "alkylene" refers to a straight or branched chain divalent aliphatic hydrocarbon group, for example having 1 to 4 carbon atoms. This term includes, for example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), etc.

[0175] As used herein, the term "alkenyl" denotes 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 (e.g., C2-C8 alkenyl) includes, but is not limited to, for example, vinyl, propenyl, prop-2-enyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0176] As used herein, the term "alkynyl" denotes 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 (e.g., C2-C8 alkynyl) includes, but is not limited to, for example, ethynyl, propynyl, prop-2-ynyl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl, etc.

[0177] As used herein, the term "alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, etc.

[0178] As used herein, the term "cycloalkyl" refers to a partially or fully saturated non-aromatic carbocyclic system having 1, 2 or 3 rings, where these rings may be fused. The term "fused" means that a second ring exists (i.e., is attached or formed) by sharing two adjacent atoms with the first ring. Cycloalkyl also includes cyclic structures which may be bridged or spirocyclic in nature, with each individual ring in the cyclic structure ranging 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]heptyl, and bicyclo[1.1.1]pentyl.

[0179] As used herein, the term "heterocyclic group" refers to a non-aromatic carbocyclic system having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, where these rings may be fused, with the definition of fusion as above. The heterocyclic group also includes bicyclic structures, which may be bridged or spirocyclic in nature, with each individual ring within the rings ranging from 3 to 8 atoms and containing 0, 1 or 2 N, O or S atoms. The term "heterocyclic group" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and particularly includes, but is not limited to, epoxy groups, oxacyclic groups, tetrahydrofuranyl groups, tetrahydropyranyl groups (i.e., oxanyl groups), pyranyl groups, dioxanyl groups, aziridinyl groups, azetidinyl groups, pyrrolidinyl groups, 2,5-dihydro-1H-pyrrolyl groups, oxazolidinyl groups, thiazolidinyl groups, piperidinyl groups, morpholinyl groups, piperazinyl groups, thiomorpholinyl groups, 1,3-oxazolidinyl groups, 1,3-thiazinyl groups, etc. For example, the term "heterocyclic group" may include 4- to 10-membered heterocyclic groups, 4- to 7-membered heterocyclic groups, 5- to 10-membered heterocyclic groups, 6- to 10-membered heterocyclic groups, 4- to 6-membered heterocyclic groups, 4-membered heterocyclic groups, 5-membered heterocyclic groups, 6-membered heterocyclic groups, 7-membered heterocyclic groups, 8-membered heterocyclic groups, 9-membered heterocyclic groups or 10-membered heterocyclic groups.

[0180] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic characteristics, i.e., having (4n + 2) delocalized π electrons, where n is an integer.

[0181] As used herein, the term "aryl" refers to an aromatic carbocyclic system having 1, 2 or 3 rings, where these rings may be fused, with the definition of fusion as above. If these rings are fused, one of the rings must be completely unsaturated, and the fused rings may be completely saturated, partially unsaturated or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indenyl and 1,2,3,4-tetrahydronaphthyl. For example, the term "aryl" may include C6 to C 10 aryl, C6 to C8 aryl or C6 aryl (i.e., phenyl).

[0182] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic system having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, where these rings may be fused, with the definition of fusion as above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. For example, the term "heteroaryl" may include 5- to 10-membered heteroaryl groups, 5- to 8-membered heteroaryl groups, 5- to 6-membered heteroaryl groups, 6- to 10-membered heteroaryl groups, 6- to 8-membered heteroaryl groups, 5-membered heteroaryl groups, 6-membered heteroaryl groups, 7-membered heteroaryl groups, 8-membered heteroaryl groups, 9-membered heteroaryl groups or 10-membered heteroaryl groups.

[0183] It should be understood that if an aryl, heteroaryl, cycloalkyl or heterocyclic group molecule can be attached or otherwise linked to a specified molecule through different ring atoms (i.e., shown or described without indicating a specific point of attachment), then all possible points are contemplated, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" refers to 2-, 3- or 4-pyridyl, the term "thienyl" refers to 2- or 3-thienyl, and the like.

[0184] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent attached to another group.

[0185] Compounds of the present invention

[0186] Thus, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof:

[0187]

[0188] Wherein:

[0189] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl;

[0190] n is 1, 2 or 3;

[0191] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR a R b 、C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0192] T is CR1R2 or O;

[0193] W is CR4R5 or O;

[0194] U is CR6R7;

[0195] X is CR8R9;

[0196] V is CR3 or N;

[0197] Y is NR 10 , O or absent;

[0198] Z is (CR 12 R 13 ) m ;

[0199] Each R is independently selected from halogen, deuterium, hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0200] p is 0, 1, 2, 3 or 4;

[0201] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0202] m is 1, 2, 3 or 4;

[0203] Furthermore, wherein:

[0204] R1, R2, R4 and R5 are each independently selected from H, hydroxy, halogen and deuterium;

[0205] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0206] R3 is selected from H, halogen, hydroxy and cyano;

[0207] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0208] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0209] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxy, halogen and deuterium;

[0210] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0211] Each R 12 and R13 independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxy or one or more halogens;

[0212] R 14 、R 15 and R 16 each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0213] each R 17 and R 18 independently selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0214] provided that one or more of (a)-(f) are present:

[0215] (a) at least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0216] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0217] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0218] (d) R 14 、R15 、R 16 、R 17 and R 18 at least one of which is an unsubstituted C1-C3 alkyl or a C1-C3 alkyl substituted with one or more halogens;

[0219] (e) at least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group; or

[0220] (f) at least one of R 12 and R 13 is a C1-C3 alkyl substituted with a hydroxyl group.

[0221] In one embodiment, provided herein is a compound of formula I-A having the structure of formula I or a pharmaceutically acceptable salt thereof:

[0222]

[0223] Wherein:

[0224] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0225] n is 1, 2 or 3;

[0226] E is selected from 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 to 10 membered heterocyclic group, C1-C3 alkylene-(4 to 10 membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5 to 10 membered heteroaryl and C1-C3 alkylene-(5 to 10 membered heteroaryl), wherein C1-C3 alkylene-NR a R b 、C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4 to 10 membered heterocyclic group, C1-C3 alkylene-(4 to 10 membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5 to 10 membered heteroaryl or C1-C3 alkylene-(5 to 10 membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0227] T is CR1R2 or O;

[0228] W is CR4R5 or O;

[0229] U is CR6R7;

[0230] X is CR8R9;

[0231] V is CR3 or N;

[0232] Y is NR 10 , O or absent;

[0233] Z is (CR 12 R 13 ) m ;

[0234] Each R is independently selected from halogen, deuterium, hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0235] p is 0, 1, 2, 3 or 4;

[0236] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0237] m is 1, 2, 3 or 4;

[0238] Further, wherein:

[0239] R1, R2, R4 and R5 are each independently selected from H, hydroxy, halogen and deuterium;

[0240] Or, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0241] R3 is selected from H, halogen, hydroxy and cyano;

[0242] Or, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0243] Or, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0244] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxy, halogen and deuterium;

[0245] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0246] Each R 12 and R 13independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxy or one or more halogens;

[0247] R 14 、R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens;

[0248] Each R 17 and R 18 is independently selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0249] provided that one or more of (a)-(f) are present:

[0250] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0251] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), where 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl)、5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0252] (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy;

[0253] (d) R 14 、R 15, R 16 , R 17 and R 18 at least one of which is an unsubstituted C1-C3 alkyl group or a C1-C3 alkyl group substituted with one or more halogen atoms;

[0254] (e) at least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group; or

[0255] (f) at least one of R 12 and R 13 is a C1-C3 alkyl group substituted with a hydroxyl group.

[0256] In one embodiment of formula (I), one or more of (a)-(d) are present:

[0257] (a) at least one R is selected from the group consisting of a cyano group, an unsubstituted C1-C3 alkyl group, and a C1-C3 alkyl group substituted with one or more halogen atoms or deuterium atoms;

[0258] (b) E is NR a R b , C1-C3 alkylene-NR a R b , C2-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C8 cycloalkyl group, C1-C3 alkylene-(C3-C8 cycloalkyl group), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl group, C1-C3 alkylene-(C6-C 10 aryl group), 5- to 10-membered heteroaryl group, or C1-C3 alkylene-(5- to 10-membered heteroaryl group), wherein C1-C3 alkylene-NR a R b , C2-C3 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C3-C8 cycloalkyl group, C1-C3 alkylene-(C3-C8 cycloalkyl group), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl group, C1-C3 alkylene-(C6-C 10 aryl group), 5- to 10-membered heteroaryl group, or C1-C3 alkylene-(5- to 10-membered heteroaryl group) is unsubstituted or substituted with one or more halogen atoms, C1-C3 alkyl groups, or C1-C3 alkoxy groups;

[0259] (c) E is a C1 alkyl group substituted with one or more halogen atoms, C1-C3 alkyl groups, or C1-C3 alkoxy groups; or

[0260] (d) R 14 , R 15 , R16 , R 17 and R 18 at least one of which is an unsubstituted C1-C3 alkyl group or a C1-C3 alkyl group substituted with one or more halogens.

[0261] In another embodiment of formula (I), at least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens or deuterium.

[0262] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), where 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxy, C1-C3 alkyl or C1-C3 alkoxy groups.

[0263] In another embodiment of formula (I), E is a C1 alkyl group substituted with one or more halogens, hydroxy, C1-C3 alkyl or C1-C3 alkoxy groups. 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 isomethyl. In another embodiment of formula (I), E is cyclopropyl. In another embodiment of formula (I), E is tetrahydrofuranyl.

[0264] In another embodiment of formula (I), R 14 , R 15 , R 16 , R17 and R 18 at least one of which is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens.

[0265] In another embodiment of formula (I), at least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group.

[0266] In another embodiment of formula (I), R 12 and R 13 at least one of which is C1-C3 alkyl substituted with a hydroxyl group.

[0267] 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.

[0268] In another embodiment of formula (I), ring A is phenyl. In another embodiment of formula (I), ring A is pyridyl. In another embodiment of formula (I), ring A is pyridazinyl.

[0269] 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.

[0270] 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 pyridyl and Y is NR 10 . In another embodiment of formula (I), ring A is pyridyl and Y is O. In another embodiment of formula (I), ring A is pyridyl 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.

[0271] 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.

[0272] In another embodiment of formula (I), V is CR3. In another embodiment of formula (I), V is N.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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 b 。In 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is unsubstituted 4- to 10-membered heterocyclic group. In another embodiment of formula (I), E is 4- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclic group). In another embodiment of formula (I), E is C1-C3 alkylene-(4- to 10-membered heterocyclic group) substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is unsubstituted C6-C 10 aryl. In another embodiment of formula (I), E is C6-C 10 aryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is C1-C3 alkylene-(C6-C 10aryl). In another embodiment of formula (I), E is an unsubstituted 5- to 10-membered heteroaryl group. In another embodiment of formula (I), E is a 5- to 10-membered heteroaryl group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

[0277] In another embodiment of formula (I), E is an unsubstituted 4- to 10-membered heterocyclic group. In another embodiment of formula (I), E is a 4- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 8- to 10-membered heterocyclic group. In another embodiment of formula (I), E is an 8- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 4- to 7-membered heterocyclic group. In another embodiment of formula (I), E is a 4- to 7-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 4- to 6-membered heterocyclic group. In another embodiment of formula (I), E is a 4- to 6-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 4-membered heterocyclic group. In another embodiment of formula (I), E is a 4-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 5-membered heterocyclic group. In another embodiment of formula (I), E is a 5-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 6-membered heterocyclic group. In another embodiment of formula (I), E is a 6-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

[0278] In another embodiment of formula (I), E is an unsubstituted 5- to 10-membered heteroaryl. In another embodiment of formula (I), E is a 5- to 10-membered heteroaryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. In another embodiment of formula (I), E is an unsubstituted 5- to 6-membered heteroaryl. In another embodiment of formula (I), E is a 5- to 6-membered heteroaryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys.

[0279] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys.

[0280] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.

[0281] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.

[0282] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group), wherein C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene (4- to 10-membered heterocyclic group) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.

[0283] 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 by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups.

[0284] In another embodiment of formula (I), E is methyl, wherein the methyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. 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 dioxane, wherein the dioxane is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (I), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted by one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy groups.

[0285] 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 15 is H. In another embodiment of formula (I), each R 15 and R 16 is H. In another embodiment of formula (I), R17 is an unsubstituted C1-C3 alkyl group, R 18 is H. In another embodiment of formula (I), R 18 is an unsubstituted C1-C3 alkyl group, R 17 is H. In another embodiment of formula (I), R 14 、R 15 、R 16 、R 17 and R 18 is one of an unsubstituted C1-C3 alkyl group, and the others are each H.

[0286] 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.

[0287] 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.

[0288] In another embodiment of formula (I), Y is absent and m is 1. In another embodiment of formula (I), Y is absent and m is 2. In another embodiment of formula (I), Y is absent and m is 3. In another embodiment of formula (I), Y is absent and m is 4. In another embodiment of formula (I), Y is absent and m is 1, 2 or 3. In another embodiment of formula (I), Y is absent and m is 2, 3 or 4. In another embodiment of formula (I), Y is absent and m is 1 or 2. In another embodiment of formula (I), Y is absent and m is 3 or 4.

[0289] 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, m is 3. In another embodiment of formula (I), Y is NR 10 , m is 4. In another embodiment of formula (I), Y is NR 10 , m is 1, 2 or 3. In another embodiment of formula (I), Y is NR 10 , m is 2, 3 or 4. In another embodiment of formula (I), Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), Y is NR 10 , m is 3 or 4.

[0290] 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 pyridyl and n is 1. In another embodiment of formula (I), ring A is pyridyl and n is 2. In another embodiment of formula (I), ring A is pyridyl 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.

[0291] 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 10。In 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.

[0292] 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 absent, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is absent, 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 10 , and 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 absent, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is absent, and m is 3 or 4.

[0293] In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is NR 10。In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is NR 10 。In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is NR 10 。In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is absent. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is absent. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is absent.

[0294] In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridyl, n is 1, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 2, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 3, and Y is NR 10, m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridyl, n is 3, Y is absent, and m is 3 or 4.

[0295] 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 NR 10 . 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, Y is absent. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is absent. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is absent.

[0296] In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is NR10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is absent, m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is absent, m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is absent, m is 3 or 4.

[0297] 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, Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is absent. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is absent. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is absent.

[0298] In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is NR 10, 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 absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is NR 10 , 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 absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is absent, and m is 3 or 4.

[0299] In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is NR 10 . In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is NR 10 . In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is NR 10 . In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is absent. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is absent. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is absent.

[0300] In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is NR10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is O, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is absent, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is absent, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is absent, m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is NR 10 , m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is O, m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is absent, m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is absent, m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is absent, m is 3 or 4.

[0301] 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 a triazinyl group, n is 1, and Y is O. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, and Y is O. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, and Y is O. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, and Y is absent. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, and Y is absent. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, and Y is absent.

[0302] In another embodiment of formula (I), ring A is a triazinyl group, n is 1, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl group, n is 3, Y is absent, and m is 3 or 4.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] In another embodiment of formula (I), p is 0, and 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; 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; R6, R7, R8, R9, and R 11 are each H; R 12 and R 13 are each H.

[0307] In another embodiment of formula (I), p is 1, and 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; 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; R6, R7, R8, R9, and R 11 are each H; R 12 and R 13 are each H.

[0308] In another embodiment of formula (I), p is 2, and 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; 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; R6, R7, R8, R9, and R 11 are each H; R 12 and R 13 are each H.

[0309] 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 hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), p is 1, 2, 3 or 4 and each R is independently selected from cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuteriums. 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.

[0310] In another embodiment of formula (I), one or more of R1, R2, R4 and R5 are fluorine. In another embodiment of formula (I), one or more of R1, R2, R4 and R5 are deuterium. In another embodiment of formula (I), R6, R7, R8, R9 and R 11 one or more of are fluorine. In another embodiment of formula (I), R6, R7, R8, R9 and R 11 one or more of are deuterium. In another embodiment of formula (I), R 12 and R 13 one or more of are fluorine. In another embodiment of formula (I), R 12 and R 13 one or more of are deuterium.

[0311] 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 18Each is H. In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 14 、R 15 、R 16 、R 17 and R 18 are each H, and m is 1. In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each H. In another embodiment of formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 12 、R 13 、R 14 、R 15 and R 18 are each H, and m is 1.

[0312] Each embodiment described herein for the compounds of formula I also applies to the compounds of formula I-A.

[0313] Also provided herein are compounds having the structure of formula II-A or pharmaceutically acceptable salts thereof:

[0314]

[0315] Wherein:

[0316] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0317] n is 1, 2 or 3;

[0318] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein C1-C3 alkylene-NR aR b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0319] T is CR1R2 or O;

[0320] W is CR4R5 or O;

[0321] U is CR6R7;

[0322] X is CR8R9;

[0323] V is CR3 or N;

[0324] Y is NR 10 , O or absent;

[0325] Z is (CR 12 R 13 ) m ;

[0326] Each R is independently selected from halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted by one or more halogens or deuterium;

[0327] p is 0, 1, 2, 3 or 4;

[0328] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0329] When Y is absent, m is 2, 3, 4 or 5; or

[0330] When Y is NR 10 or O, m is 1, 2, 3 or 4;

[0331] Furthermore, wherein:

[0332] R1, R2, R4 and R5 are each independently selected from H, hydroxyl, halogen and deuterium;

[0333] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0334] R3 is independently selected from H, halogen, hydroxyl and cyano;

[0335] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl group;

[0336] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl group;

[0337] R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxy, halogen and deuterium;

[0338] R 10 is selected from H, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens;

[0339] Each R 12 and R 13 are independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with hydroxy or one or more halogens;

[0340] R 14 、R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; and

[0341] Each R 17 and R 18 are independently selected from H, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens;

[0342] Provided that one or more of (a)-(f) are present:

[0343] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0344] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0345] (c) E is a C1 alkyl group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0346] (d) R 14 , R 15 , R 16 , R 17 and R 18 in at least one of is an unsubstituted C1-C3 alkyl or a C1-C3 alkyl substituted with one or more halogens;

[0347] (e) At least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group; or

[0348] (f) At least one of R 12 and R 13 is a C1-C3 alkyl substituted with a hydroxyl group.

[0349] In one embodiment, provided herein is a compound of formula II-A having the structure of formula II or a pharmaceutically acceptable salt thereof:

[0350]

[0351] Wherein:

[0352] Ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazinyl;

[0353] n is 1, 2 or 3;

[0354] E is selected from 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), where C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl, or C1-C3 alkoxy;

[0355] T is CR1R2 or O;

[0356] W is CR4R5 or O;

[0357] U is CR6R7;

[0358] X is CR8R9;

[0359] V is CR3 or N;

[0360] Y is NR 10 , O, or absent;

[0361] Z is (CR 12 R 13 ) m ;

[0362] Each R is independently selected from halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0363] p is 0, 1, 2, 3, or 4;

[0364] R a and R b are each independently H or unsubstituted C1-C3 alkyl;

[0365] When Y is absent, m is 2, 3, 4, or 5; or

[0366] When Y is NR 10 or O, m is 1, 2, 3, or 4;

[0367] Furthermore, where:

[0368] R1, R2, R4, and R5 are each independently selected from H, hydroxyl, halogen, and deuterium;

[0369] Alternatively, R2 and R5 together with the carbon atom to which they are attached form a single bond;

[0370] R3 is independently selected from H, halogen, hydroxy, and cyano;

[0371] Alternatively, R3 and R1 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0372] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C5 cycloalkyl;

[0373] R6, R7, R8, R9, and R 11 are each independently selected from H, hydroxy, halogen, and deuterium;

[0374] R 10 is selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0375] Each R 12 and R 13 are independently selected from H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxy or one or more halogens;

[0376] R 14 , R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; and

[0377] Each R 17 and R 18 are independently selected from H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens;

[0378] provided that one or more of (a)-(f) are present:

[0379] (a) At least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium;

[0380] (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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy;

[0381] (c) E is C1 alkyl substituted by one or more halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy;

[0382] (d) R 14 , R 15 , R 16 , R 17 and R 18 At least one of them is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogens;

[0383] (e) R1, R2, R4, R5, R6, R7, R8, R9 and R 11 At least one of is a hydroxyl group; or

[0384] (f)R 12 and R 13 At least one of the groups is a C1-C3 alkyl group substituted with a hydroxy group.

[0385] In one embodiment of formula (II), one or more of (a)-(d) are present:

[0386] (a) at least one R is selected from cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted by one or more halogens or deuterium;

[0387] (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- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10(aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, C1-C3 alkyl or C1-C3 alkoxy;

[0388] (c) E is C1 alkyl substituted by one or more halogens, C1-C3 alkyl or C1-C3 alkoxy; or

[0389] (d) R 14 、R 15 、R 16 、R 17 and R 18 in at least one of them is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogens.

[0390] In another embodiment of formula (II), at least one R is selected from hydroxy, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted by one or more halogens or deuterium.

[0391] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl, C1-C3 alkylene-(C6-C10 (aryl), 5- to 10-membered heteroaryl or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups.

[0392] In another embodiment of formula (II), E is C1 alkyl substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups. 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 isomethyl. In another embodiment of formula (II), E is cyclopropyl. In another embodiment of formula (II), E is tetrahydrofuranyl.

[0393] 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 by one or more halogens.

[0394] In another embodiment of formula (II), at least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group.

[0395] In another embodiment of formula (II), R 12 and R 13 at least one of is C1-C3 alkyl substituted by a hydroxyl group.

[0396] 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.

[0397] In another embodiment of formula (II), ring A is phenyl. In another embodiment of formula (II), ring A is pyridyl. 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.

[0398] 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 pyridyl and Y is NR 10 。In another embodiment of formula (II), ring A is pyridyl and Y is O. In another embodiment of formula (II), ring A is pyridyl 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 (II), 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.

[0399] 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.

[0400] In another embodiment of formula (II), V is CR3. In another embodiment of formula (II), V is N.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] In another embodiment of formula (II), E is NR a R b 。In another embodiment of formula (II), E is C1-C3 alkylene-NR a 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. 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 halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (II), E is unsubstituted 4- to 10-membered heterocyclic group. In another embodiment of formula (II), E is 4- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (II), E is unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclic group). In another embodiment of formula (II), E is C1-C3 alkylene-(4- to 10-membered heterocyclic group) substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (II), E is unsubstituted C6-C 10 aryl. In another embodiment of formula (II), E is C6-C 10 aryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (II), E is unsubstituted C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (II), E is C1-C3 alkylene-(C6-C 10 aryl) substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups. In another embodiment of formula (II), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of formula (II), E is 5- to 10-membered heteroaryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups.

[0405] In another embodiment of formula (II), E is an unsubstituted 4- to 10-membered heterocyclic group. In another embodiment of formula (II), E is a 4- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 8- to 10-membered heterocyclic group. In another embodiment of formula (II), E is an 8- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 4- to 7-membered heterocyclic group. In another embodiment of formula (II), E is a 4- to 7-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 4- to 6-membered heterocyclic group. In another embodiment of formula (II), E is a 4- to 6-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 4-membered heterocyclic group. In another embodiment of formula (II), E is a 4-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 5-membered heterocyclic group. In another embodiment of formula (II), E is a 5-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (II), E is an unsubstituted 6-membered heterocyclic group. In another embodiment of formula (II), E is a 6-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

[0406] In another embodiment of formula (II), E is an unsubstituted 5- to 10-membered heteroaryl. In another embodiment of formula (II), E is a 5- to 10-membered heteroaryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. In another embodiment of formula (II), E is an unsubstituted 5- to 6-membered heteroaryl. In another embodiment of formula (II), E is a 5- to 6-membered heteroaryl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys. 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 halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys.

[0407] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyls or C1-C3 alkoxys.

[0408] 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- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups.

[0409] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group, C1-C3 alkylene-(4- to 10-membered heterocyclic group), C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl) is unsubstituted or substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups.

[0410] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene (4- to 10-membered heterocyclic group) is unsubstituted or substituted with one or more halogen atoms, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups.

[0411] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkylene-(C3-C8 cycloalkyl), where C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkylene(C3-C8 cycloalkyl) is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.

[0412] In another embodiment of formula (II), E is methyl, where the methyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. 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 dioxane, where the dioxane is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. In another embodiment of formula (II), E is tetrahydropyranyl, where the tetrahydropyranyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. In another embodiment of formula (II), E is tetrahydrofuranyl, where the tetrahydrofuranyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. In another embodiment of formula (II), E is azetidinyl, where the azetidinyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. In another embodiment of formula (II), E is oxetanyl, where the oxetanyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy. In another embodiment of formula (II), E is morpholinyl, where the morpholinyl is unsubstituted or substituted by one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy.

[0413] 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 R 15 is H. In another embodiment of formula (II), each R 15 and R 16is 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 one of unsubstituted C1-C3 alkyl and the others are each H.

[0414] 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.

[0415] 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.

[0416] In another embodiment of formula (II), Y is absent and m is 2. In another embodiment of formula (II), Y is absent and m is 3. In another embodiment of formula (II), Y is absent and m is 4. In another embodiment of formula (II), Y is absent and m is 2, 3 or 4. In another embodiment of formula (II), Y is absent and m is 3 or 4.

[0417] 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, m is 3. In another embodiment of formula (II), Y is NR 10 , m is 4. In another embodiment of formula (II), Y is NR 10 , m is 1, 2 or 3. In another embodiment of formula (II), Y is NR 10 , m is 2, 3 or 4. In another embodiment of formula (II), Y is NR 10 , m is 1 or 2. In another embodiment of formula (II), Y is NR 10 , m is 3 or 4.

[0418] 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 pyridyl and n is 1. In another embodiment of formula (II), ring A is pyridyl and n is 2. In another embodiment of formula (II), ring A is pyridyl 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.

[0419] 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 10。In 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.

[0420] 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 absent, and m is 2. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is absent, and m is 2. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is absent, 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 10 , and 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 absent, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is absent, and m is 3 or 4.

[0421] In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is NR10 In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is NR 10 In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is O. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is O. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is O. In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is absent. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is absent. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is absent.

[0422] In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is NR 10 , and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyridyl, n is 1, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 2, and Y is NR 10 , and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 3, and Y is NR 10, m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridyl, n is 3, Y is absent, and m is 3 or 4.

[0423] 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 10 . In 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, Y is absent. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is absent. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is absent.

[0424] In another embodiment of formula (II), ring A is pyridazinyl, n is 1, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, and Y is NR 10 , m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, and Y is NR 10, 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 absent, and m is 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 1, Y is NR 10 , m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is NR 10 , m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is NR 10 , 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 absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is absent, and m is 3 or 4.

[0425] In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is NR 10 . In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is NR 10 . In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is NR 10 . In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is O. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is O. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is O. In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is absent. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is absent. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is absent.

[0426] In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is NR 10 and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, 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 absent, and m is 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is NR 10 and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, 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 absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is absent, and m is 3 or 4.

[0427] In another embodiment of formula (II), ring A is pyrazinyl, n is 1, Y is NR 10 . In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is NR 10 . In another embodiment of formula (II), ring A is pyrazinyl, n is 3, 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.

[0428] 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 absent, and m is 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is absent, and m is 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is absent, 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 NR 10 , 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 absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is absent, and m is 3 or 4.

[0429] In another embodiment of formula (II), ring A is a triazinyl group, n is 1, and Y is NR 10 。In another embodiment of formula (II), ring A is a triazinyl group, n is 2, and Y is NR 10 。In another embodiment of formula (II), ring A is a triazinyl group, n is 3, and Y is NR 10 。In another embodiment of formula (II), ring A is a triazinyl group, n is 1, and Y is O. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, and Y is O. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, and Y is O. In another embodiment of formula (II), ring A is a triazinyl group, n is 1, and Y is absent. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, and Y is absent. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, and Y is absent.

[0430] In another embodiment of formula (II), ring A is a triazinyl group, n is 1, and Y is NR 10 ,and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, and Y is NR 10 ,and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, and Y is NR 10 ,and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 1, Y is absent, and m is 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, Y is absent, and m is 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, Y is absent, and m is 2. In another embodiment of formula (II), ring A is a triazinyl group, n is 1, and Y is NR 10 ,and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl group, n is 2, and Y is NR 10 ,and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl group, n is 3, and Y is NR 10, 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 absent, and m is 3 or 4. In another embodiment of formula (II), ring A is triazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is triazinyl, n is 3, Y is absent, and m is 3 or 4.

[0431] 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.

[0432] 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.

[0433] 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 CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. 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 3 or 4. 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 3 or 4. 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 3 or 4. 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 3 or 4. 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 3 or 4. 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 3 or 4. 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 3 or 4.

[0434] In another embodiment of formula (II), p is 0, and 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 each H; R 12 and R 13 are each H.

[0435] In another embodiment of formula (II), p is 1, and 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 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 R 11 are each H; R 12 and R 13 are each H.

[0436] In another embodiment of formula (II), p is 2, and 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 each H; R 12 and R 13 are each H.

[0437] 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 hydroxy, 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 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.

[0438] In another embodiment of formula (II), one or more of R1, R2, R4 and R5 are fluorine. In another embodiment of formula (II), one or more of R1, R2, R4 and R5 are deuterium. In another embodiment of formula (II), R6, R7, R8, R9 and R 11 one or more of are fluorine. In another embodiment of formula (II), R6, R7, R8, R9 and R 11 one or more of are deuterium. In another embodiment of formula (II), R 12 and R 13 one or more of are fluorine. In another embodiment of formula (II), R 12 and R 13 one or more of are deuterium.

[0439] In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 is H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 is H and m is 1. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 14 、R 15 、R 16 、R 17 and R 18Each is H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 14 、R 15 、R 16 、R 17 and R 18 are each H, and m is 2. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each H. In another embodiment of formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each H, and m is 2.

[0440] Each embodiment described herein for the compounds of formula I also applies to the compounds of formula II-A.

[0441] According to formula I-A, I, II-A or II herein, when ring A is pyridyl, the position of the pyridyl N atom is designated as shown below:

[0442]

[0443] Further, according to formula I-A, I, II-A or II herein, when ring A is pyridazinyl, the position of the pyridazinyl N atom is designated as shown below:

[0444]

[0445] Further, according to formula I-A, I, II-A or II herein, when ring A is pyrimidinyl, the position of the pyrimidinyl N atom is designated as shown below:

[0446]

[0447] Further, according to formula I-A, I, II-A or II herein, when ring A is pyrazinyl, the position of the pyrazinyl N atom is designated as shown below:

[0448]

[0449] Further, according to Formula I-A, I, II-A or II herein, when ring A is a triazinyl group, the positions of the triazinyl N atoms are designated as shown below:

[0450]

[0451] All other variables described in Formula I-A, I, II-A or II are as defined above.

[0452] Certain embodiments of the compounds of Formula I-A, I, II-A or II, or pharmaceutically acceptable salts thereof, are shown in Table 1 below. The compounds of Formula I-A, I, II-A, II, or pharmaceutically acceptable salts thereof, and the compounds of Table 1, or pharmaceutically acceptable salts thereof, are sometimes collectively referred to herein as "the compounds of the present invention" or "the compounds provided herein".

[0453] Table 1

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] The disclosed compounds have one or more stereocenters, each of which can exist independently in the R or S configuration. In one embodiment, the compounds described herein exist in optically active or racemic form. It should be understood that the compounds described herein include racemates, optically active forms, positional isomers, and stereoisomeric forms, or combinations thereof, which have the therapeutically useful properties described herein.

[0480] The optically active forms are prepared in any suitable manner, including, by way of non-limiting example, resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of two or more isomers is used as the disclosed compounds described herein. In another embodiment, the pure isomers are used as the disclosed compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds can be prepared by any means, including stereoselective synthesis, enantioselective synthesis, or separation of mixtures of enantiomers or diastereomers. The resolution of the compounds and their isomers can be achieved by any means, including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0481] In one embodiment, the disclosed compounds can exist as isomers. All isomers are included within the scope of the compounds described herein.

[0482] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to2 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 S. In one embodiment, the isotopically labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with a heavy isotope (such as deuterium) can provide greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In another embodiment, the compounds described herein include 2 H (i.e., deuterium) isotopes.

[0483] In yet another embodiment, substitution with a positron emitting isotope, such as 11 C, 18 F, 15 O and 13 N, is useful for examining substrate receptor occupancy in positron emission tomography (PET) studies. The isotopically labeled compounds are prepared by any suitable method or by a process of using an appropriate isotopically labeled reagent in place of the originally used unlabeled reagent.

[0484] The specific compounds described herein, as well as other compounds included in one or more structural formulas with different substituents described herein, were synthesized using the techniques and materials described herein or from the following sources, such as 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 Reaction, Volumes 1 - 40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed. (Advanced Organic Chemistry 4th Edition), (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed. (Advanced Organic Chemistry 4th Edition), Vols. A and B (Plenum 2000, 2001) and Green and Wuts, Protective Groups in Organic Synthesis 3 rd Ed. (Protective Groups in Organic Synthesis 3rd Edition), (Wiley 1999) (all of which are incorporated herein by reference). The general methods for preparing the compounds described herein were modified by using appropriate reagents and conditions to introduce the different moieties found in the formulas provided herein.

[0485] The compounds described herein were synthesized using any suitable procedure, starting from compounds available from commercial sources or prepared using the procedures described herein.

[0486] Treatment method

[0487] The compounds of the present invention can be used in a method for treating a disease or disorder 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 disorder by acting as an orexin-2 receptor agonist.

[0488] The compounds of the present invention can be used to treat a disease or disorder selected from narcolepsy, cataplexy or hypersomnia in a subject in need thereof.

[0489] In one embodiment, the compounds of the present invention can be used to treat narcolepsy in a subject. In one embodiment, the compounds of the present invention can be used to treat cataplexy in a subject. In one embodiment, the compounds of the present invention can be used to treat hypersomnia in a subject.

[0490] The orexin-2 receptor plays an important role in a variety of biological functions. This indicates that the orexin-2 receptor plays a role in different disease processes in humans or other species. The compounds of the present invention can be used to treat, prevent or improve one or more of the following symptoms or the risk of diseases of various neurological and psychiatric diseases related to altered sleep / wake functions. That is, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndromes characterized by drowsiness (such as in subjects with Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Möbius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple system atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis or Hashimoto encephalopathy), coma, loss of consciousness, obesity (such as mastocytosis, exogenous obesity, hyperinsulinemic obesity, proliferative obesity, pituitary obesity, hypoplasmatic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, diet-induced obesity, hypogonadal obesity, systemic mastocytosis, simple obesity or centripetal obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications caused by anesthesia, sleep disorders, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, rapid eye movement sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disturbances, night terrors, depression, major depressive disorder, somnambulism, enuresis, sleep disorders, Alzheimer's twilight, sundowning, diseases related to circadian rhythms, fibromyalgia, conditions caused by decreased sleep quality, binge eating, compulsive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipoproteinemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeats, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Fröhlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual and reproductive dysfunctions such as hirsutism in women, fetal defects related to maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain,Risks of gallbladder diseases, gout, renal cancer, secondary consequences of obesity such as reducing the risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, autoimmune encephalitis, cancer-related fatigue (such as daytime excessive sleepiness or fatigue associated with 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, flushing, night sweats, reproductive / urinary system diseases, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorder, acute neurological and mental diseases such as brain function deficits after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, diseases related to muscle spasm, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Tourette syndrome, chorea, myoclonus, convulsion, restless legs syndrome, dystonia, movement disorder, attention deficit disorder (ADHD), behavioral disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy and traumatic brain injury (TBI).

[0491] In particular, the compounds of the present invention can be used as therapeutic or prophylactic drugs for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (such as Parkinson's disease, Guillain-Barré syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disorders of consciousness such as coma, side effects and complications caused by anesthesia, etc., or anesthetic antagonists.

[0492] In one embodiment, the compounds of the present invention have the activity of orexin-2 receptor agonists and can be used as prophylactic or therapeutic agents for narcolepsy.

[0493] In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for narcolepsy type 1. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for narcolepsy type 2. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for narcolepsy and excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for narcolepsy, cataplexy and excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for narcolepsy and cataplexy. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for idiopathic hypersomnia. In another embodiment, the compounds of the present invention can be used as prophylactic or therapeutic agents for obstructive sleep apnea.

[0494] In another embodiment, the compounds of the present invention have the activity of orexin-2 receptor agonists and can be used as prophylactic or therapeutic agents for narcolepsy in Parkinson's disease.

[0495] In another embodiment, the compounds of the present invention have the activity of orexin-2 receptor agonists and can be used as prophylactic or therapeutic agents for narcolepsy. In another embodiment, the compounds of the present invention have the activity of orexin-2 receptor agonists and can be used as prophylactic or therapeutic agents for excessive daytime sleepiness associated with Parkinson's disease.

[0496] In another embodiment, the compounds of the present invention have the activity of orexin-2 receptor agonists and can be used as prophylactic or therapeutic agents for excessive daytime sleepiness and fatigue associated with cancer and / or chemotherapy.

[0497] In another embodiment, the present invention provides a method for treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0498] In another embodiment, the present invention provides a method for treating narcolepsy type 1 in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0499] In another embodiment, the present invention provides a method for treating narcolepsy type 1 in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0500] In another embodiment, the present invention provides a method for treating narcolepsy and excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0501] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy and excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0502] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0503] In another embodiment, the present invention provides a method for excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0504] In another embodiment, the present invention provides a method for treating idiopathic narcolepsy in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0505] In another embodiment, the present invention provides a method for treating idiopathic hypersomnia and excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0506] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0507] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of formula I-A, I, II-A or II or a pharmaceutically acceptable salt thereof.

[0508] In any of the methods described herein, a compound of formula I is administered to the subject. In any of the methods described herein, a compound of formula II is administered to the subject.

[0509] Each embodiment of the use of the compounds of formula I described herein is also applicable to the compounds of formula I-A. Each embodiment of the use of the compounds of formula II described herein is also applicable to the compounds of formula II-A.

[0510] In any of the compositions or methods described herein, the compounds of formula I-A, I, II-A or II, or a pharmaceutically acceptable salt thereof, are present and / or administered in a therapeutically effective amount.

[0511] Usage / Dosage / Formulation

[0512] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0513] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may vary so as to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without undue toxicity to the patient.

[0514] In particular, the selected dosage level will depend upon various factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0515] A physician or veterinarian of ordinary skill in the art, such as an internist or a veterinarian, can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start administering the pharmaceutical composition at a dosage level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0516] In a particular embodiment, it is especially advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. The dosage unit form used herein refers to physically discrete units suitable as unit doses for the patient to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The dosage unit form of the present invention depends on and is dependent upon (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding / formulating such disclosed compound for the treatment of narcolepsy or cataplexy in a patient.

[0517] In one embodiment, the compounds of the present invention are formulated with one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0518] In some embodiments, the dose of the disclosed compounds is from about 1 mg to about 1000 mg. In some embodiments, the dose of the disclosed compounds used in the compositions described herein is less than about 1000 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 dose is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or about 600 mg.

[0519] The route of administration of any of the compositions of the invention includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical administration. The compounds used in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, such as transdermal, transmucosal (e.g., sublingual, lingual, (trans)oral, (trans)urethral, vaginal (e.g., transvaginal and perivaginal), nasal (intranasal) and (trans)rectal), intravenous, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration. In one embodiment, the preferred route of administration is oral.

[0520] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, microspheres, transdermal patches, gels, powders, pellets, emulsions, troches, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral use, dry powder or aerosol formulations for inhalation, compositions and dosage forms for intravenous injection, etc. It should be understood that the formulations and compositions useful for the present invention are not limited to the specific formulations and compositions described herein.

[0521] For oral administration, tablets, pills, liquids, drops, suppositories, or capsules, cachets, and gelatin caps are particularly suitable. The compositions for oral use can be prepared by any method known in the art, and such compositions can contain one or more agents selected from inert non-toxic pharmaceutical excipients that are suitable for manufacturing tablets. These excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets can be uncoated or coated using known techniques for aesthetic purposes or to delay the release of the active ingredient. The preparations for oral use can also be in the form of hard capsules, in which the active ingredient is mixed with an inert diluent.

[0522] For parenteral administration, the disclosed compounds can be formulated as injections or infusions, for example, intravenous, intramuscular, or subcutaneous injections or infusions, or administered in embolization doses or by continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous carriers can be used, and other formulations such as suspending agents, stabilizers, or dispersing agents can also be selected.

[0523] Those skilled in the art will recognize or be able to ascertain using routine experimentation many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims appended hereto. For example, it should be understood that modifications of reaction conditions, including but not limited to reaction time, reaction scale / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions (such as nitrogen atmosphere), and reducing / oxidizing agents, recognized alternatives in the art and using no more than routine experimentation, are within the scope of this application.

[0524] It should be understood that all numerical values and ranges provided herein, all numerical values and ranges subsumed within such values and ranges, are meant to be included within the scope of the present invention. Additionally, all numerical values belonging to these ranges, as well as the upper or lower limits of the numerical ranges, are also contemplated by this application.

[0525] The following examples further illustrate various aspects of the present invention. However, they are in no way a limitation of the teachings or disclosures of the present invention described herein.

[0526] Examples

[0527] The following examples further illustrate the present invention, and these examples should not be construed as further limitations. Unless otherwise indicated, the practice of the present invention will employ conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology, which are within the skill of the art.

[0528] General procedure

[0529] Liquid chromatography-mass spectrometry (LCMS) data was obtained on a Shimadzu LCMS-2020 using LabSolutions software. The mass spectrometry data was reported by LCMS analysis. Mass spectrometry (MS) was performed using an atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ionization source.

[0530] Nuclear magnetic resonance (NMR) data was obtained on a Bruker AVANCE III HD or Bruker AVANCE NEO instrument using Topspin 3.5pI7 or Topspin 4.1.1 software. Unless otherwise noted, proton nuclear magnetic resonance ( 1 1H NMR) chemical shifts were reported in parts per million downfield from tetramethylsilane and were recorded on a spectrometer operating at 300 or 400 megahertz. Chemical shifts are expressed in parts per million (ppm, δ) and referenced to the residual peak of the deuterated solvent.

[0531] Example 1: Synthesis procedure

[0532] The synthetic procedures for preparing the compounds of the present invention are readily available to those of ordinary skill in the art. Unless otherwise noted, starting materials are generally obtained from commercial sources. Synthetic procedures for related compounds can be found, for example, in U.S. Application No. 17 / 104,993 and PCT Application No. PCT / US20 / 62320, both filed on November 25, 2020, and both of which are hereby incorporated by reference in their entirety.

[0533] The following abbreviations were used in the synthetic examples below:

[0534] AcOH = acetic acid

[0535] DCM = dichloromethane

[0536] MsCl = methanesulfonyl chloride

[0537] MeOH = methanol

[0538] THF = tetrahydrofuran

[0539] EtOH = ethanol

[0540] PtO2 = platinum dioxide

[0541] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridin-3-ol hexafluorophosphate

[0542] DIPEA or DIEA = N,N-diisopropylethylamine

[0543] t Bu = tert-butyl

[0544] ACN or MeCN = acetonitrile

[0545] PE = petroleum ether

[0546] EtOAc = ethyl acetate

[0547] DMF = dimethylformamide

[0548] TFA = trifluoroacetic acid

[0549] LiOH = lithium hydroxide

[0550] min = minute

[0551] hr = hour

[0552] NaH = sodium hydride

[0553] Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0)

[0554] DMSO = dimethyl sulfoxide

[0555] i-PrOH = isopropyl alcohol

[0556] Pd / C = palladium on carbon

[0557] XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0558] Boc = tert-butoxycarbonyl

[0559] Ms = methanesulfonyl

[0560] Bn = benzyl

[0561] Et = ethyl

[0562] Cbz = benzyloxycarbonyl

[0563] PMB = p-methoxybenzyl

[0564] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

[0565] NBS = N-bromosuccinimide

[0566] Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0567] DMAP = 4-(dimethylamino)pyridine

[0568] NCS = N-chlorosuccinimide

[0569] DMPU = 1,3 - Methyl - 3,4,5,6 - tetrahydro - 2(1H) - pyrimidinone

[0570] LDA = Lithium diisopropylamide

[0571] TfO = Trifluoromethanesulfonate

[0572] KHMDS = Potassium bis(trimethylsilyl)amide

[0573] KOAc = Potassium acetate

[0574] XPhos = 2 - Bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl

[0575] Et3N or TEA = Triethylamine

[0576] TMSOTf = Trimethylsilyl trifluoromethanesulfonate.

[0577] Scheme 1

[0578]

[0579] Example 1.1

[0580]

[0581] 4 - [2 - (Benzyloxy)phenyl]cyclohexan - 1 - one (210 g, 749 mmol, 1.00 equivalent) in tetrahydrofuran (2.1 L) was placed in a 5 L four - necked round - bottom flask, purged with nitrogen and maintained under an inert atmosphere. Subsequently, lithium tri - sec - butylborohydride (1 mol / L, THF) (1123 mL, 5257 mmol, 1.50 equivalents) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 4 hours. Then the reaction was quenched by adding 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 in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 - 1:5) to give 137 g (64%) of (1s,4s)-4 - [2 - (benzyloxy)phenyl]cyclohexan - 1 - ol as a solid. 1 1H NMR (400 MHz, CDCl3): δ 7.45–7.26 (6H, m), 7.16 (1H, dd), 6.98–6.90 (2H, m), 5.09 (2H, s), 4.13 (1H, s), 3.12–3.02 (1H, m), 1.93–1.82 (4H, m), 1.73–1.41 (4H, m).

[0582]

[0583] NaH (60 wt%, 26.9 g, 2.00 equiv) in tetrahydrofuran (200 mL) was placed in a 2 L four-necked round-bottom flask, purged with nitrogen and maintained under an inert atmosphere. Subsequently, 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 to 55 °C. After stirring for 2 h, a solution of 3-bromo-2-(bromomethyl)pyridine (143.5 g, 571 mmol, 1.70 equiv) in tetrahydrofuran (550 mL) was added dropwise with stirring at 50 to 55 °C. The resulting solution was stirred at 50 to 55 °C for 14 h. The reaction mixture was cooled. Then the reaction was quenched by adding water. The resulting solution was extracted with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. The solid material was filtered off. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:100 - 1:2) to give 94 g (62%) of 3-bromo-2([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine as a solid. 1 H NMR (400 MHz, CDCl3): δ 8.57 (1H, d), 7.90 (1H, dd), 7.48–7.26 (6H, m), 7.18–7.14 (2H, m), 6.98–6.91 (2H, m), 5.12 (2H, s), 4.77 (2H, s), 3.86 (1H, s), 3.17–3.10 (1H, m), 2.20–2.15 (2H, m), 1.98–1.88 (2H, m), 1.69–1.57 (4H, m).

[0584]

[0585] In a 2 L four-necked round-bottom flask, purged with nitrogen and maintained under an inert atmosphere, Xantphos (10.7 g, 18 mmol, 0.10 equiv), Cs2CO3 (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), Pd2(dba)3 (8.5 g, 9 mmol, 0.05 equiv) and tert-butyl carbamate (26 g, 222 mmol, 1.20 equiv) in dioxane (840 mL) were added. The resulting solution was stirred at 100 °C for 5 h. The solid material 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 - 1:4) to afford 74 g (82%) of tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid.

[0586]

[0587] 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 ethanol (740 mL) were placed in a 2 L three-necked round-bottom flask, and then hydrogen was bubbled through. The resulting solution was stirred at room temperature for 14 h. The solid material 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 - 1:2) to afford 51.36 g (85%) of tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid. LCMS (ESI): m / z + = 399.1; 1 H NMR (300 MHz, CDCl3): δ 8.65 (1H, s), 8.47 (1H, d), 8.19 (1H, q), 7.26–7.21 (1H, m), 7.09–7.03 (1H, m), 6.92–6.86 (1H, m), 6.75 (1H, q), 5.77 (1H, s), 4.84 (1H, s), 3.80 (1H, s), 2.94–2.93 (1H, m), 2.15–2.06 (2H, m), 1.88–1.47 (7H, m), 1.45 (9H, s), 1.26 (1H, d).

[0588]

[0589] A 250 mL round-bottom flask was purged with nitrogen and maintained under an inert atmosphere. N-[2-[[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl]pyridin-3-yl]carbamic acid tert-butyl ester (8 g, 20.075 mmol, 1 equiv), K2CO3 (13.97 g, 100.35 mmol, 5 equiv), acetone (120 mL), and ethyl bromoacetate (5.03 g, 30.119 mmol, 1.5 equiv) were added. The resulting solution was stirred at 50 °C for 24 h. The solid material was filtered off. The filtrate was concentrated under vacuum. 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. LCMS (ESI): m / z [M+H] + = 485.

[0590]

[0591] Under a hydrogen atmosphere at room temperature, PtO2 (1.85 g, 8.142 mmol, 0.50 equiv) was added 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). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The resulting mixture was filtered and the cake was concentrated under reduced pressure. At 0 °C, the reaction was quenched with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of diastereomeric cis and trans forms (7 g, 88.7%) as a solid. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 20:1) to give a cis racemic mixture 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 (4.1 g). LCMS (ESI): m / z [M+H] + = 491.

[0592]

[0593] Under a nitrogen atmosphere, to a 500 mL round-bottom flask was added 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), H2O (30 mL), and lithium hydroxide (83 mg, 3.465 mmol, 5 equiv). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography under the following conditions and then lyophilized 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. LCMS (ESI): m / z [M+H] + = 463.

[0594]

[0595] Under a nitrogen atmosphere, 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). The resulting solution was stirred at room temperature for 3 h. LCMS showed complete conversion. The resulting mixture was concentrated. The crude product ((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzo-2(1,4)-cyclohexano-cyclooctane-5 3 -yl) tert-butyl carbamate was used directly in the next step without purification. LCMS (ESI): m / z [M+H] + = 445.

[0596]

[0597] A 500 mL round-bottom flask was purged with nitrogen and maintained under an inert atmosphere, and the crude mixture ((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzo-2(1,4)-cyclohexano-cyclooctane-53 tert-Butyl (2S,2S,5R,5S)-5-amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)-cyclohexano[1,2-b]octahydro-6-one-3-carboxylate (2 g, 4.499 mmol, 1 equiv), DCM (120 mL) and TFA (40 mL). The resulting solution was stirred at 25 °C for 1 h. LCMS showed complete conversion. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give (2S,2S,5R,5S)-5-amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)-cyclohexano[1,2-b]octahydro-6-one 32.1 g (800 mg, 51.6%), as a solid. LCMS (ESI): m / z [M+H]+ = 345. 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)-cyclohexano[1,2-b]octahydro-6-one 32.1 g (800 mg, 51.6%), as a solid. LCMS (ESI): m / z [M+H]+ = 345.

[0598]

[0599] Under a nitrogen atmosphere, at room temperature, cyclopropylsulfonyl chloride (81 mg, 2.0 equiv, 0.6 mmol) was added to a stirred mixture of (2S,2S,5R,5S)-5-amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)-cyclohexano[1,2-b]octahydro-6-one (100 mg, 1.0 equiv, 0.3 mmol) and DIEA (112 mg, 3.0 equiv, 0.9 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC and chiral HPLC to give N-((2S,2S,5R,5S)-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)cyclohexano[1,2-b]octahydro-5-yl)cyclopropanesulfonamide (55 mg, 41%), as a solid. LCMS (ESI): m / z [M+H] 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)-cyclohexano[1,2-b]octahydro-6-one (100 mg, 1.0 equiv, 0.3 mmol) and DIEA (112 mg, 3.0 equiv, 0.9 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC and chiral HPLC to give N-((2S,2S,5R,5S)-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)cyclohexano[1,2-b]octahydro-5-yl)cyclopropanesulfonamide (55 mg, 41%), as a solid. LCMS (ESI): m / z [M+H] 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzisoxazolo-2(1,4)cyclohexano[1,2-b]octahydro-5 3 -yl)cyclopropanesulfonamide (55 mg, 41%), as a solid. LCMS (ESI): m / z [M+H] + = 449; 11H NMR (400 MHz, chloroform-d) δ 7.16 - 7.22 (m, 1H), 7.11 (dd, J = 7.5, 1.7 Hz, 1H), 6.89 - 6.95 (m, 1H), 6.77 (dd, J = 8.0, 1.2 Hz, 1H), 5.23 - 5.35 (m, 1H), 5.13 (d, J = 10.5 Hz, 1H), 4.32 (dd, J = 9.3, 6.3 Hz, 2H), 3.82 - 3.87 (m, 1H), 3.67 - 3.75 (m, 3H), 3.46 - 3.63 (m, 2H), 2.49 - 2.73 (m, 3H), 2.17 - 2.30 (m, 1H), 2.03 (s, 2H), 1.84 - 1.99 (m, 3H), 1.58 - 1.63 (m, 1H), 1.48 - 1.58 (m, 1H), 1.34 - 1.47 (m, 3H), 1.13 - 1.32 (m, 5H), 1.01 - 1.11 (m, 1H), 0.84 - 0.94 (m, 1H).

[0600] Example 1.2

[0601]

[0602] Under a nitrogen atmosphere, at room temperature, propane-2-sulfonyl chloride (82 mg, 2.0 eq, 0.6 mmol) was added to a stirred mixture of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexano-6-one (100 mg, 1.0 eq, 0.3 mmol) and DBU (132 mg, 3.0 eq, 0.9 mmol) in dichloromethane (20 mL). The resulting mixture was stirred for 2 hours under a nitrogen atmosphere at room temperature. The residue was purified by reverse flash chromatography and chiral HPLC to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)cyclohexano-5 3 -yl)propane-2-sulfonyl chloride (50 mg, 37%), as a solid. LCMS (ESI): m / z [M+H] + = 451; 11H NMR (400 MHz, chloroform-d) δ 7.15 - 7.22 (m, 1H), 7.11 (dd, J = 7.4, 1.8 Hz, 1H), 6.85 - 6.95 (m, 1H), 6.77 (dd, J = 8.1, 1.2 Hz, 1H), 5.16 - 5.23 (m, 1H), 5.11 - 5.15 (m, 1H), 4.27 - 4.35 (m, 1H), 4.23 - 4.27 (m, 1H), 3.83 - 3.87 (m, 1H), 3.65 - 3.77 (m, 3H), 3.51 - 3.54 (m, 2H), 3.05 - 3.28 (m, 1H), 2.50 - 2.73 (m, 2H), 2.18 - 2.31 (m, 1H), 2.09 - 2.11 (m, 3H), 1.92 - 1.97 (m, 1H), 1.85 - 1.87 (m, 1H), 1.65 - 1.68 (m, 2H), 1.46 - 1.51 (m, 1H), 1.41 - 1.46 (m, 7H), 1.33 - 1.40 (m, 2H).

[0603] Example 1.3

[0604]

[0605] Under a nitrogen atmosphere, at room temperature, to a stirred mixture of tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexanocinoctane-53-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). 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 1 S,2 4 S,5 2 R,5 3 S)-1 5 -bromo-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)cyclohexanocinoctane-5 3 -yl)carbamate (2.0 g, 90.5%), as a solid. LCMS (ESI): m / z [M+H] + = 523.

[0606]

[0607] Under a nitrogen atmosphere, at room temperature, to a stirred mixture of tert-butyl (2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -bromo-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodioxolo-2(1,4)cyclohexadioxocine-5 3 -yl)carbamate (1.0 g, 1.0 equiv, 1.9 mmol), MeB(OH)2 (0.23 g, 2.0 equiv, 3.8 mmol) and Pd(dppf)Cl2 (0.14 g, 0.1 equiv, 0.2 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was added K2CO3 (0.79 g, 3.0 equiv, 5.7 mmol). The resulting mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give tert-butyl (2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -methyl-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodioxolo-2(1,4)cyclohexadioxocine-5 3 -yl)carbamate (525 mg, 41.9%) as a solid. LCMS (ESI): m / z [M+H] + = 459.

[0608]

[0609] To a solution of tert-butyl (2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -methyl-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodioxolo-2(1,4)cyclohexadioxocine-5 3 -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 h. 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), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (2 1 S,24 S,5 2 R,5 3 S)-5 3 -Amino--1 5 -Methyl-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodino-2(1,4)-cyclohexanodinooctan-6-one (440 mg, 51.0%), a solid. LCMS (ESI): m / z [M+H] + = 359; 1 H NMR (400 MHz, DMSO-d6) δ 6.94 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.77 - 4.88 (m, 1H), 3.88 (d, J = 10.5 Hz, 1H), 3.72 - 3.81 (m, 1H), 3.59 - 3.65 (m, 2H), 3.45 (dd, J = 9.0, 3.8 Hz, 1H), 2.87–2.91 (m, 1H), 2.59 - 2.70 (m, 1H), 2.16 - 2.19 (m, 4H), 2.07–2.11 (m, 1H), 1.55 - 1.74 (m, 5H), 1.15 - 1.46 (m, 6H).

[0610]

[0611] To a solution of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-1 5 -Methyl-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodino-2(1,4)-cyclohexanodinooctan-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 cyclopropylsulfonyl chloride (173 mg, 2.0 equiv, 1.2 mmol). After stirring for 4 h under a nitrogen atmosphere and at 25 °C, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography and chiral preparative HPLC to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5-Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxaoctane-5 3 -yl)cyclopropanesulfonamide (89.5 mg, 33%), a solid. LCMS (ESI): m / z [M+H] + = 463; 1 H NMR (400Mhz, chloroform-d) δ 6.97 (dd, J = 8.3, 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.23 - 5.34 (m, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.54 (d, J = 8.1 Hz, 1H), 4.27 (d, J = 10.6 Hz, 1H), 3.81 - 3.86 (m, 1H), 3.69 - 3.72 (m, 3H), 3.42 - 3.62 (m, 2H), 2.58 - 2.73 (m, 1H), 2.47 - 2.57 (m, 2H), 2.13 - 2.30 (m, 4H), 2.00 - 2.04 (m, 2H), 1.82 - 1.96 (m, 2H), 1.32 - 1.54 (m, 5H), 1.01 - 1.31 (m, 5H).

[0612] Example 1.4

[0613]

[0614] At 0 °C, NaH (60%, 5.26 g, 5.0 equiv, 131.6 mmol) was added portionwise to a stirred mixture of benzyl 2-hydroxyacetate (21.9 g, 5.0 equiv, 131.6 mmol) in DMF (100 mL).

[0615] Under a nitrogen atmosphere, the resulting mixture was stirred at 0 °C for 30 minutes. At room temperature, 3-bromo-2-fluoro-4-methylpyridine (5.00 g, 1.0 equiv, 26.314 mmol) was added to the above mixture, 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 (aqueous solution) (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), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give benzyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (7.3 g, 83.0%), an oil. LCMS (ESI): m / z [M+H] + = 337.

[0616]

[0617] To a solution of 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 equiv, 3.51 mmol) and benzyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (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). Under a nitrogen atmosphere, the reaction mixture was stirred at 80 °C for 2 h. The crude product was purified by reverse flash chromatography to give benzyl (2R,3S)-2-(((4-(2-(benzyloxy)-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-1-enyl)oxy)methyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (2.0 g, 80.0%) as an oil.

[0618]

[0619] Under a nitrogen atmosphere, to a solution of benzyl (2R,3S)-2-(((4-(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 equiv, 2.86 mmol) in isopropanol (30 mL) was added Pd / C (152 mg, 0.5 equiv, 1.43 mmol). At room temperature, the resulting mixture was hydrogenated in a hydrogen atmosphere with a hydrogen balloon for 15 h. The mixture was filtered through a (Imerys Minerals California Inc., San Jose, CA) pad and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse flash chromatography to give 2-((3-(4-((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-enyl)-4-methylpyridin-2-yl)oxy)acetic acid (950 mg, 69.9%) as a solid. LCMS (ESI): m / z [M+H] + = 477.

[0620]

[0621] Under a nitrogen atmosphere, at 25 °C, HATU (1.08 g, 1.5 equiv, 2.84 mmol) was added to a stirred mixture of 2-((3-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-enyl)-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). The resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give tert-butyl ((5 2 R,5 3 S,E)-1 4 -methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazacyclooct-2 1 -en-5 3 -yl)carbamate (650 mg, 75.1%) as a solid. LCMS (ESI): m / z [M+H] + = 469.

[0622]

[0623] To a solution of tert-butyl ((5 2 R,5 3 S,E)-1 4 -methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazacyclooct-2 1 -en-5 3 -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 for 5 days under a nitrogen atmosphere. The crude product was purified by reverse flash chromatography to give tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-1 4 -methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazacyclooct-5 3 -yl)carbamate (500 mg, 41.0%) as a solid. LCMS (ESI): m / z [M+H] + = 461.

[0624]

[0625] To ((2 1 S,2 4 S,5 2 R,5 3 S)-1 4 -methyl-6-oxo-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazinooctane-5 3 -yl) tert-butyl carbamate (400 mg, 1.0 equiv, 0.87 mmol) in a solution of DCM (15 mL) and TFA (3 mL). Under a nitrogen atmosphere, at 25 °C, the reaction mixture was stirred for 1 h. The resulting mixture was extracted with dichloromethane (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate.

[0626] After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4 -methyl-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazinooctane-6-one (230 mg, 73.5%), as a solid. LCMS (ESI): m / z [M+H] + = 360.

[0627]

[0628] Under a nitrogen atmosphere, at 25 °C, to a stirred solution of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4 -methyl-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazinooctane-6-one (50 mg, 1.0 equiv, 0.14 mmol) and DBU (170 mg, 8.0 equiv, 1.12 mmol) in DCM (6 mL), a solution of propane-2-sulfonyl chloride (99 mg, 5.0 equiv, 0.70 mmol) in DCM (0.4 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 4 h. The filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexanoazocane-5 3 -yl)propane-2-sulfonamide (55 mg, 85%), a solid. The crude product was purified by preparative chiral HPLC to obtain the pure enantiomer. LCMS (ESI): m / z [M+H] + = 466; 1 H NMR (400 Mhz, methanol-d4) δ 7.77 - 7.85 (m, 1H), 6.81 (dd, 1H), 5.18 - 5.37 (m, 2H), 4.53 (dd, 1H), 3.98 (t, 1H), 3.81 (d, 1H), 3.54 - 3.64 (m, 2H), 3.45 (d, 1H), 3.23 - 3.30 (m, 1H), 2.89 - 3.11 (m, 2H), 2.67 (dd, 1H), 2.34 (s, 4H), 2.21 (d, 1H), 1.88 (d, 3H), 1.62 - 1.82 (m, 2H), 1.42 - 1.60 (m, 2H), 1.27 - 1.42 (m, 8H), 1.20 (d, 1H).

[0629] Example 1.5

[0630]

[0631] Under a nitrogen atmosphere, at room temperature, to a stirred solution of N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperazino-1(1,2)-benzene-2(1,4) cyclohexanoazocane-5 3 -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). Under a nitrogen atmosphere, at room temperature, the resulting mixture was stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -Chloro-6-oxo-3,8-dioxa-5(2,1)-piperazino-1(1,2)-benzene-2(1,4)-cyclohexanoazocane-5 3-yl)cyclopropanesulfonamide (64.6 mg, 60%), a solid. LCMS (ESI): m / z [M+H] + = 483; 1 H NMR (400Mhz, chloroform-d) δ 7.14 (dd, J = 8.5, 2.6 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.25 - 5.33 (m, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.40 (d, J = 8.1 Hz, 1H), 4.27 (d, J = 10.4 Hz, 1H), 3.83 (t, J = 9.2 Hz, 1H), 3.65 - 3.70 (m, 3H), 3.42 - 3.62 (m, 2H), 2.44 - 2.67 (m, 3H), 2.12 - 2.27 (m, 1H), 2.00 - 2.07 (m, 2H), 1.84 - 1.97 (m, 2H), 1.62 - 1.67 (m, 2H), 1.33 - 1.54 (m, 4H), 1.02 - 1.30 (m, 5H).

[0632] Example 1.6

[0633]

[0634] Under a nitrogen atmosphere, at -78 °C, to a stirred solution of 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), LDA (5.19 mL, 8.8 equiv, 48.4 mmol) was added dropwise over 5 minutes. The resulting mixture was stirred at -78 °C for an additional 1.5 hours. At -78 °C, a solution of 1-(benzyloxy)-2-[4-(chloromethoxy)cyclohexyl]-3-methylbenzene (1.58 g, 1.1 equiv, 4.57 mmol) in THF (5 mL) was added dropwise to the above mixture over 5 minutes. The resulting mixture was stirred at -78 °C for 30 minutes, and then the resulting mixture was stirred at room temperature for an additional hour. The reaction was quenched with water, and the mixture was extracted with EtOAc (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 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%), an oil. LCMS (ESI): m / z [M+H] + = 566; 11H NMR (400 MHz, chloroform-d) δ 7.33–7.49 (m, 4H), 7.29 - 7.33 (m, 1H), 6.91 - 7.03 (m, 1H), 6.62 - 6.81 (m, 2H), 5.13 - 5.16 (m, 2H), 3.96 - 4.35 (m, 5H), 3.72 - 3.94 (m, 2H), 3.39 - 3.67 (m, 2H), 2.56 - 2.74 (m, 1H), 2.30 - 2.34 (m, 5H), 1.86 - 2.12 (m, 2H), 1.50 (d, J = 3.5 Hz, 9H), 1.37 - 1.47 (m, 4H), 1.22 - 1.27 (m, 3H).

[0635]

[0636] At 125 °C, a solution of 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 for 2 h. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse 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%) as an oil. LCMS (ESI): m / z [M+H] + = 494; 1 1H NMR (400 MHz, chloroform-d) δ 7.34 - 7.44 (m, 4H), 7.29 - 7.34 (m, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 5.21 (s, 2H), 3.90 - 3.94 (m, 2H), 3.83 (s, 2H), 3.70 (s, 1H), 3.52–3.57 (m, 1H), 2.36 - 2.41 (m, 7H), 1.93 - 2.02 (m, 2H), 1.47 - 1.50 (m, 10H), 1.38 - 1.47 (m, 4H).

[0637]

[0638] Under a nitrogen atmosphere, at room temperature, a mixture of 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) in EtOH (25 mL) was stirred overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse 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 an oil. LCMS (ESI): m / z [M+H] + = 404; 1 H NMR (400 Mhz, chloroform-d) δ 6.93 (t, J = 7.7 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 3.92 - 3.96 (m, 4H), 3.67 (d, J = 8.2 Hz, 1H), 3.59 (s, 1H), 2.61 - 2.63 (m, 2H), 2.45 - 2.47 (m, 1H), 2.31 - 2.33 (m, 3H), 2.01 - 2.05 (m, 1H), 1.85 - 1.87 (m, 1H), 1.43 - 1.60 (m, 11H), 1.22 - 1.43 (m, 3H).

[0639]

[0640] Under a nitrogen atmosphere, to a stirred mixture of tert-butyl 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 K3PO4 (5.34 g, 8.0 equiv, 25.2 mmol) in MeCN (25 mL), tert-butyl 2-bromoacetate (3.68 g, 6.0 equiv, 18.9 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred at 25 °C for 5 h. The reaction mixture was purified by reverse 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. LCMS (ESI): m / z [M+H] + = 518; 11H NMR (400 MHz, chloroform-d) δ 7.00 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 4.66 (s, 2H), 4.48 - 4.62 (m, 1H), 4.01 (d, J = 11.0 Hz, 1H), 3.92 (s, 1H), 3.80 - 3.86 (m, 2H), 3.78 (s, 1H), 3.55 (s, 1H), 2.48 - 2.67 (m, 2H), 2.32 - 2.35 (m, 3H), 1.93 - 1.96 (m, 2H), 1.52 (s, 18H), 1.40 - 1.43 (m, 2H), 1.33 - 1.36 (m, 2H).

[0641]

[0642] Under a nitrogen atmosphere, sodium triacetoxyborohydride (4.39 g, 8.0 equiv, 20.7 mmol) was added 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 MgSO4 (623 mg, 2.0 equiv, 5.18 mmol) in DCM (40 mL). The resulting mixture was stirred at 25 °C for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse 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. LCMS (ESI): m / z [M+H] + = 640.45; 11H NMR (400 MHz, chloroform-d) δ 7.30 (d, J = 7.9 Hz, 2H), 7.00 (t, J = 8.1 Hz, 1H), 6.83 - 6.90 (m, 2H), 6.77 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.57 (d, J = 8.6 Hz, 2H), 4.03 (s, 1H), 3.91 (s, 1H), 3.87 (s, 2H), 3.80 (s, 3H), 3.72 (d, J = 10.5 Hz, 2H), 3.56 (s, 1H), 3.47 - 3.50 (m, 1H), 3.39 (s, 1H), 3.17 - 3.31 (m, 1H), 2.36 (s, 3H), 2.11 - 2.14 (m, 2H), 2.00 - 2.03 (m, 4H), 1.37 - 1.52 (m, 22H).

[0643]

[0644] Under a nitrogen atmosphere, trifluoroacetic acid (TFA, 5 mL) was added 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). The resulting mixture was stirred at 25 °C for 2 h and concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give 2-(2-((1S,4S)-4-(((2R,3S)-3-((4-methoxybenzyl)amino)pyrrol-2-yl)methoxy)cyclohexyl)-3-methylphenoxy)acetic acid (1.52 g, 95%) as an oil. Under a nitrogen atmosphere, propylphosphonic anhydride cyclic (3.01 g, 3.0 equiv, 9.45 mmol) was added dropwise to the above mixture and diisopropylethylamine (4.07 g, 10.0 equiv, 31.5 mmol) in DCM (30 mL) over 2 min. The resulting mixture was stirred at 25 °C for 1.5 h. The crude product was purified by reverse flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-((4-methoxybenzyl)amino)-16-methyl-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctan-6-one (0.77 g, 45%) as a solid.

[0645] LCMS (ESI): m / z [M+H] + = 465;1 1H NMR (400 MHz, chloroform-d) δ 7.30 - 7.37 (m, 2H), 7.05 (t, J = 7.8 Hz, 1H), 6.87 - 6.95 (m, 2H), 6.81 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 9.9 Hz, 1H), 4.48 (dd, J = 7.7, 3.1 Hz, 1H), 4.22 - 4.32 (m, 2H), 4.14 - 4.18 (m, 1H), 3.81 - 3.87 (m, 5H), 3.79 (s, 1H), 3.40 - 3.56 (m, 3H), 2.87 - 2.90 (m, 1H), 2.52 - 2.56 (m, 1H), 2.31 - 2.35 (m, 3H), 2.13 - 2.28 (m, 4H), 1.81 - 1.85 (m, 1H), 1.43 - 1.54 (m, 1H), 1.32 - 1.42 (m, 2H), 1.25 - 1.28 (m, 2H).

[0646]

[0647] Under a nitrogen atmosphere, ammonium formate (801 mg, 25.0 equiv, 12.7 mmol) was added to a stirred mixture of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((4-methoxybenzyl)amino)-16-methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctan-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). The resulting mixture was stirred at 85 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-16-methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclooctan-6-one (169 mg, 96%), as a solid. LCMS (ESI): m / z [M+H] + = 345; 11H NMR (400 MHz, chloroform-d) δ 7.05 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.63 (dd, J = 8.1, 1.2 Hz, 1H), 4.97 (d, J = 9.9 Hz, 1H), 4.18 - 4.31 (m, 4H), 3.74 - 3.79 (m, 1H), 3.63 - 3.66 (m, 1H), 3.50 - 3.55 (m, 1H), 3.42 (d, J = 9.1 Hz, 1H), 2.87 - 2.91 (m, 1H), 2.52 - 2.56 (m, 1H), 2.33 (s, 3H), 2.09 - 2.29 (m, 4H), 1.80 - 1.89 (m, 1H), 1.47 - 1.50 (m, 1H), 1.23 - 1.44 (m, 3H).

[0648]

[0649] Under a nitrogen atmosphere, to a stirred mixture of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-16-methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclooctan-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 dropwise MsCl (77.3 mg, 1.5 equiv, 0.68 mmol) over 2 minutes. 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 flash chromatography to afford N-((2 1 S,2 4 S,5 2 R,5 3 S)-16-methyl-6-oxo-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexano[1,2]cyclooctan-5 3 -yl)methanesulfonamide (126 mg, 65.9%), as a solid. LCMS (ESI): m / z [M+H] + = 423; 11H NMR (400 MHz, methanol-d4) δ 7.03 (t, J = 7.8 Hz, 1H), 6.77 - 6.83 (m, 1H), 6.71 (d, J = 8.1 Hz, 1H), 5.11 (d, J = 10.3 Hz, 1H), 4.37 (dd, J = 7.9, 3.4 Hz, 1H), 4.26 (td, J = 10.0, 2.1 Hz, 1H), 4.10 - 4.22 (m, 3H), 3.80 (s, 1H), 3.69 (td, J = 10.0, 7.7 Hz, 1H), 3.51 (d, J = 9.2 Hz, 1H), 3.04 (s, 3H), 2.95 - 2.97 (m, 1H), 2.60 - 2.65 (m, 1H), 2.34 - 2.48 (m, 1H), 2.31 (s, 3H), 2.12 - 2.30 (m, 3H), 1.89 - 1.91 (m, 1H), 1.46 - 1.60 (m, 2H), 1.29 - 1.42 (m, 2H), 1.17 - 1.25 (m, 1H).

[0650] Example 1.7

[0651]

[0652] Under a nitrogen atmosphere and at 0 °C, sodium hydride (3.20 g, 60% by weight, 2.0 equivalents, 80.0 mmol) was added portionwise to a stirred solution of ethyl glycolate (5.42 g, 1.3 equivalents, 52.0 mmol) in DMF (150 mL). The resulting mixture was stirred at 0 °C for 30 minutes. At room temperature, 5-bromo-4-chloro-6-methylpyrimidine (8.30 g, 1.0 equivalent, 40.0 mmol) and potassium fluoride (2.32 g, 1.0 equivalent, 40.0 mmol) were added to the above mixture. The resulting mixture was stirred at 80 °C for another 30 minutes. At 0 °C, saturated aqueous ammonium chloride solution was added to quench the reaction. The resulting mixture was diluted with ethyl acetate. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, 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. 1 1H NMR (300 MHz, CDCl3): δ 8.49 (s, 1H), 4.98 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0653]

[0654] To a solution of ethyl 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)acetate (3.30 g, 1.2 equiv, 12.0 mmol) and (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 benzyl ester (5.70 g, 1.0 equiv, 10.0 mmol) in 1,4-dioxane (60 mL) and water (15 mL) was added Pd(dppf)Cl2 (0.73 g, 0.1 equiv, 1.00 mmol) and Na2CO3 (3.20 g, 3.0 equiv, 30.0 mmol). After stirring for 2 h at 80 °C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (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 benzyl ester (5.40 g, 85.0 %), as a solid. LCMS (ESI): m / z + = 639.40; 1 H NMR (400Mhz, chloroform-d) δ 8.48 (s, 1H), 7.28 - 7.37 (m, 6H), 5.63 (s, 1H), 5.49 (s, 1H), 5.00 - 5.25 (m, 3H), 4.80 - 4.96 (m, 2H), 4.58 (s, 1H), 4.17 - 4.19 (m, 2H), 3.98 - 4.12 (m, 2H), 3.88 (s, 1H), 3.54 - 3.82 (m, 5H), 2.77 - 2.81 (m, 1H), 2.41 - 2.62 (m, 4H), 2.37 (s, 3H), 2.13 - 2.31 (m, 4H), 1.77 - 2.10 (m, 5H), 1.50 - 1.73 (m, 4H), 1.34 - 1.47 (m, 13H), 1.22 - 1.27 (m, 4H), 1.17 - 1.21 (m, 10H).

[0655]

[0656] Under a nitrogen atmosphere, palladium (0.95 g, 10 wt%, 0.1 eq, 0.89 mmol) was added 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 eq, 8.9 mmol) in 2-propanol (210 mL). The resulting mixture was hydrogenated with a hydrogen balloon at room temperature for 4 hours, filtered through a Celite pad, and concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next step without further purification.

[0657]

[0658] 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 eq, 8.9 mmol) in THF (24 mL) and H2O (8.0 mL) was added LiOH (0.32 g, 1.5 eq, 13 mmol). The resulting mixture was stirred at 25 °C for 1 hour, the resulting mixture was acidified to pH = 5, and then concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to obtain 2-((5-(4-((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-6-methylpyrimidin-2-yl)oxy)acetic acid (3.5 g, 82%) as a solid. LCMS (ESI): m / z [M+H] + = 477.

[0659]

[0660] Under a nitrogen atmosphere, 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 eq, 4.6 mmol) in DMF (25 mL) was added dropwise to a mixture of HATU (2.6 g, 1.5 eq, 6.9 mmol) and DIEA (1.8 g, 3.0 eq, 14 mmol) in acetonitrile (1.1 L) over 5 minutes. The resulting mixture was stirred at 25 °C for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse flash chromatography to obtain ((5 2 R,5 3 S,E)-1 6-Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimido-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctane-2 1 -ene-5 3 -yl)tert-butyl carbamate (1.8 g, 85%), a solid. LCMS (ESI): m / z [M+H] + = 459; 1 H NMR (400Mhz, methanol-d4) δ 8.50 - 8.58 (m, 1H), 5.20 - 5.42 (m, 2H), 4.53 - 4.72 (m, 2H), 4.40 - 4.43 (m, 1H), 4.05 - 4.08 (m, 1H), 3.79 - 3.97 (m, 1H), 3.71 (dd, J = 11.6, 3.4 Hz, 1H), 3.50 - 3.53 (m, 1H), 2.80 - 2.89 (m, 1H), 2.50 - 2.55 (m, 1H), 2.37 - 2.41 (m, 4H), 2.13 - 2.38 (m, 3H), 1.70 - 2.12 (m, 5H), 1.52 - 1.70 (m, 2H), 1.35 - 1.53 (m, 9H), 1.32 (s, 1H).

[0661]

[0662] Under a nitrogen atmosphere, to a solution of ((5 2 R,5 3 S,E)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimidino-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctane-2 1 -ene-5 3 -yl)tert-butyl 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). The resulting mixture was hydrogenated with a hydrogen balloon at room temperature for 7 days, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give ((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -Methyl-6-oxo-3,8-dioxa-1(5,4)-pyrimido-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctane-5 3 -yl)tert-butyl carbamate (310 mg, 62%), a solid. LCMS (ESI): m / z [M+H] += 461; 1 H NMR (400 Mhz, chloroform-d) δ 8.52 (d, J = 9.5 Hz, 1H), 5.56 (d, J = 11.8 Hz, 1H), 5.33 (s, 1H), 5.19 (d, J = 11.1 Hz, 1H), 4.96 (s, 1H), 4.72 - 4.76 (m, 1H), 4.61 (d, J = 11.2 Hz, 1H), 4.43 (s, 1H), 3.78 - 3.98 (m, 2H), 3.56 - 3.75 (m, 2H), 3.39 - 3.51 (m, 1H), 2.84 - 2.88 (m, 2H), 2.47 - 2.20 (m, 5H), 2.25 - 2.30 (m, 1H), 2.07 - 2.12 (m, 3H), 1.85 - 1.90 (m, 4H), 1.19 - 1.75 (m, 18H).

[0663]

[0664] To a solution of tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -methyl-6-oxo-3,8-dioxo-1(5,4)-pyrimido-5(2,1)-piperidine-2(1,4)-cyclohexaneheterocyclooctan-5 3 -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 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-16-methyl-3,8-dioxo-1(5,4)-pyrimido-5(2,1)-piperidine-2(1,4)-cyclohexaneheterocyclooctan-6-one (299 mg, 89.0%), as a solid. LCMS (ESI): m / z [M+H] + = 361.

[0665]

[0666] To (2 1 S,2 4 S,5 2 R,5 3 S)-5 3A solution of 1 S,2 4 S,5 2 R,5 3 S)-1 6 -methyl-6-oxo-3,8-dioxabicyclo[5.4.1]undec-5-en-5 3 -yl)methanesulfonamide (35 mg, 62.0%), as a solid. The racemic product was purified by chiral preparative-HPLC to the pure enantiomer. LCMS (ESI): m / z [M+H] + = 439; 1 H NMR (400 Mhz, methanol-d4) δ 8.44 - 8.48 (m, 1H), 5.37 - 5.40 (m, 1H), 5.22 - 5.25 (m, 1H), 4.75 - 4.80 (m, 1H), 4.39 - 4.54 (m, 1H), 3.84 - 4.04 (m, 2H), 3.73 - 3.76 (m, 1H), 3.62 - 3.65 (m, 1H), 3.40 - 3.60 (m, 1H), 2.89 - 3.13 (m, 5H), 2.52 - 2.57 (m, 1H), 2.45 - 2.51 (m, 3H), 2.16 - 2.40 (m, 2H), 1.83 - 1.87 (m, 3H), 1.62 - 1.82 (m, 2H), 1.39 - 1.61 (m, 3H), 1.22 - 1.38 (m, 2H).

[0667] Example 1.8

[0668]

[0669] Under a nitrogen atmosphere, at 0 °C, to the stirred ((2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6A solution of N-methyl-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2-(1,4)-cyclohexanoheterocyclooctan-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 dropwise with MsCl (137.6 mg, 1.5 equiv, 1.20 mmol). Under a nitrogen atmosphere, at room temperature, the resulting mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -methyl-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)cyclohexanoheterocyclooctan-5 3 -yl)methanesulfonamide (260 mg, 74.4%), as a solid. LCMS (ESI): m / z [M+H] + = 437; 1 H NMR (400 Mhz, methanol-d4) δ 7.02 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.74 - 6.67 (m, 1H), 5.31 - 5.20 (m, 2H), 4.09 (d, J = 10.5 Hz, 1H), 3.95 - 3.92 (m, 1H), 3.83 - 3.70 (m, 2H), 3.69 - 3.60 (m, 1H), 3.58 - 3.44 (m, 2H), 3.37 - 3.33 (m, 6H), 3.04 (s, 3H), 2.98 - 2.94 (m, 1H), 2.81 - 2.68 (m, 1H), 2.39 - 2.24 (m, 4H), 2.23 - 2.13 (m, 1H), 1.98 - 1.81 (m, 3H), 1.79 - 1.63 (m, 2H), 1.56 - 1.32 (m, 3H), 1.22 - 1.20 (m, 1H).

[0670] Example 1.9

[0671]

[0672] Under a nitrogen atmosphere, at room temperature, to ((2 1 S,2 4 S,5 2 R,5 3 S)-5 3-Amino-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctan-6-one (100 mg, 1.0 eq, 0.30 mmol) was added to a stirred solution in dichloromethane (10 mL) with Et3N (176 mg, 6.0 eq, 1.74 mmol) and trifluoromethanesulfonyl chloride (196 mg, 4.0 eq, 1.16 mmol). Under a nitrogen atmosphere, at 40 °C, the resulting mixture was stirred for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer 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)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctan-5 3 -yl)methanesulfonamide (75.0 mg, 54.2%), as a solid. LCMS (ESI): m / z [M+H] + = 477; 1 H NMR (400Mhz, methanol-d4) δ 7.20 - 7.13 (m, 1H), 7.09 (dd, J = 7.4, 1.8 Hz, 1H), 6.92 - 6.80 (m, 2H), 5.31 (d, J = 10.6 Hz, 1H), 5.25 - 5.17 (m, 1H), 4.13 (d, J = 10.6 Hz, 1H), 4.02 - 3.94 (m, 1H), 3.87 - 3.71 (m, 3H), 3.54 - 3.46 (m, 2H), 3.06 - 3.03 (m, 2H), 2.79 - 2.69 (m, 1H), 2.64 - 2.51 (m, 1H), 2.35 - 2.23 (m, 1H), 2.18 - 2.15 (m, 1H), 1.99 - 1.78 (m, 4H), 1.74 - 1.62 (m, 2H), 1.58 - 1.40 (m, 3H), 1.32 - 1.29 (m, 4H).

[0673] Example 1.10

[0674]

[0675] Under a nitrogen atmosphere, at room temperature, to (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 3 ,1 5-Difluoro-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzene-2(1,4)-cyclohexanooctan-6-one (500.0 mg, 1.0 eq, 1.365 mmol) and DBU (1039 mg, 5.0 eq, 6.823 mmol) were added dropwise to a stirred mixture of propane-2-sulfonyl chloride (574 mg, 3.0 eq, 4.026 mmol) in DCM (40 ml). The resulting mixture was stirred for 1.5 h at room temperature under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous sodium sulfate. 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-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzene-2(1,4)-cyclohexanooctan-5 3 -yl)propane-2-sulfonamide (500 mg, 77.5%), as a solid.

[0676] LCMS (ESI): m / z [M+H] + = 473; 1 H NMR (400Mhz, methanol-d4) δ 6.94 - 6.86 (m, 1H), 6.80 - 6.73 (m, 1H), 5.34 - 5.32 (m, 1H), 4.37 - 4.28 (m, 2H), 4.19 - 4.05 (m, 3H), 3.81 - 3.79 (s, 1H), 3.74 - 3.64 (m, 1H), 3.56 - 3.53 (m, 1H), 3.32 - 3.27 (m, 1H), 2.69 - 2.58 (m, 2H), 2.46 - 2.33 (m, 2H), 2.29 - 2.14 (m, 2H), 2.04 - 1.87 (m, 2H), 1.50 - 1.46 (m, 2H), 1.39 - 1.36 (m, 8H), 1.35 - 1.25 (m, 3H), 0.96 - 0.84 (m, 1H).

[0677] Example 1.11

[0678]

[0679] At room temperature, to (2 1 S,2 4 S,5 2 R,53 (S)-5 3 -Amino-1 3 -Methyl-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodino-2-(1,4)-cyclohexanodinooctan-6-one (740.0 mg, 1.0 eq, 2.06 mmol) and TEA (1040 mg, 5.0 eq, 10.3 mmol) were added dropwise to a stirred solution of MsCl (709.4 mg, 3.0 eq, 6.193 mmol) in dichloromethane (40.0 mL). The resulting mixture was stirred for 1.5 h under a nitrogen atmosphere at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give N-((2 1 (S,2 4 (S,5 2 (R,5 3 (S)-1 3 -Methyl-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzodino-2(1,4)cyclohexanodinooctane-5 3 -yl)methanesulfonamide (450 mg, 49.9%), as a solid. LCMS (ESI): m / z [M+H] + = 437; 1 H NMR (400Mhz, methanol-d4) δ 7.02 (dd, J = 6.9, 2.1 Hz, 1H), 6.97 - 6.87 (m, 2H), 5.36 (d, J = 12.7 Hz, 1H), 5.24 (dd, J = 11.4, 5.1 Hz, 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.99 (d, J = 13.9 Hz, 1H), 3.87 (dd, J = 10.9, 8.8 Hz, 1H), 3.75 (s, 1H), 3.67 - 3.60 (m, 1H), 3.59 - 3.47 (m, 2H), 3.04 - 3.00 (m, 3H), 2.75 - 2.63 (m, 1H), 2.61 - 2.51 (m, 1H), 2.32 - 2.29 (m, 3H), 2.24 - 2.09 (m, 2H), 1.90 - 1.86 (m, 3H), 1.75 - 1.64 (m, 2H), 1.54 - 1.31 (m, 5H).

[0680] Example 1.12

[0681]

[0682] To (2 1 (S,2 4 (S,5 2 (R,5 3 (S)-5 3-Amino-3,8-dioxa-1(2,3)-pyrazino-5(2,1)-piperidine-2(1,4)-cyclohexane heterocyclooctan-6-one (50 mg, 1.0 eq, 144.33 alk, 8. and cyclopropylsulfonyl chloride (30.5 mg, 1.5 eq, 216.5 mg 8) in DCM (2 mL) was added DIPEA (37.4 mg, 2.0 eq, 288.7 (37. and DMAP (3.6 mg, 0.2 eq, 28.87 (3.6. 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 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)-pyrazino-5(2,1)-piperidine-2(1,4)-cyclohexane heterocyclooctane-5 3 -yl)cyclopropanesulfonamide (55 mg, 80%). LCMS (ESI): m / z [M+H] + = 451; 1 H NMR (400 MHz, DMSO-d6) δ 8.13 - 7.96 (m, 2H), 7.34 - 7.32 (m, 1H), 5.24 - 5.21 (m, 1H), 5.05 - 4.68 (m, 1H), 4.27 - 4.25 (m, 1H), 3.96 - 3.73 (m, 2H), 3.69 - 3.66 (m, 2H), 3.44 - 3.41 (m, 2H), 3.26 - 3.22 (m, 1H), 2.86 - 2.85 (m, 1H), 2.78 - 2.59 (m, 2H), 2.31 - 2.08 (m, 2H), 1.89 - 1.62 (m, 4H), 1.60 - 1.28 (m, 5H), 1.28 - 1.10 (m, 1H), 1.10 - 0.78 (m, 4H).

[0683] Example 1.13

[0684]

[0685] To (2 1 S,2 4 S,5 2 R,5 3 S)-5 3-Amino-3,8-dioxa-1(2,3)-pyrazino-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctan-6-one (50 mg, 1.0 eq, 144.33) in DCM (5 mL) was added to propane-3- and propane-2-sulfonyl chloride (30.9 mg, 1.5 eq, 216.49 mg), followed by DIPEA (37.4 mg, 2.0 eq, 288.7) and DMAP (3.6 mg, 0.2 eq, 28.87). 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 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)-pyrazino-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctan-5 3 -yl)propane-2-sulfonamide (35 mg, 51%). LCMS (ESI): m / z [M+H] + = 453; 1 H NMR (400 MHz, DMSO-d6) δ 8.12 - 8.00 (m, 2H), 7.28 - 7.25 (m, 2H), 5.24 - 5.21 (m, 2H), 4.98 - 4.95 (m, 1H), 4.67 - 4.64 (m, 1H), 4.26 - 4.22 (m, 1H), 4.01 - 3.76 (m, 2H), 3.67 - 3.65 (m, 1H), 3.44 - 3.41 (m, 2H), 3.30 - 3.09 (m, 2H), 2.86 - 2.84 (m, 2H), 2.41–2.04 (m, 3H), 1.71 - 1.67 (m, 4H), 1.39 - 1.36 (m, 5H), 1.30 - 0.93 (m, 7H).

[0686] Example 1.14

[0687]

[0688] Under a nitrogen atmosphere, to (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6To a solution of N-methyl-3,8-dioxo-1(5,4)-pyrimido-2(1,4)-cyclohexanoheterocyclooctan-6-one (760 mg, 1.0 eq., 2.11 mmol) in DCM (30 mL) was added DMAP (25.8 mg, 0.1 eq., 210.8 μmol), DIEA (1.47 mL, 4.0 eq., 8.43 mmol) and cyclopropanesulfonyl chloride (889.2 mg, 3.0 eq., 6.33 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -methyl-6-oxo-3,8-dioxo-1(5,4)-pyrimido-5(2,1)-piperidino-2(1,4)-cyclohexanoheterocyclooctan-5 3 -yl)cyclopropanesulfonamide (990 mg, 93.8%) as a solid. LCMS (ESI): m / z [M+H] + = 465; 1 H NMR (400Mhz, methanol-d4) δ 8.46 (d, J = 8.1 Hz, 1H), 5.40 - 5.38 (m, 1H), 5.29 - 5.25 (m, 1H), 4.79 - 4.75 (m, 1H), 4.48 - 4.45 (m, 1H), 4.07 - 3.84 (m, 2H), 3.82 - 3.64 (m, 2H), 3.59 - 3.56 (m, 1H), 3.52 - 3.38 (m, 1H), 3.13 - 2.89 (m, 1H), 2.68 - 2.52 (m, 2H), 2.51 - 2.48 (m, 3H), 2.39 - 2.16 (m, 2H), 2.00 - 1.83 (m, 3H), 1.82 - 1.59 (m, 2H), 1.55 - 1.52 (m, 1H), 1.51 - 1.38 (m, 2H), 1.38 - 1.23 (m, 1H), 1.18 - 0.89 (m, 4H).

[0689] Example 1.15

[0690]

[0691] At room temperature, to (2 1 S,2 4 S,5 2 R,5 3 S)-5 3To a solution of (1.5 g, 1.0 equiv, 4.35 mmol) of 6-amino-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-piperazino-2-(1,4)-cyclohexazinooctan-6-one in dichloromethane (30 mL) was added TEA (1.32 g, 3.0 equiv, 13.0 mmol). The solution was cooled to -50 °C, and then Tf2O (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 minutes. The resulting mixture was quenched with saturated aqueous sodium bicarbonate and diluted with 20 mL of water. Then the mixture was extracted with ethyl acetate (3 X 100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1,1,1-trifluoro-N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-piperazino-2(1,4)-cyclohexazinooctan-5 3 -yl)methanesulfonamide (1.68 g, 81.0%), as a solid. LCMS (ESI): m / z [M+H] + = 478; 1 H NMR (400Mhz, methanol-d4) δ 7.99 (ddd, J = 9.6, 5.1, 1.9 Hz, 1H), 7.50 (ddd, J = 7.1, 5.1, 1.9 Hz, 1H), 6.92 (dd, J = 7.2, 5.2 Hz, 1H), 5.34 - 5.32 (m, 1H), 5.22 - 5.19 (m, 1H), 4.81 - 4.63 (m, 1H), 4.43 - 4.40 (m, 1H), 4.08 - 3.94 (m, 1H), 3.81 - 3.77 (m, 3H), 3.54 - 3.42 (m, 2H), 2.99 - 2.58 (m, 2H), 2.40 - 2.26 (m, 1H), 2.19 - 2.16 (m, 1H), 1.97 - 1.79 (m, 4H), 1.79 - 1.62 (m, 1H), 1.62 - 1.35 (m, 3H), 1.35 - 1.21 (m, 1H).

[0692] Example 1.16

[0693]

[0694] To a stirred mixture of (2R,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (20.0 g, 1.0 eq., 86.5 mmol) and K2CO3 (19.1 g, 1.6 eq., 138.0 mmol) in DMF (300 mL) was added MeI (14.9 g, 1.2 eq., 104.7 mmol). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. 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 magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-methyl 2-tert-butyl ester (21.0 g, 99.0%) as an oil. LCMS (ESI): m / z [M+H] + = 246; 1 HNMR (400 Mhz, chloroform-d) δ 4.45 (d, J = 4.6 Hz, 1H), 4.25 - 4.22 (m, 1H), 3.76 (s, 3H), 3.71 - 3.46 (m, 2H), 2.14 - 2.11 (m, 1H), 1.92 - 1.89 (m, 1H), 1.46 - 1.43 (m, 9H).

[0695]

[0696] A mixture of (2R,3R)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-methyl 2-tert-butyl ester (21.0 g, 1.0 eq., 85.6 mmol) and 4N HCl in 1,4-dioxane (300.0 mL) was stirred at room temperature under a nitrogen atmosphere for 4 h. The precipitated solid was collected by filtration and washed with ether to give (2R,3R)-3-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride (14.4 g, 92.6%) as a solid. LCMS (ESI): m / z [M+H] + = 146.

[0697]

[0698] Under a nitrogen atmosphere, at 0 °C, benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.8 g, 1.0 equiv, 79.3 mmol) was added portionwise 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). Under a nitrogen atmosphere, at room temperature, the resulting mixture was stirred for 4 h. The resulting mixture was diluted with dichloromethane (300 mL). The resulting mixture was washed with 2 N aqueous hydrochloric acid (500 mL * 3). The resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (2R,3R)-3-hydroxy-1,2-pyrrolidinedicarboxylate 1-benzyl-2-ester (18 g, 81.3%) as a solid. LCMS (ESI): m / z [M+H] + = 280; 1 H NMR (400 Mhz, chloroform-d) δ 7.45 - 7.21 (m, 5H), 5.31 - 4.96 (m, 2H), 4.54 - 4.24 (m, 2H), 3.88 - 3.53 (m, 5H), 2.66 (s, 1H), 2.11 - 2.07 (m, 1H), 1.95 - 1.87 (m, 1H).

[0699]

[0700] Under a nitrogen atmosphere, Ag2O (44.8 g, 3.0 equiv, 193.3 mmol) was added to a stirred solution of methyl (2R,3R)-3-hydroxy-1,2-pyrrolidinedicarboxylate 1-benzyl-2-ester (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). The mixture was shielded from light with foil and stirred at room temperature for 2 days. The resulting mixture was filtered and the cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (2R,3R)-3-(benzyloxy)pyrrolidine-1,2-dicarboxylate 1-benzyl-2-ester (17.2 g, 72.2%) as an oil. LCMS (ESI): m / z [M+H] + = 370; 1 H NMR (400 Mhz, chloroform-d) δ 7.36 - 7.33 (m, 10H), 5.36 - 4.95 (m, 2H), 4.83 - 4.42 (m, 3H), 4.18 - 4.15 (m, 1H), 3.89 - 3.56 (m, 5H), 2.10 - 2.07 (m, 2H).

[0701]

[0702] At 0 °C and under a nitrogen atmosphere, NaBH4 (17.6 g, 10 equivalents, 465.6 mmol) and LiCl (19.7 g, 10 equivalents, 465.6 mmol) were added portionwise to a stirred solution of (2R,3R)-3-(benzyloxy)pyrrolidine-1,2-dicarboxylic acid 1-benzyl 2-methyl ester (17.2 g, 1.0 equivalent, 46.6 mmol) in THF (400 mL). The resulting mixture was stirred for 2 days at room temperature under a nitrogen atmosphere. The mixture was cooled to 0 °C. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc.

[0703] The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,3R)-3-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (15 g, 94.4%) as an oil. LCMS: m / z (ES+), [M+H] + = 342; 1 H NMR (400Mhz, chloroform-d) δ 7.36 - 7.33 (m, 10H), 5.28 - 5.04 (m, 2H), 4.71 - 4.41 (m, 2H), 4.13 (m, 1H), 3.95 - 3.92 (m, 1H), 3.80 - 3.43 (m, 5H), 2.04 - 2.01 (m, 2H).

[0704]

[0705] At -78 °C, under a nitrogen atmosphere, a solution of DMSO (8.24 g, 2.4 equiv, 105.4 mmol) in DCM (50.0 mL) was added dropwise to a stirred solution of (COCl)2 (6.69 g, 1.2 equiv, 52.7 mmol) in DCM (300 mL). The mixture was stirred at this temperature for 1.5 h. A solution of (2S,3R)-3-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (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 h, and then TEA (22.2 g, 5.0 equiv, 219.7 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 h, and the reaction mixture was warmed to room temperature. The reaction was quenched by the addition of water. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2R,3R)-3-(benzyloxy)-2-formylpyrrolidine-1-carboxylic acid benzyl ester (13.8 g, 80.7%) as an oil. LCMS: m / z (ES+), [M+H]+ = 340; 1H NMR (400 Mhz, chloroform-d) δ 9.60 - 9.55 (m, 1H), 7.45 - 7.29 (m, 10H), 5.26 - 5.06 (m, 2H), 4.71 - 4.33 (m, 3H), 4.23 - 4.20 (m, 1H), 3.71 - 3.65 (m, 2H), 2.14 - 2.10 (m, 1H), 1.91 - 1.86 (m, 1H).

[0706]

[0707] Under N2 atmosphere, to (2R,3R)-3-(benzyloxy)-2-formylpyrrolidine-1-carboxylic acid benzyl ester (10.0 g, 1.0 equiv, 29.5 mmol) dried under high vacuum for 1 h in a three-necked round-bottom flask was added tert-butyl dimethyl((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). The mixture was cooled to -78 °C. At -78 °C, a solution of TMSOTf (7.20 g, 1.1 equiv, 32.4 mmol) in DCM (20 mL) was added dropwise to the mixture solution, and then, at -78 °C, a solution of triethylsilane (6.17 g, 1.8 equiv, 53.0 mmol) in DCM (20 mL) was added dropwise. The resulting reaction solution was stirred at -78 °C for 0.5 h. Then, the temperature was raised to 20 °C and stirred for 0.5 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The obtained 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 (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-carboxylic acid benzyl ester (10.0 g, 62.0%) as an oil. LCMS: m / z (ES+), [M+H] + = 548, 1 H NMR (400 Mhz, chloroform-d) δ 7.43 - 7.22 (m, 10H), 6.44 (s, 1H), 5.32 - 5.03 (m, 2H), 4.72 - 4.43 (m, 2H), 4.19 - 3.99 (m, 2H), 3.80 - 3.18 (m, 5H), 2.54 - 2.23 (m, 2H), 2.18 - 1.94 (m, 4H), 1.78 (m, 1H), 1.44 (s, 1H), 1.28 - 1.25 (m, 11H).

[0708] To a stirred solution of 3-bromo-2-fluoro-4-methylpyridine (10 g, 1.0 eq, 53 mmol) in DMF (150 mL) was added sodium 2-hydroxyacetate (27 g, 5.0 eq, 0.26 mol) and cesium carbonate (26 g, 1.5 eq, 79 mmol). The mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The mixture was filtered and the resulting mixture was extracted with EtOAc (3, the resulting mixture was extracted. The combined organic layers were washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give ethyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (11 g, 40 mmol, 76%) as a solid. LCMS (ESI): m / z [M+H] + = 274.

[0709]

[0710] Under a nitrogen atmosphere, to a solution of (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-carboxylic acid benzyl ester (20 g, 1.0 eq, 37 mmol) and ethyl 2-((3-bromo-4-methylpyridin-2-yl)oxy)acetate (11 g, 1.1 eq, 40 mmol) in 1,4-dioxane (400 mL) and H2O (100 mL) was added Na2CO3 (12 g, 3.0 eq, 0.11 mol) and Pd(dppf)Cl2 (2.7 g, 0.1 eq, 3.7 mmol), 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 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give (2S,3R)-3-(benzyloxy)-2-(((4-(2-(2-ethoxy-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylic acid benzyl ester (16 g, 26 mmol, 71%) as an oil. LCMS (ESI): m / z [M+H] + = 615.

[0711] Under a nitrogen atmosphere, Pd / C (0.28 g, 0.1 equiv, 2.6 mmol) was added to a solution of (2S,3R)-3-(benzyloxy)-2-(((4-(2-(2-ethoxy-2-oxoethoxy)-4-methylpyridin-3-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylic acid benzyl ester (16 g, 1.0 equiv, 26 mmol) in i-PrOH (500 mL). At room temperature, the resulting mixture was hydrogenated in a hydrogen atmosphere with a hydrogen balloon for 5 h. Then, the resulting mixture was filtered through a 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. LCMS (ESI): m / z [M+H] + = 481.

[0712]

[0713] 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 H2O (75 mL). The resulting mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to 5 - 6. The crude product was purified by reverse 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. LCMS (ESI): m / z [M+H] + = 453.

[0714]

[0715] To a stirred mixture of HATU (12 g, 1.5 eq, 31 mmol) and diisopropylethylamine (8.1 g, 3.0 eq, 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 eq, 21 mmol). The resulting mixture was stirred at 25 °C for 2 h. The crude product was purified by reverse flash chromatography to give (5 2 S,5 3 R,E)-5 3 -(benzyloxy)-14-methyl-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexacyclooct-21-en-6-one (5.6 g, 13 mmol, 61%), as a solid. LCMS (ESI): m / z [M+H] + = 435.

[0716]

[0717] Under a nitrogen atmosphere, to a solution of (5 2 S,5 3 R,E)-5 3 -(benzyloxy)-14-methyl-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexacyclooct-2 1 -en-6-one (5.6 g, 1.0 eq, 13 mmol) in MeOH (300 mL) was added Pd / C (1.4 g, 1.0 eq, 13 mmol). The resulting mixture was hydrogenated with a hydrogen balloon at room temperature for 5 days, filtered through a pad, concentrated under reduced pressure to give the crude product. Then under a nitrogen atmosphere, Pd / C (0.01 g, 5% Wt) was added to the crude product. The resulting mixture was hydrogenated at 50 °C under 6 atm for 24 h, filtered through a pad and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse 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)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexacyclooct-6-one (2.9 g, 8.4 mmol, 63%), as a solid. LCMS (ESI): m / z [M+H] + = 347.

[0718]

[0719] To (2 1 R,2 4 R,5 2 S,5 3 R)-5 3 -hydroxy-14-methyl-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexazocan-6-one (2.9 g, 1.0 equiv, 8.4 mmol) in a stirred mixture of dichloromethane (15 mL) was added p-toluenesulfonyl chloride (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 flash chromatography to give (2 1 R,2 4 R,5 2 S,5 3 R)-1 4 -methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexazocan-5 3 -yl 4-methylbenzenesulfonate (3.4 g, 6.8 mmol, 81%), as a solid. LCMS (ESI): m / z [M+H] + = 501.

[0720]

[0721] To (2 1 R,2 4 R,5 2 S,5 3 R)-1 4 -methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexazocan-5 3 -yl 4-methylbenzenesulfonate (3.4 g, 1.0 equiv, 6.8 mmol) in a stirred solution of 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, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give (2 1 S,2 4S,5 2 R,5 3 S)-5 3 -azido-1 4 -methyl-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexano-6-one (1.6 g, 4.3 mmol, 63%), an oil. LCMS (ESI): m / z [M+H] + = 372.

[0722]

[0723] Under a nitrogen atmosphere, Pd / C (4.6 g, 10 wt%, 4.3 mmol) was added to a solution of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -azido-1-methyl-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexano-6-one (1.6 g, 1.0 equiv, 4.3 mmol) in methanol (100 mL). At room temperature, the resulting mixture was hydrogenated in a hydrogen atmosphere using a hydrogen balloon for 16 h. The crude product was purified by reverse flash chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4 -methyl-3,8-dioxo-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexano-6-one (905 mg, 2.62 mmol, 61%), an oil. LCMS (ESI): m / z [M+H] + = 346.

[0724]

[0725] To (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 4-Methyl-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexanoazocan-6-one (10 mg, 1.0 eq, 29 mg) in dichloromethane (2 mL) was added trifluoromethanesulfonic anhydride (9.8 mg, 1.2 eq, 35.8 μL) and triethylamine (8.8 mg, 3.0 eq, 87.8 μL). 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 1 S,2 4 S,5 2 R,5 3 S)-14-methyl-6-oxo-3,8-dioxa-1(3,2)-pyridazino-5(2,1)-pyrrolidino-2(1,4)-cyclohexanoazocan-5 3 -yl)methanesulfonamide (4.4 mg, 9.24 mg, 32%), as a solid. LCMS (ESI): m / z [M+H] + = 478; 1H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 5.1 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 4.96 (d, J = 10.7 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 4.33 (m, 2H), 4.23 - 4.10 (m, 2H), 3.83 (s, 1H), 3.74 (m, 1H), 3.43 (m, 1H), 3.03 (m, 1H), 2.64 - 2.45 (m, 2H), 2.35 (m, 4H), 2.17 (m, 2H), 1.94 (m, 1H), 1.57 (m, 1H), 1.47 - 1.27 (m, 2H), 1.23 - 1.14 (m, 1H).

[0726] Example 1.17

[0727]

[0728] Under a nitrogen atmosphere at 0 °C, potassium tert-butoxide (534.3 g, 1.3 equivalents, 4.8 mol) was added portionwise to a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (753.0 g, 1.0 equivalent, 4.8 mol) in THF (10 L). The resulting solution was stirred at 0 °C for 30 minutes. A solution of 3-bromo-2-(bromomethyl)pyridine (919.0 g, 1.0 equivalent, 4.8 mol) in THF (1.0 L) was added dropwise thereto with stirring at 0 °C. The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of 10 L of saturated NH4Cl (aqueous solution). The resulting solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3-bromo-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridine (962.0 g, 80.0%) as an oil.

[0729]

[0730] Under a nitrogen atmosphere, Pd2(dba)3 (134.2 g, 0.05 equivalent, 0.15 mol), Xantphos (169.6 g, 0.10 equivalent, 0.29 mol) and Cs2CO3 (2395 g, 2.5 equivalents, 7.3 mol) were added to a stirred solution of 3-bromo-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridine (962.0 g, 1.0 equivalent, 2.9 mol) and tert-butyl carbamate (686.7 g, 2.0 equivalents, 5.9 mol) in 1,4-dioxane (10.0 L). The resulting solution was stirred at 100 °C for 20 hours. The solid material 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.

[0731]

[0732] 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 eq, 1.7 mmol) in methanol (6.0 L) and acetic acid (600 mL) was added Pt2O (77.26 g, 0.20 eq, 340.2 mmol). At room temperature, the mixture was hydrogenated under 20 atm of hydrogen. The resulting solution was stirred overnight at room temperature. The solid material was filtered off. The resulting mixture was concentrated in vacuo to afford 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.

[0733]

[0734] At room temperature, 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 eq, 1.7 mmol) in DCM (6.0 L) was added N-(benzyloxycarbonyloxy)succinimide (845.9 g, 1.2 eq, 2.0 mol) and DIEA (648.9 g, 3.0 eq, 5.0 mol). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 5 L of water / ice. The resulting mixture was extracted with 2 x 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 afford benzyl 3-[(tert-butoxycarbonyl)amino]-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidine-1-carboxylate (422.0 g, 50.0%) as an oil.

[0735]

[0736] At room temperature, water (140 mL) was added to a stirred solution of benzyl 3-[(tert-butoxycarbonyl)amino]-2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)piperidine-1-carboxylate (422.0 g, 1.0 equiv, 0.84 mol) in acetic acid (280 mL). The resulting solution was stirred at 30 °C for 12 h. The mixture was cooled to 10 °C. The reaction was then quenched by the addition of 6 L of ice water. The resulting solution was stirred at 10 °C for 1 h. The precipitated solid was collected by filtration. The crude product was purified by recrystallization three times with 5 Et2O:1 EA (10 mL / g) to give racemic-(cis)-benzyl 3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (108.7 g, 28.2%), as a solid, which was concentrated in vacuo and filtered to give (2R,3S)-benzyl 3-[(tert-butoxycarbonyl)amino]-2-[[(4-oxocyclohexyl)oxy]methyl]piperidine-1-carboxylate (64.0 g), as an oil. LCMS (ESI): m / z + = 461; 1 H-NMR (300 MHz, DMSO-d6) δ 7.38 - 7.26 (m, 5H), 6.97 - 6.95 (m, 1H), 5.06 (brs, 2H), 4.60 (brs, 1H), 3.92 - 3.81 (m, 1H), 3.76 - 3.42 (m, 4H), 2.95 - 2.72 (m, 1H), 2.39 - 2.23 (s, 2H), 2.18 - 2.05 (m, 2H), 1.93 - 1.80 (m, 4H), 1.73 - 1.48 (m, 3H), 1.39 - 1.36 (m, 10H).

[0737]

[0738] Under -78 °C and in a nitrogen atmosphere, potassium bis(trimethylsilyl)amide (KHMDS) (78.2 mL, 1.2 equiv, 78.2 mmol) was added 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). The resulting mixture was stirred at -78 °C for 3 hours, and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (27.9 g, 1.2 equiv, 78.2 mmol) in THF (100 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 2 hours. At 0 °C, the mixture was added dropwise to 200 mL of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(trifluoromethylsulfonyloxy)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (41.0 g, crude product) as an oil.

[0739] Under a nitrogen atmosphere, Pd(dppf)Cl2 (24.1 g, 0.05 equiv, 29.5 mmol) and potassium acetate (116 g, 2.0 equiv, 1.18 mol) were added to a solution of benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(trifluoromethylsulfonyloxy)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (350 g, 1.0 equiv, 0.59 mol) and bis(pinacolato)diboron (180 g, 1.2 equiv, 0.71 mol) in 1,4-dioxane (3.5 L). Under a nitrogen atmosphere, the resulting mixture was stirred at 100 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by reverse flash chromatography to obtain benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (90.8 g, 26.2%) as a solid. LCMS (ESI): m / z [M+H] + = 571; 11H-NMR (300 MHz, DMSO-d6): δ 7.41 - 7.24 (m, 5H), 6.91 (brs, 1H), 6.30 (brs, 1H), 5.08 (brs, 2H), 4.54 (brs, 1H), 3.85 (d, J = 13.3 Hz, 1H), 3.75 - 3.40 (m, 4H), 2.91 - 2.70 (s, 1H), 2.40 - 2.24 (m, 1H), 2.21 - 2.05 (m, 1H), 2.02 - 1.85 (m, 2H), 1.80 - 1.70 (m, 1H), 1.70 - 1.61 (m, 1H), 1.60 - 1.50 (m, 2H), 1.39 (s, 11H), 1.18 (s, 12H).

[0740]

[0741] (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-carboxylic acid benzyl ester (500.0 mg, 1.0 equiv, 0.876 mmol), benzyl 2-(2-bromo-3-fluorophenoxy)acetate (386.4 mg, 1.3 equiv, 1.14 mmol), Pd(dppf)Cl2·CH2Cl2 (142.8 mg, 0.2 equiv, 0.175 mmol) and K2CO3 (302.8 mg, 2.5 equiv, 2.19 mmol) in a mixture of 1,4-dioxane (8.0 mL) and H2O (2.0 mL) were stirred overnight at 80 °C under a nitrogen atmosphere. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 20 mL) and dried over anhydrous sodium sulfate. 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. LCMS (ESI): m / z [M+H] + = 703.

[0742]

[0743] At room temperature and in a hydrogen atmosphere, a mixture of 2-[[(4-[2-[2-(benzyloxy)-2-oxoethoxy]-6-fluorophenyl]cyclohex-3-en-1-yl)oxy]methyl]-3-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylic acid benzyl ester (100.0 mg, 1.0 equiv, 0.142 mmol) and Pd / C (30.3 mg, 2.0 equiv, 0.285 mmol) in i-PrOH (6.0 mL) was stirred for 1 hour. The resulting mixture was filtered, and the filter cake was washed with i-PrOH (3 x 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. LCMS (ESI): m / z [M+H] + = 479.

[0744]

[0745] 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 equiv, 0.11 mmol) and diisopropylethylamine (43 mg, 3.0 equiv, 0.33 mmol) in acetonitrile (53 mL) was added HATU (63.0 mg, 1.5 equiv, 0.17 mmol). After stirring for 2 hours under a nitrogen atmosphere at room temperature, the resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give ((5 2 R,5 3 S,E)-1 6 -fluoro-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexano-2 1 -ene-5 3 -yl)carbamic acid tert-butyl ester (36.0 mg, 71%) as a solid. LCMS (ESI): m / z [M+H] + = 461.

[0746]

[0747] At room temperature and in a hydrogen atmosphere, ((5 2 R,5 3 S,E)-1 6 -fluoro-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexano-2 1 -ene-5 3tert-Butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -fluoro-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexano-cyclooctan-5 3 -yl)carbamate (30.0 mg, 1.0 eq, 65,.0 m and Pd / C (6.9 mg, 1 eq, 65 / C(6 in MeOH (6 mL) was stirred for 3 h. The resulting mixture was filtered, and the cake was washed with MeOH (3x3 mL). The filtrate was concentrated under reduced pressure to give ((2 + = 463.

[0748]

[0749] ((2 1 S,2 4 S,5 2 R,5 3 S)-1 6 -fluoro-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexano-cyclooctan-5 3 -yl)carbamate (28.0 mg, 1.0 eq, 61,.0 m in TFA (1.25 mL) and dichloromethane (5 mL) was stirred at room temperature for 1 h. 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-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexano-cyclooctan-6-one (20.0 mg, 91%), as a solid. LCMS (ESI): m / z [M+H] + = 363.

[0750]

[0751] At -40 °C, to (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 6A solution of -fluoro-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctan-6-one (2.00 g, 1.0 equiv, 5.52 mmol) and diisopropylethylamine (1.44 mL, 1.5 equiv, 8.28 mmol) in dichloromethane (80 mL) was added dropwise a solution of Tf2O (1.21 mL, 1.3 equiv, 7.17 mmol) in dichloromethane (0.2 mL). The resulting mixture was stirred at -40 °C for 2 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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-dioxo-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctan-5 3 -yl)methanesulfonamide (2.2 g, 4.2 mmol, 75%), as a solid. The isomer mixture was purified by chiral preparative HPLC to give the pure enantiomer, as a white solid. LCMS (ESI): m / z [M+H] + = 495; 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.17 (td, J = 8.3, 6.6 Hz, 1H), 6.84 - 6.63 (m, 2H), 5.32 (d, J = 10.4 Hz, 1H), 4.98 (dt, J = 10.5, 4.5 Hz, 1H), 4.00 (d, J = 10.4 Hz, 1H), 3.86 (dd, J = 11.2, 9.2 Hz, 1H), 3.67 (s, 2H), 3.63 - 3.51 (m, 1H), 3.37 (dd, J = 9.1, 3.7 Hz, 1H), 3.28 (m, 1H), 3.05 (m, 1H), 2.58 (m, 1H), 2.22 (m, 1H), 2.17 - 2.05 (m, 1H), 1.75 (m, 4H), 1.63 - 1.49 (m, 1H), 1.49 - 1.39 (m, 1H), 1.30 (m, 2H), 1.13 (m, 1H).

[0752] Example 1.18

[0753]

[0754] To N-((2 1 S,24 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzisoxa-2(1,4)-cyclohexanocinoctane-5 3 -yl)methanesulfonamide (4.00 g, 1.0 eq, 9.0 mmol) in a solution of MeCN (40 mL) and THF (40 mL) was added N-bromosuccinimide (3.37 g, 2.0 eq, 0.02 mol). The resulting mixture was stirred at 25 °C for 18 h. At 0 °C, saturated aqueous ammonium chloride was added to quench the reaction. The resulting mixture was extracted with ethyl acetate (3 * 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to give N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5 -bromo-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzisoxa-2(1,4)-cyclohexanocinoctane-5 3 -yl)methanesulfonamide (4.7 g, 9.4 mmol, 100%), as a solid. LCMS (ESI): m / z [M+H] + = 502; 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (dd, J = 8.5, 2.5 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 5.31 (m, 1H), 4.98 (m, 1H), 3.95 (m, 1H), 3.84–3.75 (m, 1H), 3.65 (m, 2H), 3.41 (m, 2H), 3.26 (m, 1H), 2.96 (s, 3H), 2.57 (m, 6H), 2.19 (m, 1H), 2.09 (m, 1H), 1.75 (m, 2H), 1.68 (m, 1H), 1.64 - 1.49 (m, 2H), 1.34 (s, 1H), 1.27 (m, 1H), 1.17 (m, 1H).

[0755]

[0756] To N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 5-Bromo-6-oxo-3,8-dioxa-5(2,1)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctane-5 3 A solution of (2.50 g, 1.0 equiv, 4.99 mmol) of 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)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctane-5 3 -yl)methanesulfonamide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.90 g, 1.5 equiv, 7.48 mmol) in 1,4-dioxane (50 mL) was added KOAc (1.47 g, 3.0 equiv, 15.0 mmol), Pd2(dba)3 (457 mg, 0.1 equiv, 0.499 mmol), and XPhos (475 mg, 0.2 equiv, 0.997 mmol). The resulting mixture was stirred at 100 °C for 3.5 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography to give N-((2 + S,2

[0757]

[0758] At 0 °C, hydrogen peroxide (30 wt%, 20 equiv, 80.2 mmol) was added dropwise to a stirred mixture of 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)-piperidino-1(1,2)-benzino-2(1,4)-cyclohexanoheterocyclooctane-5 3 -yl)methanesulfonamide (2.20 g, 1.0 equiv, 4.01 mmol) in 1,4-dioxane (25 mL). The resulting mixture was stirred at 25 °C for 4 h. At 0 °C, the reaction was quenched by the addition of saturated NaHSO3. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to give N-((21 S,2 4 S,5 2 R,5 3 S)-1 5 -hydroxy-6-oxo-3,8-dioxo-5(2,1)-piperidino-1(1,2)-benzene-2(1,4)-cyclohexane heterocyclooctane-5 3 -yl)methanesulfonamide (1.2 g, 2.7 mmol, 68%), a solid. LCMS (ESI): m / z [M+H] + = 439; 1 HNMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.22 (d, J = 6.8 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.54 - 6.47 (m, 2H), 5.21 (m, 1H), 4.97 (m, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.77 (m, 1H), 3.46 - 3.37 (m, 2H), 3.26 (m, 1H), 2.96 (s, 3H), 2.68 - 2.56 (m, 1H), 2.38 (m, 1H), 2.19 - 2.02 (m, 2H), 1.75 (m, 2H), 1.69 - 1.51 (m, 3H), 1.42 - 1.10 (m, 5H).

[0759] Example 1.19

[0760]

[0761] At -78 °C and under a nitrogen atmosphere, to a stirred mixture of (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzene-2(1,4)-cyclohexane heterocyclooctan-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 dropwise a solution of trifluoromethanesulfonic anhydride (1.4 g, 1.2 equiv, 5.1 mmol) in DCM (5 mL). The resulting mixture was stirred at -78 °C for 40 minutes and the reaction was terminated by adding an aqueous NaHCO3 solution 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 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to give 1,1,1-trifluoro-N-((2 1 S,2 4 S,52 R,5 3 (S)-6-oxo-3,8-dioxa-5(2,1)-pyrrolidino-1(1,2)-benzisoxa-2(1,4)-cyclohexaisooctane-5 3 -yl)methanesulfonamide (1.5 g, 3.2 mmol, 77%), a solid. LCMS (ESI): m / z [M+H] + = 463; 1 H NMR (400 Mhz, chloroform-d) δ 7.20 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.8 Hz, 1H), 6.94 (dd, J = 8.0, 6.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 5.07 (d, J = 10.7 Hz, 1H), 4.56 (dd, J = 8.3, 2.7 Hz, 1H), 4.46 - 4.44 (m, 2H), 4.27 (d, J = 10.6 Hz, 1H), 4.13 (dt, J = 10.6, 7.6 Hz, 1H), 3.89 (d, J = 4.0 Hz, 1H), 3.72 (dt, J = 10.6, 6.3 Hz, 1H), 3.38 (d, J = 9.8 Hz, 1H), 2.62 - 2.46 (m, 2H), 2.35 - 2.23 (m, 2H), 2.19 - 2.00 (m, 2H), 1.88 - 1.80 (m, 1H), 1.63 - 1.50 (m, 2H), 1.40 - 1.37 (m, 2H).

[0762] Example 1.20

[0763]

[0764] Under N2 atmosphere, n-butyllithium (2.0 g, 1.5 eq, 0.03 mol) was added portionwise to a stirred solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.0 g, 1.5 eq, 0.03 mol) and DMPU (7.0 mL, 3.0 eq, 0.05 mol) in THF (50 mL) at -78 °C. At -78 °C, 1-(benzyloxy)-2-((1S,4S)-4-(chloromethoxy)cyclohexyl)benzene (6.0 g, 1.0 eq, 0.02 mol) was added portionwise to the above mixture over 3 hours. The resulting mixture was stirred at -78 °C for an additional 4 hours. The resulting mixture was extracted with EtOAC (3 * 80 mL). The combined organic layers were washed with brine (3 * 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse 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. LCMS (ESI): m / z [M+H] + = 479.

[0765]

[0766] HCl (30%) (72 mL) was added to a solution of (2S,5R)-2-(((((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.2 g, 1.0 eq, 10 mmol) in acetonitrile (72 mL), and the resulting mixture was stirred at 40 °C for 2 hours. The crude product was purified by reverse flash chromatography to give O-((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serine methyl ester hydrochloride (3.8 g, 90%) as an oil.

[0767]

[0768] To a solution of O-((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serine methyl ester hydrochloride (3.8 g, 1.0 equiv, 9.0 mmol) and aqueous NaHCO3 (40 mL) in THF (40 mL) was added benzyl chloride (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 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to give N-((benzyloxy)carbonyl)-O-((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serine methyl ester (3.23 g, 69%) as an oil. LCMS (ESI): m / z [M+H] + = 518.

[0769]

[0770] Under -20 °C and a nitrogen atmosphere, to a stirred mixture of N-((benzyloxy)carbonyl)-O-((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)-L-serine methyl ester (3.0 g, 1.0 equiv, 6 mmol) in diethyl ether (150 mL) was added LiAlH4 (0.3 g, 1.5 equiv, 9 mmol). The resulting mixture was stirred at -20 °C for 18 h. THF was added to the above mixture at -20 °C. The resulting mixture was stirred at -20 °C for an additional 10 min. The reaction was quenched by adding Na2SO4·10H2O 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 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to give ((R)-1-(((1S,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxypropan-2-yl)carbamic acid benzyl ester (2.1 g, 70%) as an oil. LCMS (ESI): m / z [M+H] + = 490.

[0771]

[0772] 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 product 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. LCMS (ESI): m / z [M+H] + = 488.

[0773]

[0774] Under -78 °C and a nitrogen atmosphere, a solution of propan-2-one (0.20 g, 1.0 equiv, 3.4 mmol) was added dropwise to a stirred mixture of lithium diisopropylethylamide (0.91 g, 2.5 equiv, 8.5 mmol) in THF (2 mL). The resulting mixture was stirred at -78 °C for 1 h. Under -78 °C and a nitrogen atmosphere, 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) was added dropwise to the above mixture. The resulting mixture was stirred at -78 °C for an additional 1 h. The reaction was warmed to room temperature and quenched with 5 mL of saturated NH4Cl at 0 °C. The resulting mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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, 9160 mg, 27%) as an oil. LCMS (ESI): m / z [M+H] + = 546.

[0775]

[0776] Under a nitrogen atmosphere, Pd / C (0.3 g, 10 wt%, 0.3 eq, 0.3 mmol) was added to a solution of benzyl ((2S)-1-(((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)-3-hydroxy-5-oxohex-2-yl)carbamate (0.5 g, 1.0 eq, 0.9 mmol) in i-PrOH (50 mL). The resulting mixture was hydrogenated with a hydrogen balloon at room temperature and filtered through a pad, concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] + = 304.

[0777]

[0778] NaBH(OAc)3 (2.0 eq, 1.8 mmol) was added 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 eq, 2 mmol) in i-PrOH (30 mL). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] + = 306.

[0779]

[0780] Di-tert-butyl dicarbonate (536 mg, 1.5 eq, 2.46 mmol) was added to a solution of (2S,3R)-2-(((((1S,4R)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidin-3-ol (500 mg, 1.0 eq, 1.64 mmol) and aqueous NaHCO3 (10 mL) in acetonitrile (30 mL). 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 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to obtain tert-butyl (2R,3R)-3-hydroxy-2-(((((1S,4S)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-5-methylpyrrolidine-1-carboxylate (210 mg, 5180 mg, 31.6%), as a solid. LCMS (ESI): m / z [M+H] + = 406.

[0781]

[0782] 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., 5180 mgS) and tert-butyl 2-bromoacetate (121 mg, 1.2 equiv., 6211 mgS) in acetonitrile (5 mL) was added K2CO3 (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 thin layer chromatography 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, 3755 mg, 72.5%), as a semi-solid. 1 H NMR (400Mhz, methanol-d4) δ 7.83 (d, J = 5.2 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 4.98 (d, J = 10.7 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 4.38 (dd, J = 7.9, 3.4 Hz, 1H), 4.23 - 4.08 (m, 3H), 3.82 (s, 1H), 3.73 (m, 1H), 3.52 (d, J = 9.1 Hz, 1H), 3.04 - 3.00 (m, 4H), 2.60 - 2.57 (m, 1H), 2.50 - 2.37 (m, 1H), 2.35 (s, 3H), 2.34 - 2.23 (m, 1H), 2.23 - 2.12 (m, 2H), 1.92 (m, 1H), 1.63 - 1.51 (m, 1H), 1.45 - 1.34 (m, 2H), 1.22 - 1.14 (m, 1H). LCMS (ESI): m / z [M+H] + = 519.

[0783]

[0784] 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., 3660 mg) in dichloromethane (10 mL) was added Dess-Martin periodinane (310 mg, 2.0 equiv., 7310 mg). The resulting mixture was stirred at 25 °C for 2 h. The residue was purified by preparative thin layer chromatography 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, 2510 mg, 68.7%) as a solid. LCMS (ESI): m / z [M+H] + = 518.

[0785]

[0786] 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., 2320 mgS) in dichloromethane (8 mL) was added triethylamine (4 mL). The resulting mixture was stirred at 25 °C for 3.5 h. The crude product was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] + = 362.

[0787]

[0788] 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., 2770 mgS) and HATU (158 mg, 1.5 equiv., 415U(15) in acetonitrile (50 mL) was added DIEA (145m, 3.0 equiv., 830A(14). The resulting mixture was stirred at 25 °C for 1 h. Two peaks were detected by LCMS. The residue was purified by preparative thin layer chromatography to give (2 1 R,2 4 R,5 2 S)-5 5 -methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctane-5 3 ,6-dione (30 mg, 870 mg, 32%) as a solid. LCMS (ESI): m / z [M+H]+ = 344; 1 H NMR (400Mhz, chloroform-d) δ 7.21 (td, J = 7.7, 1.8Hz, 1H), 7.11 (dd, J = 7.5, 1.7Hz, 1H), 6.95 (td, J = 7.4, 1.2Hz, 1H), 6.86 (dd, J = 8.0, 1.2Hz, 1H), 5.22 (d, J = 10.6Hz, 1H), 4.96 - 4.93 (m, 1H), 4.40 - 4.37 (m, 1H), 4.33 - 4.29 (m, 2H), 3.71 (s, 1H), 3.38 - 3.34 (m, 1H), 3.12 - 3.07 (m, 1H), 2.59–2.56 (m, 2H), 2.30 - 2.27 (m, 1H), 1.78 - 1.75 (m, 1H), 1.47 (d, J = 6.5Hz, 4H), 1.28 - 1.25 (m, 4H), 0.93 - 0.82 (m, 2H).

[0789]

[0790] To (2 1 R,2 4 R,5 2 S)-5 5 -methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxocane-5 3 ,6-dione (25 mg, 1.0 equivalent, 73, mg alkane and MgSO4 (1.8 mg, 0.2 equivalent, 15,.8 m in dichloromethane (1 mL) solution was added (4-methoxyphenyl)methanamine (12 mg, 1.2 equivalents, 87, mg added and sodium triacetoxyborohydride (31 mg, 2.0 equivalents, 0.15 mmol). The resulting mixture was stirred at 25 °C for 12 hours. The residue was purified by preparative thin layer chromatography to give (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((4-methoxybenzyl)amino)-5 5 -methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxocane-6-one (28 mg, 608 mg, 83%), as a solid. LCMS (ESI): m / z [M+H] + = 465.

[0791]

[0792] Under N2 atmosphere, to (21 S,2 4 S,5 2 R,5 3 S)-5 3 -((4-Methoxybenzyl)amino)-5 5 -methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctan-6-one (28.0 mg, 1.0 eq, 60.30 mg I) and ammonium formate (114 mg, 90.1 m, 30.0 eq, 1.81 mmol) in 2-propanol (1.5 mL) was added dry Pd / C (64.1 mg, 10 wt%, 1.0 eq, 60.3(64.. The resulting mixture was stirred at 85 °C for 2 h. The crude product was used for the next step without further purification. LCMS (ESI): m / z [M+H] + = 345.

[0793]

[0794] At room temperature, to (2 1 S,2 4 S,5 2 R,5 3 S,5 5 R)-5 3 -amino-5 5 -methyl-3,8-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctan-6-one (15 mg, 1.0 eq, 44, mg in dichloromethane (1 mL) was added DIEA (17 mg, 23 EA, 3.0 eq, 0.13 mmol) and methanesulfonic anhydride (15 mg, 2.0 eq, 87, mgm. The resulting mixture was stirred at 20 °C for 1 h. The residue was purified by preparative thin layer chromatography 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-dioxo-5(2,1)-pyrrolidino-1(1,2)-benzoxa-2(1,4)-cyclohexoxacyclooctane-5 3 -yl)methanesulfonamide (3.0 mg, 7.00 mg, 16%), as a solid. LCMS (ESI): m / z [M+H] + = 423. 11H NMR (400 MHz, chloroform-d) δ 7.19 (td, J = 7.7, 1.8 Hz, 1H), 7.10 (dd, J = 7.4, 1.7 Hz, 1H), 6.93 (td, J = 7.4, 1.1 Hz, 1H), 6.80 (dd, J = 8.1, 1.2 Hz, 1H), 5.08 - 5.06 (m, 1H), 4.80 - 4.77 (m, 1H), 4.69 - 4.59 (m, 1H), 4.47 - 4.44 (m, 1H), 4.36 - 4.27 (m, 2H), 4.24 - 4.21 (m, 1H), 3.84 - 3.79 (m, 1H), 3.35 - 3.32 (m, 1H), 3.06 (s, 3H), 2.60 - 2.46 (m, 3H), 2.11 - 2.08 (m, 2H), 1.99 - 1.97 (m, 1H), 1.80 - 1.77 (m, 1H), 1.49 - 1.47 (m, 2H), 1.37 - 1.33 (m, 4H).

[0795] Example 2: Human OX2R IP1 assay

[0796] T-Rex CHO cells stably overexpressing human orexin-2 receptor (OX2R) were induced overnight with 1 μg / mL doxycycline in a T225 flask. Twenty-four hours after induction, the cells were lifted with cell digestion solution and seeded into a 384-well clear bottom plate at 30,000 cells / well. Then, at 37 °C, the cells were treated with different test compounds in 1X stimulation buffer for 1 h. The stimulation buffer contained 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, pH 7.4. After incubation, the reaction was terminated by adding a detection mixture consisting of IP1-d2 and anti-IP1 cryptate diluted in lysis buffer as well as 1X stimulation buffer. The plate was incubated at room temperature for 1 h and then read in a multimode plate reader to measure inositol phosphate levels.

[0797] Cisbio IP1 is a cell-based functional assay that quantitatively measures the accumulation of inositol monophosphate (IP), a metabolite released as a result of activation of the orexin 2 receptor via the phospholipase C-Gq signaling pathway. This is a competitive immunoassay in which IP1 produced by the cells upon receptor activation competes with an IP1 analogue conjugated to a d2 fluorophore (receptor) for binding to an anti-IP1 monoclonal antibody labeled with an Eu cryptate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0798] The EC reported in Table 250 The value was obtained based on the above-mentioned human OX2R Ip1 determination. The data are mean EC 50 values ± obtained. The 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). The 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).

[0799] Table 2

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] ***EC 50 <10nM

[0825] **EC 50 10 - 1000nM

[0826] *EC 50 >1000nM

[0827] ^Racemic mixture

[0828] Example 3: MDCK-MDR1 permeability test

[0829] Using MDCK-MDR1 cells seeded in Solvo PreadyPort TM MDCK 96-well plates, the bidirectional permeability (apical-to-basolateral and basolateral-to-apical directions) of test compounds in MDCK-MDR1 cells was evaluated. After receiving the plates from ReadyCell (Barcelona, Spain), they were processed according to the PreadyPort TM User manual.

[0830] For apical-to-basolateral (A-to-top) permeability, 80 μL of assay buffer of HBSS (Hank's balanced salt solution) co-administered with test compound (3 μM) and LY (lucifer yellow) (100 μM) was added to the donor side (A), while 250 μL of HBSS buffer was added to the acceptor side (B). For basolateral-to-apical (B-to-A) permeability, 255 μL of test compound (3 μM) in HBSS assay buffer was added to the donor side (B), while 75 μL of HBSS buffer containing LY (100 μM) was added to the acceptor side (A).

[0831] Place the plate in an incubator at 37 °C. After preheating for 10 minutes, take a 5 μL aliquot from the donor chamber as the dosing solution for standby. Return the MDCK-MDR1 incubation plate to the incubator and incubate at 37 °C for 2 hours. After 2 hours of incubation, take 25 μL and 5 μL aliquots from the receptor side and the donor side respectively. Dilute the 5 μL aliquot taken from the donor side (before and after 2 hours of incubation) with 20 μL of HBSS buffer. Mix all samples with 150 μL of acetonitrile containing internal standard (IS) and 200 μL of water, and analyze by LC-MS / MS.

[0832] The apparent permeability (P app ) is calculated using the following formula:

[0833] P app = dQ / dt x 1 / A x C0

[0834] Where:

[0835] dQ / dt: The amount of substance transferred during the incubation time (nmol / s).

[0836] A: The area of the insert (PreadyPort TM MDR1-96 is 0.14 cm2)

[0837] C0: The initial concentration of the product applied in the apical (A at the top) or basal (B at the base) compartment (nmol / mL).

[0838] The efflux rate (ER) is measured by dividing P app (from the basal to the apical direction) by Papp (from the apical to the basal direction). It is a general measure of the participation in the active process. Er > 2 is considered active transport.

[0839] The recovery rate is measured using the following formula:

[0840]

[0841] Where:

[0842] V R : The volume of the receptor chamber (mL)

[0843] V D : The volume of the donor chamber (mL)

[0844] C N : The concentration of the dosing solution collected after 10 minutes of incubation (μM)

[0845] C R final : The receptor concentration at the end of incubation (μM)

[0846] C D final : Donor concentration (μM) at the end of incubation

[0847] The data reported in Table 3 were obtained from the MDCK-MDR1 permeability test described above.

[0848] Table 3

[0849]

[0850]

[0851]

[0852] Example 4: Hepatocyte stability determination

[0853] In vitro metabolic stability was evaluated using cryopreserved hepatocytes (BioIVT, Baltimore, MD) from male Sprague Dawley rats and 50 mixed gender humans. In a 48-well plate, a pre-warmed KHB (Krebs-Henseleit buffer) containing 250 μL of hepatocytes at 2 million cells / mL was mixed with a pre-warmed KHB buffer containing 250 μL of the test compound to prepare an incubation mixture with a final concentration of 1 μM of the test compound (0.1% DMSO) and 1.1% 6 of hepatocytes at 2 million cells / mL. The reaction mixture was incubated at 37 °C. At time points (0, 15, 30, 60, 120, and 240 minutes), 50 μL of the incubation mixture was taken and transferred to a 96-well plate containing 300 μL of ice-cold acetonitrile (containing 30 ng / mL of labetalol and 10 ng / mL of naltrexone-d3 as internal standards) and immediately placed on ice to terminate the reaction. The samples were centrifuged and the supernatant was transferred to a 96-well plate for liquid chromatography with tandem mass spectrometry (LC-MS / MS) analysis to monitor the consumption of the test compound.

[0854] Assuming the peak area ratio (analyte / IS) at the zero-minute time point is 100%, the data were calculated as the remaining percentage by dividing the peak area ratio at the remaining time points by the peak area ratio at the zero-minute time point. The data were fitted to a first-order decay model to determine the half-life. From the plot of log(ln) peak area versus time, the slope of the line was determined. Subsequently, the half-life (T 1 / 2 ) and intrinsic clearance (CL int ) were calculated using the following formulas:

[0855] Elimination rate constant (k) = (-slope)

[0856] Half-life (T 1 / 2 ) min = 0.693 / k

[0857] Intrinsic clearance (CL int )(mL / min / million cells) = (V cell rate0) / T 1 / 2

[0858] V = Incubation volume mL / Number of cells

[0859] In vitro T 1 / 2 Converted to in vitro intrinsic clearance (CL int,hep ), in units of mL / min / kg, using the following formula:

[0860]

[0861] In vitro intrinsic clearance (CL int,hep ) and the ratio of in vivo hepatic clearance (C L,hep ) is calculated using the following formula, which is adapted from a well-stirred model.

[0862]

[0863] Where Q is hepatic blood flow and fu is the unbound fraction (assumed to be uniform here). All parameters used in the calculation are shown below (Table 4).

[0864] Table 4: Physiological parameters used in scaling from in vitro to in vivo

[0865]

[0866] Davies B. and Morris T. (1993) Physiological parameters in experimental animals and humans. Pharma Res. 10(7):1093 - 1095.

[0867] The extraction ratio (ER) is calculated by dividing the hepatic clearance of a compound by the hepatic blood flow. The data reported in Table 5 were obtained from the human hepatocyte stability test described above.

[0868] Table 5

[0869]

[0870]

[0871]

[0872] Example 5: Evaluation of the arousal effect in Sprague-Dawley rats

[0873] The arousal of adult male Sprague-Dawley rats was evaluated using electroencephalogram (EEG) and electromyogram (EMG). All rats (Charles River Laboratories, Raleigh, NC, USA) were implanted with a telemetry device (F50-EEE, Data Sciences International Inc., MN, USA) intraperitoneally under isoflurane anesthesia. For EEG, stainless steel screws were implanted on the frontal cortex and parietal cortex, and a reference screw was placed on the cerebellum. In addition, an electrode was placed in the neck muscles for EMG. The rats were given carprofen after surgery and underwent a recovery period of 7 to 10 days. The rats were habituated to the laboratory for 7 days and maintained a 12-hour light-dark cycle.

[0874] EEG and EMG data were recorded using a DSI telemetry system and Ponemah software (Data Sciences International Inc., MN, USA). The sleep-wake stages were scored manually and by Somnivore (a supervised machine learning software platform) in 10-second epochs. Visual inspection of the recordings was performed for post-processing as needed.

[0875] All test compounds were dissolved in 5% DMSO and suspended in 95% saline containing 0.5% methylcellulose and 0.5% Tween. In a crossover design, the rats were dosed at Zeitgeber time 5 (ZT5) during the inactive light phase at a dose of 3.33 ml / kg body weight. Unless otherwise stated, all compounds were administered orally. The recordings for each rat were started immediately after dosing and continued for 6 hours after dosing.

[0876] Two key endpoints included wake time and cortical activation time. Wake time was derived from the sleep-wake stage analysis. Cortical activation time was based on the duration of frontal gamma oscillation activity (30 - 100 Hz), which is a key feature of wakefulness and was elevated relative to the pre-treatment baseline. The mean cortical activation time 6 hours after dosing was calculated relative to vehicle treatment. The results are shown in Table 6 below.

[0877] Table 6

[0878]

[0879]

[0880] PO (oral); SC (subcutaneous); mpk (milligrams / kg)

[0881] While the present invention has been particularly shown and described with reference to its preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. A compound of formula I-A or a pharmaceutically acceptable salt thereof: Wherein: Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; Said triazinyl is selected from n is 1, 2 or 3; E is selected from 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- to 6-membered heterocyclic group, and C1-C3 alkylene-(4- to 6-membered heterocyclic group), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 6-membered heterocyclic group, or C1-C3 alkylene-(4- to 6-membered heterocyclic group) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl, or C1-C3 alkoxy; T is CR1R2; W is CR4R5; U is CR6R7; X is CR8R9; V is CR3; Y is O; Z is (CR 12 R 13 ) m ; Each R is independently selected from halogen, deuterium, hydroxy, 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 each independently is H or an unsubstituted C1-C3 alkyl group; m is 1; R1, R2, R4 and R5 are each independently selected from H, hydroxy, halogen and deuterium; R3 is selected from H, halogen, hydroxy and cyano; R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxy, halogen, and deuterium; Each R 12 and R 13 is H; R 14 、R 15 and R 16 each independently selected from H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens; and Each R 17 and R 18 is H; Provided that one or more of (a)-(e) are present: (a) At least one R is selected from hydroxy, 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- to 6-membered heterocyclic group or C1-C3 alkylene-(4- to 6-membered heterocyclic group), wherein 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- to 6-membered heterocyclic group or C1-C3 alkylene-(4- to 6-membered heterocyclic group) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups; (c) E is C1 alkyl substituted with one or more halogens, hydroxy, C1-C3 alkyl or C1-C3 alkoxy; (d)R 14 、R 15 and R 16 at least one of which is an unsubstituted C1-C3 alkyl or a C1-C3 alkyl substituted by one or more halogens; or (e)At least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group.

2. The compound according to claim 1, wherein the compound of formula I-A or a pharmaceutically acceptable salt thereof is a compound of formula I or a pharmaceutically acceptable salt thereof.

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

4. The compound according to claim 3, wherein E is C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkylene (C3-C8 cycloalkyl) is unsubstituted or substituted with halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy.

5. The compound according to claim 3, wherein E is methyl, and wherein the methyl is unsubstituted or substituted with halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy.

6. The compound according to claim 3, wherein ring A is phenyl or pyridyl.

7. The compound according to claim 6, wherein ring A is phenyl.

8. The compound according to claim 6, wherein ring A is pyridyl.

9. The compound according to claim 2, wherein the compound or a pharmaceutically acceptable salt thereof is selected from 10. A compound of formula II-A or a pharmaceutically acceptable salt thereof: Wherein: Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; Said triazinyl is selected from n is 1, 2 or 3; E is selected from 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- to 6-membered heterocyclic group and C1-C3 alkylene-(4- to 6-membered heterocyclic group), wherein C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 6-membered heterocyclic group or C1-C3 alkylene-(4- to 6-membered heterocyclic group) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups; T is CR1R2; W is CR4R5; U is CR6R7; X is CR8R9; V is CR3; Y is O; Z is (CR 12 R 13 ) m ; Each R is independently selected from halogen, deuterium, hydroxy, 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 each independently is H or an unsubstituted C1-C3 alkyl group; m is 1; R1, R2, R4 and R5 are each independently selected from H, hydroxy, halogen and deuterium; R3 is selected from H, halogen, hydroxy and cyano; R6, R7, R8, R9 and R 11 are each independently selected from H, hydroxy, halogen and deuterium; Each R 12 and R 13 is H; R 14 、R 15 and R 16 are each independently selected from H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 is H; Provided that one or more of (a)-(e) are present: (a) At least one R is selected from hydroxy, 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- to 6-membered heterocyclic group or C1-C3 alkylene-(4- to 6-membered heterocyclic group), wherein 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- to 6-membered heterocyclic group or C1-C3 alkylene-(4- to 6-membered heterocyclic group) is unsubstituted or substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy; (c) E is a C1 alkyl group substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups; (d)R 14 、R 15 and R 16 at least one of which is an unsubstituted C1-C3 alkyl or a C1-C3 alkyl substituted by one or more halogens; or (e)At least one of R1, R2, R4, R5, R6, R7, R8, R9 and R 11 is a hydroxyl group.

11. The compound according to claim 10, wherein the compound of formula II-A or a pharmaceutically acceptable salt thereof is a compound of formula II: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 10 or 11, wherein n is 1 or 2.

13. The compound according to claim 12, wherein E is a C1-C3 alkyl group, a C3-C8 cycloalkyl group or a C1-C3 alkylene-(C3-C8 cycloalkyl) group, wherein the C1-C3 alkyl group, the C3-C8 cycloalkyl group or the C1-C3 alkylene(C3-C8 cycloalkyl) group is unsubstituted or substituted by a halogen, a hydroxyl group, a C1-C3 alkyl group or a C1-C3 alkoxy group.

14. The compound according to claim 12, wherein E is a methyl group, and wherein the methyl group is unsubstituted or substituted by a halogen, a hydroxyl group, a C1-C3 alkyl group or a C1-C3 alkoxy group.

15. The compound according to claim 12, wherein ring A is a phenyl group or a pyridyl group.

16. The compound according to claim 15, wherein ring A is a phenyl group.

17. The compound according to claim 15, wherein ring A is a pyridyl group.

18. The compound according to claim 11, wherein the compound or a pharmaceutically acceptable salt thereof is selected from:

19. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 9, wherein the compound is or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound according to any one of claims 1-24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. Use of the compound according to any one of claims 1-24 or a pharmaceutically acceptable salt thereof, or the composition according to claim 25, in the preparation of a medicament for treating narcolepsy.

27. Use of the compound according to any one of claims 1-24 or a pharmaceutically acceptable salt thereof, or the composition according to claim 25, in the preparation of a medicament for treating cataplexy.

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