SUBSTITUTED FUSED BICYCLIC MACROCYCLIC COMPOUNDS AND RELATED METHODS OF TREATMENT

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

TECHNICAL FIELD

The present invention relates to substituted macrocyclic compounds, particularly, substituted macrocyclic compounds having agonist activity.

BACKGROUND OF THE INVENTION

Orexin is a neuropeptide synthesized and released by a subpopulation of neurons within 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 expressed preferentially in the brain. There are two subtypes (type 1 and type 2) of orexin receptors (Cell, Vol 92, 573-585, 1998). Activation of orexin receptors is known to be important for a variety of central nervous system functions, such as maintenance of wakefulness, energy homeostasis, reward processing and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

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

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, it is considered that these compounds are not satisfactory, for example, in terms of activity, pharmacokinetics, permeability into the brain/central nervous system or safety, and the development of an improved compound having orexin-2 receptor agonist activity is desired.

SUMMARY OF THE INVENTION

The present invention aims to provide fused bicyclic macrocyclic compounds having orexin-2 receptor agonist activity.

Accordingly, in an initial aspect, the present invention provides a compound represented by Formula I-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, orC1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In one embodiment, provided herein are compounds of Formula I-A having the structure of Formula I or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

Also provided herein are compounds having the structure of Formula II-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula II-A having the structure of Formula II or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

Also provided herein are compounds having the structure of Formula III-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula III-A having the structure of Formula III or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

Also provided herein are compounds having the structure of Formula IV-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula IV-A having the structure of Formula IV or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

Also provided herein are compounds having the structure of Formula V-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula V-A having the structure of Formula V or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

Also provided herein are compounds having the structure of Formula VI-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula VI-A having the structure of Formula VI or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds, e.g., the compounds of Formula I-A, I, II-A, II, III-A, III, IV-A, IV, V-A, V, VI-A, or VI, or pharmaceutically acceptable salts thereof, that are useful in the treatment of narcolepsy or cataplexy in a subject.

In a non-limiting aspect, these compounds may modulate the orexin-2 receptor. In a particular embodiment, the compounds provided herein are considered orexin-2 agonists. As such, in one aspect, the compounds provided herein are useful in treatment of narcolepsy in a subject by acting as an agonist of the orexin-2 receptor.

Definitions

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

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

As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used to herein, the term “EC50” refers to the concentration of a compound required to achieve an effect that is 50% of the maximal observed effect of a compound.

The term “agonist,” as used herein, refers to a compound that, when contacted with a target of interest (e.g., the orexin-2 receptor), causes an increase in the magnitude of a certain activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.

The term “treat,” “treated,” “treating,” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises bringing into contact with the orexin-2 receptor an effective amount of a compound of the invention for conditions related to narcolepsy or cataplexy.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject, or individual is human.

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

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

As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C1-6alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

As used herein, the term “alkylene” refers to divalent aliphatic hydrocarbyl groups, for example, having from 1 to 4 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (—CH2CH2CH2—), iso-propylene (—CH2CH(CH3)—), and the like.

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 groups (e.g., C2-C8-alkenyl) include, but are not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

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 groups (e.g., C2-C8-alkynyl) include, but are not limited to, for example, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl and the like.

As used herein, the term “alkoxy,” refers to the group —O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like.

As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is partially or fully saturated having 1, 2 or 3 rings wherein such rings may be fused. The term “fused” means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms. The term “cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π(pi) electrons, where n is an integer.

As used herein, the term “aryl” means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term “aryl” can include C6-C10aryl, C6-C8aryl, or C6aryl (i.e., phenyl).

It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thiophenyl” means 2- or 3-thiophenyl, and so forth.

As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

Compounds of the Invention

Accordingly, in an initial aspect, the present invention provides a compound represented by Formula I-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In one embodiment, provided herein are compounds of Formula I-A having the structure of Formula I or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In one embodiment of Formula (I), n is 1. In another embodiment of Formula (I), n is 2.

In another embodiment of Formula (I), n is 3.

In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (I), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (I), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (I), fused ring A is 6-membered heterocyclyl.

In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (I), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (I), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (I), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (I), Y is NR10. In another embodiment of Formula (I), is O. In another embodiment of Formula (I), Y is absent. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and Y is absent. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

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 CR1R2and W is CR4R5. In another embodiment of Formula (I), T is O and W is CR4R5. In another embodiment of Formula (I), T is CR1R2and W is O.

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

In another embodiment of Formula (I), T is CR1R2and V is CR3. In another embodiment of Formula (I), T is O and V is CR3. In another embodiment of Formula (I), T is CR1R2and V is N. In another embodiment of Formula (I), T is O and V is N.

In another embodiment of Formula (I), W is CR4R5and V is CR3. In another embodiment of Formula (I), W is O and V is CR3. In another embodiment of Formula (I), W is CR4R5and V is N. In another embodiment of Formula (I), W is O and V is N.

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.

In another embodiment of Formula (I), E is H. In another embodiment of Formula (I), E is hydroxyl. In another embodiment of Formula (I), E is NRaRb. In another embodiment of Formula (I), E is C(═O)NRaRb. In another embodiment of Formula (I), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (I), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (I), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (I), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (I), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (I), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (I), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (I), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C6-C10aryl. In another embodiment of Formula (I), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (I), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of Formula (I), E is 5- to 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (I), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (I), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (I), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (I), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 5-membered heterocyclyl. In another embodiment of Formula (I), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (I), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (I), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (I), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (I), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is methyl. In another embodiment of Formula (I), E is trifluoromethyl. In another embodiment of Formula (I), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (I), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (I), R14is H. In another embodiment of Formula (I), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (I), R15and R16are each H. In another embodiment of Formula (I), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (I), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (I), each R17and R18is H. In another embodiment of Formula (I), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (I), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (I), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (I), each of R14, R15, R16, R17and R18is H.

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.

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.

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.

In another embodiment of Formula (I), Y is NR10and m is 1. In another embodiment of Formula (I), Y is NR10and m is 2. In another embodiment of Formula (I), Y is NR10and m is 3. In another embodiment of Formula (I), Y is NR10and m is 4. In another embodiment of Formula (I), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (I), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (I), Y is NR10and m is 1 or 2. In another embodiment of Formula (I), Y is NR10and m is 3 or 4.

In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and n is 2. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is C4-C5cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is C4-C5cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (I), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

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

In another embodiment of Formula (I), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (I), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (I), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (I), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (I), one or more of each R12and R13is fluorine. In another embodiment of Formula (I), one or more of each R12and R13is deuterium.

In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 1. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R14, R15, R16, R17, and R18is H, and m is 1. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R12, R13, R14, R15, R16, R17, and R18is H, and m is 1.

Each of the embodiments described herein with respect to compounds of Formula I also applies to compounds of Formula I-A.

Also provided herein is a compound having the structure of Formula II-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula II-A having the structure of Formula II or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (II), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (II), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 6-membered heterocyclyl. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (II), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (II), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (II), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (II), Y is NR10. In another embodiment of Formula (II), Y is O. In another embodiment of Formula (II), Y is absent. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl and Y is absent. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

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 CR1R2and W is CR4R5. In another embodiment of Formula (II), T is O and W is CR4R5. In another embodiment of Formula (II), T is CR1R2and W is O.

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

In another embodiment of Formula (II), T is CR1R2and V is CR3. In another embodiment of Formula (II), T is O and V is CR3. In another embodiment of Formula (II), T is CR1R2and V is N. In another embodiment of Formula (II), T is O and V is N.

In another embodiment of Formula (II), W is CR4R5and V is CR3. In another embodiment of Formula (II), W is O and V is CR3. In another embodiment of Formula (II), W is CR4R5and V is N. In another embodiment of Formula (II), W is O and V is N.

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.

In another embodiment of Formula (II), E is H. In another embodiment of Formula (II), E is hydroxyl. In another embodiment of Formula (II), E is NRaRb. In another embodiment of Formula (II), E is C(═O)NRaRb. In another embodiment of Formula (II), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (II), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (II), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (II), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (II), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (II), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (II), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (II), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C6-C10aryl. In another embodiment of Formula (II), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (II), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. 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 halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (II), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (II), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (II), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (II), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted 5-membered heterocyclyl.

In another embodiment of Formula (II), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (II), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (II), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (II), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (II), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is methyl. In another embodiment of Formula (II), E is trifluoromethyl. In another embodiment of Formula (II), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (II), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (II), R14is H. In another embodiment of Formula (II), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (II), R15and R16are each H. In another embodiment of Formula (II), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (II), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (II), each R17and R18is H. In another embodiment of Formula (II), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (II), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (II), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (II), each of R14, R15, R16, R17and R18is H.

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

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.

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

In another embodiment of Formula (II), Y is NR10and m is 1. In another embodiment of Formula (II), Y is NR10and m is 2. In another embodiment of Formula (II), Y is NR10and m is 3. In another embodiment of Formula (II), Y is NR10and m is 4. In another embodiment of Formula (II), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (II), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (II), Y is NR10and m is 1 or 2. In another embodiment of Formula (II), Y is NR10and m is 3 or 4.

In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (II), fused ring A is C4-C5cycloalkyl and n is 2. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is C4-C5cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is C4-C5cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (II), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

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

In another embodiment of Formula (II), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (II), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (II), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (II), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (II), one or more of each R12and R13is fluorine. In another embodiment of Formula (II), one or more of each R12and R13is deuterium.

In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 1. In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R14, R15, R16, R17, and R18is H, and m is 1. In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R12, R13, R14, R15, R16, R17, and R18is H, and m is 1.

Each of the embodiments described herein with respect to compounds of Formula II also applies to compounds of Formula II-A.

Also provided herein is a compound having the structure of Formula III-A or a pharmaceutically acceptable salt thereof.

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula III-A having the structure of Formula III or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 1, 2, 3, or 4;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (III), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (III), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 6-membered heterocyclyl. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (III), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (III), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (III), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (III), Y is NR10. In another embodiment of Formula (III), Y is O. In another embodiment of Formula (III), Y is absent. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (III), fused ring A is C4-C5cycloalkyl and Y is O. In another embodiment of Formula (III), fused ring A is C4-C5cycloalkyl and Y is absent. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

In another embodiment of Formula (III), T is CR1R2. In another embodiment of Formula (III), T is O. In another embodiment of Formula (III), W is CR4R5. In another embodiment of Formula (III), W is O. In another embodiment of Formula (III), T is CR1R2and W is CR4R5. In another embodiment of Formula (III), T is O and W is CR4R5. In another embodiment of Formula (III), T is CR1R2and W is O.

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

In another embodiment of Formula (III), T is CR1R2and V is CR3. In another embodiment of Formula (III), T is O and V is CR3. In another embodiment of Formula (III), T is CR1R2and V is N. In another embodiment of Formula (III), T is O and V is N.

In another embodiment of Formula (III), W is CR4R5and V is CR3. In another embodiment of Formula (III), W is O and V is CR3. In another embodiment of Formula (III), W is CR4R5and V is N. In another embodiment of Formula (III), W is O and V is N.

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

In another embodiment of Formula (III), E is H. In another embodiment of Formula (III), E is hydroxyl. In another embodiment of Formula (III), E is NRaRb. In another embodiment of Formula (III), E is C(═O)NRaRb. In another embodiment of Formula (III), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (III), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (III), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (III), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (III), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (III), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (III), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (III), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C6-C10aryl. In another embodiment of Formula (III), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (III), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of Formula (III), E is 5- to 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (III), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (III), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (III), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (III), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 5-membered heterocyclyl. In another embodiment of Formula (III), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (III), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (III), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (III), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (III), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is methyl. In another embodiment of Formula (III), E is trifluoromethyl. In another embodiment of Formula (III), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (III), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (III), R14is H. In another embodiment of Formula (III), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (III), R15and R16are each H. In another embodiment of Formula (III), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (III), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (III), each R17and R18is H. In another embodiment of Formula (III), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (III), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (III), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (III), each of R14, R15, R16, R17and R18is H.

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

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

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

In another embodiment of Formula (III), Y is NR10and m is 1. In another embodiment of Formula (III), Y is NR10and m is 2. In another embodiment of Formula (III), Y is NR10and m is 3. In another embodiment of Formula (III), Y is NR10and m is 4. In another embodiment of Formula (III), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (III), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (III), Y is NR10and m is 1 or 2. In another embodiment of Formula (III), Y is NR10and m is 3 or 4.

In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl and n is 2. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is C4-C8cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (III), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

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

In another embodiment of Formula (III), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (III), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (III), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (III), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (III), one or more of each R12and R13is fluorine. In another embodiment of Formula (III), one or more of each R12and R13is deuterium.

In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 1. In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R14, R15, R16, R17, and R18is H, and m is 1. In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (III), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R11, R12, R13, R14, R15, R16, R17, and R18is H, and m is 1.

Each of the embodiments described herein with respect to compounds of Formula III also applies to compounds of Formula III-A.

Also provided herein is a compound having the structure of Formula IV-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula IV-A having the structure of Formula IV or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (IV), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (IV), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 6-membered heterocyclyl. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (IV), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (IV), Y is NR10. In another embodiment of Formula (IV), Y is O. In another embodiment of Formula (IV), Y is absent. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and Y is absent. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

In another embodiment of Formula (IV), T is CR1R2. In another embodiment of Formula (IV), T is O. In another embodiment of Formula (IV), W is CR4R5. In another embodiment of Formula (IV), W is O. In another embodiment of Formula (IV), T is CR1R2and W is CR4R5. In another embodiment of Formula (IV), T is O and W is CR4R5. In another embodiment of Formula (IV), T is CR1R2and W is O.

In another embodiment of Formula (IV), V is CR3. In another embodiment of Formula (IV), V is N.

In another embodiment of Formula (IV), T is CR1R2and V is CR3. In another embodiment of Formula (IV), T is O and V is CR3. In another embodiment of Formula (IV), T is CR1R2and V is N. In another embodiment of Formula (IV), T is O and V is N.

In another embodiment of Formula (IV), W is CR4R5and V is CR3. In another embodiment of Formula (IV), W is O and V is CR3. In another embodiment of Formula (IV), W is CR4R5and V is N. In another embodiment of Formula (IV), W is O and V is N.

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

In another embodiment of Formula (IV), E is H. In another embodiment of Formula (IV), E is hydroxyl. In another embodiment of Formula (IV), E is NRaRb. In another embodiment of Formula (IV), E is C(═O)NRaRb. In another embodiment of Formula (IV), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (IV), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (IV), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (IV), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (IV), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (IV), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (IV), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (IV), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C6-C10aryl. In another embodiment of Formula (IV), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (IV), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of Formula (IV), E is 5- to 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (IV), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (IV), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (IV), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (IV), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 5-membered heterocyclyl. In another embodiment of Formula (IV), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (IV), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (IV), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (IV), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (IV), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is methyl. In another embodiment of Formula (IV), E is trifluoromethyl. In another embodiment of Formula (IV), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (IV), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (IV), R14is H. In another embodiment of Formula (IV), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (IV), R15and R16are each H. In another embodiment of Formula (IV), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (IV), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (IV), each R17and R18is H. In another embodiment of Formula (IV), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (IV), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (IV), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (IV), each of R14, R15, R16, R17and R18is H.

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

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

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

In another embodiment of Formula (IV), Y is NR10and m is 1. In another embodiment of Formula (IV), Y is NR10and m is 2. In another embodiment of Formula (IV), Y is NR10and m is 3. In another embodiment of Formula (IV), Y is NR10and m is 4. In another embodiment of Formula (IV), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (IV), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (IV), Y is NR10and m is 1 or 2. In another embodiment of Formula (IV), Y is NR10and m is 3 or 4.

In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and n is 2. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 4-to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is 4-to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (IV), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, Y is NR10, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, Y is NR10, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, Y is NR10, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C5cycloalkyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C5cycloalkyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, Y is absent, and m is 2 or 3. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, Y is NR10, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, Y is NR10, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C5cycloalkyl, n is 3, Y is NR10, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of Formula (IV), fused ring A is C4-C8cycloalkyl, n is 3, Y is absent, and m is 3 or 4.

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

In another embodiment of Formula (IV), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (IV), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (IV), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (IV), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (IV), one or more of each R12and R13is fluorine. In another embodiment of Formula (IV), one or more of each R12and R13is deuterium.

In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 2. In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R14, R15, R16, R17, and R18is H, and m is 2. In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (IV), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R11, R12, R13, R14, R15, R16, R17, and R18is H, and m is 2.

Each of the embodiments described herein with respect to compounds of Formula IV also applies to compounds of Formula IV-A.

Also provided herein is a compound having the structure of Formula V-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula V-A having the structure of Formula V or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (V), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (V), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 6-membered heterocyclyl. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (V), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (V), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (V), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (V), Y is NR10. In another embodiment of Formula (V), Y is O. In another embodiment of Formula (V), Y is absent. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and Y is absent. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

In another embodiment of Formula (V), T is CR1R2. In another embodiment of Formula (V), T is O. In another embodiment of Formula (V), W is CR4R5. In another embodiment of Formula (V), W is O. In another embodiment of Formula (V), T is CR1R2and W is CR4R5. In another embodiment of Formula (V), T is O and W is CR4R5. In another embodiment of Formula (V), T is CR1R2and W is O.

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

In another embodiment of Formula (V), T is CR1R2and V is CR3. In another embodiment of Formula (V), T is O and V is CR3. In another embodiment of Formula (V), T is CR1R2and V is N. In another embodiment of Formula (V), T is O and V is N.

In another embodiment of Formula (V), W is CR4R5and V is CR3. In another embodiment of Formula (V), W is O and V is CR3. In another embodiment of Formula (V), W is CR4R5and V is N. In another embodiment of Formula (V), W is O and V is N.

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

In another embodiment of Formula (V), E is H. In another embodiment of Formula (V), E is hydroxyl. In another embodiment of Formula (V), E is NRaRb. In another embodiment of Formula (V), E is C(═O)NRaRb. In another embodiment of Formula (V), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (V), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (V), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (V), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (V), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (V), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (V), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (V), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C6-C10aryl. In another embodiment of Formula (V), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (V), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of Formula (V), E is 5- to 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (V), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (V), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (V), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (V), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 5-membered heterocyclyl. In another embodiment of Formula (V), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (V), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (V), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (V), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (V), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is methyl. In another embodiment of Formula (V), E is trifluoromethyl. In another embodiment of Formula (V), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (V), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (V), R14is H. In another embodiment of Formula (V), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (V), R15and R16are each H. In another embodiment of Formula (V), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (V), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (V), each R17and R18is H. In another embodiment of Formula (V), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (V), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (V), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (V), each of R14, R15, R16, R17and R18is H.

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

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

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

In another embodiment of Formula (V), Y is NR10and m is 1. In another embodiment of Formula (V), Y is NR10and m is 2. In another embodiment of Formula (V), Y is NR10and m is 3. In another embodiment of Formula (V), Y is NR10and m is 4. In another embodiment of Formula (V), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (V), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (V), Y is NR10and m is 1 or 2. In another embodiment of Formula (V), Y is NR10and m is 3 or 4.

In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and n is 2. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is C4-C5cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is C4-C5cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (V), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of Formula (V), T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4. In another embodiment of Formula (V), R1, R2, R4, and R5are each H. In another embodiment of Formula (V), R1, R2, R4, and R5are each H; and R3is H. In another embodiment of Formula (V), R1, R2, R4, and R5are each H; R3is H; and R6, R7, R8, R9, and R11are each H. In another embodiment of Formula (V), R1, R2, R4, and R5are each H; R3is H; R6, R7, R8, R9, and R11are each H; and R12and R13are each H.

In another embodiment of Formula (V), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (V), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (V), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (V), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (V), one or more of each R12and R13is fluorine. In another embodiment of Formula (V), one or more of each R12and R13is deuterium.

In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 2. In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R14, R15, R16, R17, and R18is H, and m is 2. In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R1, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (V), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R12, R13, R14, R15, R16, R17, and R18is H, and m is 2.

Each of the embodiments described herein with respect to compounds of Formula V also applies to compounds of Formula V-A.

Also provided herein is a compound having the structure of Formula VI-A or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

In another embodiment, provided herein are compounds of Formula VI-A having the structure of Formula VI or a pharmaceutically acceptable salt thereof:

wherein:fused ring A is a C4-C8cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3alkoxyl, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium;is a single bond or double bond;J and L are each, independently, C or N;M is N or CR19;Q is N or CR20;G is C(═O) or S(═O)2;n is 1, 2, or 3;E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, and C1-C3alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3alkylene-NRaRb, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3alkylene-(4- to 10-membered heterocyclyl), C6-C10aryl, C1-C3alkylene-(C6-C10aryl), 5- to 10-membered heteroaryl, or C1-C3alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl;T is CR1R2or O;W is CR4R5or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CR12R13)m;Raand Rbare each, independently, H or unsubstituted C1-C3alkyl;m is 2, 3, 4, or 5 when Y is absent; orm is 1, 2, 3, or 4 when Y is NR10or O;
and further wherein:R1, R2, R4, and R5are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;or, alternatively, R2and R5together with the carbon atoms to which they are attached, form a single bond;R3is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R3and R1, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;or, alternatively, R3and R4, together with the carbon atoms to which they are attached, form a C3-C5cycloalkyl;R6, R7, R8, R9, and R11are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;R10is selected from the group consisting of H, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen;each R12and R13is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with hydroxyl or one or more halogen; andR14, R15, and R16are each, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen;each R17and R18is, independently, selected from the group consisting of H, unsubstituted C1-C3alkyl or C1-C3alkyl substituted with one or more halogen; andR19and R20are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3alkyl, and C1-C3alkyl substituted with one or more halogen or deuterium.

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

In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl. In another embodiment of Formula (VI), fused ring A is C4-C6cycloalkyl. In another embodiment of Formula (VI), fused ring A is C4-C5cycloalkyl. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5- to 6-membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5-membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 6-membered heterocyclyl. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 5- to 6-membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 5-membered heteroaryl. In another embodiment of Formula (VI), fused ring A is 6-membered heteroaryl.

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

In another embodiment of Formula (VI), Y is NR10. In another embodiment of Formula (VI), Y is O. In another embodiment of Formula (VI), Y is absent. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and Y is NR10. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and Y is O. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and Y is absent. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and Y is NR10. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and Y is absent. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and Y is NR10. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and Y is O. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and Y is absent.

In another embodiment of Formula (VI), T is CR1R2. In another embodiment of Formula (VI), T is O. In another embodiment of Formula (VI), W is CR4R5. In another embodiment of Formula (VI), W is O. In another embodiment of Formula (VI), T is CR1R2and W is CR4R5. In another embodiment of Formula (VI), T is O and W is CR4R5. In another embodiment of Formula (VI), T is CR1R2and W is O.

In another embodiment of Formula (VI), V is CR3. In another embodiment of Formula (VI), V is N.

In another embodiment of Formula (VI), T is CR1R2and V is CR3. In another embodiment of Formula (VI), T is O and V is CR3. In another embodiment of Formula (VI), T is CR1R2and V is N. In another embodiment of Formula (VI), T is O and V is N.

In another embodiment of Formula (VI), W is CR4R5and V is CR3. In another embodiment of Formula (VI), W is O and V is CR3. In another embodiment of Formula (VI), W is CR4R5and V is N. In another embodiment of Formula (VI), W is O and V is N.

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

In another embodiment of Formula (VI), E is H. In another embodiment of Formula (VI), E is hydroxyl. In another embodiment of Formula (VI), E is NRaRb. In another embodiment of Formula (VI), E is C(═O)NRaRb. In another embodiment of Formula (VI), E is C1-C3alkylene-NRaRb. In another embodiment of Formula (VI), E is unsubstituted C1-C3alkyl, unsubstituted C2-C4alkenyl or unsubstituted C2-C4alkynyl. In another embodiment of Formula (VI), E is C1-C3alkyl, C2-C4alkenyl or C2-C4alkynyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3alkyl. In another embodiment of Formula (VI), E is C1-C3alkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C3-C8cycloalkyl. In another embodiment of Formula (VI), E is C3-C8cycloalkyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3alkylene-(C3-C8cycloalkyl). In another embodiment of Formula (VI), E is C1-C3alkylene-(C3-C8cycloalkyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of Formula (VI), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3alkylene-(4- to 10-membered heterocyclyl). In another embodiment of Formula (VI), E is C1-C3alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C6-C10aryl. In another embodiment of Formula (VI), E is C6-C10aryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted C1-C3alkylene-(C6-C10aryl). In another embodiment of Formula (VI), E is C1-C3alkylene-(C6-C10aryl) substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 5- to 10-membered heteroaryl. In another embodiment of Formula (VI), E is 5- to 10-membered heteroaryl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), E is unsubstituted 4- to 7-membered heterocyclyl. In another embodiment of Formula (VI), E is 4- to 7-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 4- to 6-membered heterocyclyl. In another embodiment of Formula (VI), E is 4- to 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 4-membered heterocyclyl. In another embodiment of Formula (VI), E is 4-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 5-membered heterocyclyl.

In another embodiment of Formula (VI), E is 5-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is unsubstituted 6-membered heterocyclyl. In another embodiment of Formula (VI), E is 6-membered heterocyclyl substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), E is C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, C1-C3alkylene-(C3-C8cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), E is C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl), wherein the C1-C3alkyl, C3-C8cycloalkyl, or C1-C3alkylene-(C3-C8cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), E is methyl, wherein the methyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is methyl. In another embodiment of Formula (VI), E is trifluoromethyl. In another embodiment of Formula (VI), E is dioxanyl, wherein the dioxanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is tetrahydropyranyl, wherein the tetrahydropyranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is tetrahydrofuranyl, wherein the tetrahydrofuranyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), E is azetidinyl, wherein the azetidinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is oxetanyl, wherein the oxetanyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl. In another embodiment of Formula (VI), E is morpholinyl, wherein the morpholinyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3alkyl, or C1-C3alkoxyl.

In another embodiment of Formula (VI), R14is H. In another embodiment of Formula (VI), R14is unsubstituted C1-C3alkyl. In another embodiment of Formula (VI), R15and R16are each H. In another embodiment of Formula (VI), R15is unsubstituted C1-C3alkyl and R16is H. In another embodiment of Formula (VI), R16is unsubstituted C1-C3alkyl and R15is H. In another embodiment of Formula (VI), each R17and R18is H. In another embodiment of Formula (VI), R17is unsubstituted C1-C3alkyl and R18is H. In another embodiment of Formula (VI), R18is unsubstituted C1-C3alkyl and R17is H. In another embodiment of Formula (VI), one of R14, R15, R16, R17and R18is unsubstituted C1-C3alkyl and the others are each H. In another embodiment of Formula (VI), each of R14, R15, R16, R17and R18is H.

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

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

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

In another embodiment of Formula (VI), Y is NR10and m is 1. In another embodiment of Formula (VI), Y is NR10and m is 2. In another embodiment of Formula (VI), Y is NR10and m is 3. In another embodiment of Formula (VI), Y is NR10and m is 4. In another embodiment of Formula (VI), Y is NR10and m is 1, 2, or 3. In another embodiment of Formula (VI), Y is NR10and m is 2, 3, or 4. In another embodiment of Formula (VI), Y is NR10and m is 1 or 2. In another embodiment of Formula (VI), Y is NR10and m is 3 or 4.

In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and n is 1. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and n is 2. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl and n is 3. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and n is 1. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and n is 2. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl and n is 3. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and n is 1. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and n is 2. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl and n is 3.

In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 1, and Y is NR10. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 2, and Y is NR10. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 3, and Y is NR10. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is C4-C5cycloalkyl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is C4-C8cycloalkyl, n is 3, and Y is absent.

In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 4-to 7-membered heterocyclyl, n is 3, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is 4- to 7-membered heterocyclyl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is 4-to 7-membered heterocyclyl, n is 3, and Y is absent.

In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is NR10. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is O. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is O. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is O. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 1, and Y is absent. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 2, and Y is absent. In another embodiment of Formula (VI), fused ring A is 5- to 8-membered heteroaryl, n is 3, and Y is absent.

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

In another embodiment of Formula (VI), one or more of R1, R2, R4, and R5is fluorine. In another embodiment of Formula (VI), one or more of R1, R2, R4, and R5is deuterium. In another embodiment of Formula (VI), one or more of R6, R7, R8, R9, and R11is fluorine. In another embodiment of Formula (VI), one or more of R6, R7, R8, R9, and R11is deuterium. In another embodiment of Formula (VI), one or more of each R12and R13is fluorine. In another embodiment of Formula (VI), one or more of each R12and R13is deuterium.

In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R11is H. In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, R11is H, and m is 2. In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R11, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R11, R14, R15, R16, R17, and R18is H, and m is 2. In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, and each of R11, R12, R13, R14, R15, R16, R17, and R18is H. In another embodiment of Formula (VI), Y is O, T is CR1R2, V is CR3, W is CR4R5, each of R1, R12, R13, R14, R15, R16, R17, and R18is H, and m is 2.

Each of the embodiments described herein with respect to compounds of Formula VI also applies to compounds of Formula VI-A.

Certain embodiments of compounds of Formula I-A, I, II-A, II, III-A, III, IV-A, IV, V-A, V, VI-A, or VI, or pharmaceutically acceptable salts thereof, are shown below in Table 1. Compounds of Formula I-A, I, II-A, II, III-A, III, IV-A, IV, V-A, V, VI-A, or VI, or pharmaceutically acceptable salts thereof, and compounds of Table 1, or pharmaceutically acceptable salts thereof, collectively or individually are sometimes referred to herein as “compounds of the invention” or “compounds provided herein”.

The disclosed compounds possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with 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 utilized as the disclosed compound described herein. In another embodiment, a pure isomer is utilized as the disclosed compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In one embodiment, isotopically-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In another embodiment, the compounds described herein include a2H (i.e., deuterium) isotope.

In yet another embodiment, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein.

Methods of Treatment

The compounds of the invention can be used in a method of treating a disease or condition in a subject, said method comprising administering to the subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention. In one embodiment of the methods described herein, the subject is human. In one aspect, the compounds provided herein are useful in treatment of a disease or condition by acting as an agonist of the orexin-2 receptor.

The compounds of the invention can be used to treat a disease or condition selected from the group consisting of narcolepsy, cataplexy, or hypersomnia in a subject in need thereof.

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

Particularly, the compound of the present invention is useful as a therapeutic or prophylactic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnolence syndrome characterized by hypersomnia (e.g., in Parkinson's disease, Guillain-Barre syndrome or Kleine Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, and the like, or anesthetic antagonist.

In one embodiment, the compound of the present invention has orexin-2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for narcolepsy.

In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy type-1. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy type-2. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for idiopathic hypersomnia. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for obstructive sleep apnea.

In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for hypersomnia in Parkinson's disease.

In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for hypersomnia. In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness associated with Parkinson's disease.

In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity, and is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness or fatigue associated with cancer and/or chemotherapy.

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

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

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

In another embodiment, the present invention provides a method of 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, II, III-A, III, IV-A, IV, V-A, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of 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, II, III-A, III, IV-A, IV, V-A, V, VI-A, or VI, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

Each of the embodiments described herein with respect to the use of compounds of Formula I also applies to compounds of Formula I-A. Each of the embodiments described herein with respect to the use of compounds of Formula II also applies to compounds of Formula II-A. Each of the embodiments described herein with respect to the use of compounds of Formula III also applies to compounds of Formula III-A. Each of the embodiments described herein with respect to the use of compounds of Formula IV also applies to compounds of Formula IV-A. Each of the embodiments described herein with respect to the use of compounds of Formula V also applies to compounds of Formula V-A. Each of the embodiments described herein with respect to the use of compounds of Formula VI also applies to compounds of Formula VI-A.

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

Administration Dosage Formulations

In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of the invention, together with a pharmaceutically acceptable carrier.

In particular, the selected dosage level will depend upon a variety of 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.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

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

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

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

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

EXAMPLES

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

General Procedures

Example 1: Synthesis Procedures

Synthesis procedures for preparation of the compounds of the invention are readily available to the ordinary skilled artisan. Unless otherwise indicated, starting materials were generally obtained from commercial sources. Synthetic procedures for other macrocyclic compounds can be found, for example, in U.S. application Ser. No. 17/104,993 and in PCT Application No.: PCT/US20/62320, both filed Nov. 25, 2020, in U.S. Provisional Application No. 63/128,404, filed Dec. 21, 2020, and in U.S. Provisional Application No. 63/179,616, filed Apr. 26, 2021; all of which are expressly incorporated by reference herein.

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

To a stirred solution of tert-butyl N-[2-([1,4-dioxaspiro[4.5]decan-8-yloxy]methyl)pyridin-3-yl]carbamate (620.0 g, 1.0 equiv., 1.7 mmol) in methanol (6.0 L) and acetic acid (600 mL) was added Pt2(77.26 g, 0.20 equiv., 340.2 mmol). The mixture was hydrogenated under 20 atm of hydrogen at room temperature. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum 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.

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

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 THE (300 mL) was added KHMDS (78.2 mL, 1.2 equiv., 78.2 mmol) at −78 degrees C. under nitrogen atmosphere. The resulting mixture was stirred for 3 hr at −78 degrees C. and followed by addition of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (27.9 g, 1.2 equiv., 78.2 mmol) in THE (100 mL) dropwise at −78 degrees C. The resulting mixture was stirred for 2 hr at −78 degrees C. The mixture was added dropwise to 200 mL of sat. NH4Cl (aq.) at 0 degrees C. The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-([[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]oxy]methyl)piperidine-1-carboxylate (41.0 g, crude) as an oil.

To the solution of ethyl 2-((5-bromo-1H-indazol-6-yl)oxy)acetate (8.00 g, 1.0 equiv., 26.7 mmol) in DCM (200 mL) was added chloromethyl 2-trimethylsilylethyl ether (6.69 g, 1.5 equiv., 40.1 mmol) and K3PO4(17.0 g, 3.0 equiv., 80.2 mmol) at room temperature. The mixture solution was stirred for 4 hr at 25 degrees C. The resulting solution was filtered and concentrated under reduced pressure. The residue was purified by reverse flash chromatography to provide ethyl 2-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (8.9 g, 77%) as a solid. LCMS (ESI): m/z [M+H]+=431.

To a solution of benzyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(((4-(6-(2-ethoxy-2-oxoethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)cyclohex-3-en-1-yl)oxy)methyl)piperidine-1-carboxylate (2.06 g, 1.0 equiv., 2.60 mmol) in i-PrOH (20 mL) was added Pd/C (387 mg, 1.4 equiv., 3.64 mmol) at nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 2 hr under hydrogen atmosphere using a hydrogen balloon. The reaction solution was filtered through a Celite pad and concentrated under reduced pressure to afford ethyl 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (1.65 g, 96.4%) as an oil.

To a solution of ethyl 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (1.55 g, 1.0 equiv., 2.35 mmol) in MeOH (28 mL) was added LiOH (169 mg, 3.0 equiv., 7.06 mmol) in H2O (14 mL). The resulting mixture was stirred for 1 hr at 25 degrees C. The mixture was basified to pH=7 with aq. 1 M HCl solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to provide 2-((5-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetic acid (1.4 g, 94.0%) as a solid. LCMS (ESI): m/z [M+H]+=631.

To a stirred solution of tert-butyl tert-butyl ((21S, 24S, 52R, 53S)-6-oxo-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-piperidina-2 (1,4)-cyclohexanacyclooctaphane-53-yl)carbamate (690 mg, 1.0 equiv., 1.12 mmol) in DCM (8 mL) was added trifluoroacetic acid (2 mL) at room temperature. The mixture solution was stirred for 1 hr at room temperature. The reaction was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were washed with brine (3*20 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by reverse flash chromatography to afford (21S, 24S, 52R, 53S)-53-amino-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-piperidina-2 (1,4)-cyclohexanacyclooctaphan-6-one (300 mg, 51.9%) as a solid. LCMS (ESI): m/z [M+H]+=515.

To a solution of (21S, 24S, 52R, 53S)-53-amino-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-piperidina-2 (1,4)-cyclohexanacyclooctaphan-6-one (300 mg, eq uiv., 583 μmol) in DCM (12 mL) was added TEA (177 mg, 244 μL, 3.0 equiv., 1.75 mmol). The resulting mixture was stirred for 10 min at 0 degrees C. Then to the mixture was added Ms2O (122 mg, 1.2 equiv., 699 μmol). The resulting mixture was stirred for 30 min at 25 d egrees C. The mixture was quenched with saturated NaHCO3solution. The resulting mixture was diluted with H2O (10 mL) and extracted with DCM (3*10 mL), ethyl acetate (10 m L). The combined organic layers were concentrated under reduced pressure. The crude was purified by reverse flash chromatography to afford N-((21S, 24S, 52R, 53S)-6-oxo-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-piperidina-2 (1,4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide (300 mg, 86.8%) as a solid. LCMS (ESI): m/z [M+H]+=593.

To a solution of benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (10.4 g, 1.0 equiv., 19.0 mmol) and ethyl 2-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (8.97 g, 1.1 equiv., 20.9 mmol) in 1,4-dioxane (120 mL) and H2O (30.0 mL) were added Na2CO3(6.04 g, 3.0 equiv., 57.0 mmol) and Pd(dppf)Cl2(2.78 g, 0.2 equiv., 3.80 mmol) under nitrogen atmosphere, the resulting mixture was stirred for 2 hr at 80 degrees C. The reaction solution was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic phase was washed with saturated aqueous NaCl (1×100 mL). The resulting organic phase was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(6-(2-ethoxy-2-oxoethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)cyclohex-3-en-1-yl)oxy)methyl)cyclopentane-1-carboxylate (12.0 g, 82.2%) as an oil. LCMS (ESI): m/z [M+H]+=771.

To a solution of benzyl (2S,3R)-3-(benzyloxy)-2-(((4-(6-(2-ethoxy-2-oxoethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)cyclohex-3-en-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (12.0 g, 1.0 equiv., 15.6 mmol) in i-PrOH (300 mL) was added Pd/C (3.32 g, 10% Wt, 0.2 equiv., 3.11 mmol) at nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 2 hr under hydrogen atmosphere using a hydrogen balloon. The resulting solution was filtered through Celite pad; the filter cake was washed with MeOH (3×10 mL).

The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford ethyl 2-((5-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (8.00 g, 80.7%) as an oil. LCMS (ESI): m/z [M+H]+=637.

To the solution of ethyl 2-((5-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetate (8.00 g, 1.0 equiv., 12.6 mmol) in MeOH (150 mL) was added the solution of lithium hydroxide (904 mg, 3.0 equiv., 37.7 mmol) in H2O (75.0 mL) at room temperature. The mixture solution was stirred for 1 hr at 25 degrees C. The mixture was basified to pH=7 with aq. 1M HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to provide 2-((5-(4-(((2S,3R)-3-(benzyloxy)pyrrolidin-2-yl)methoxy)cyclohex-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)oxy)acetic acid (5.30 g, 69.3%) as a solid. LCMS (ESI): m/z [M+H]+=608.

To a solution of (52S, 53R, E)-53-(benzyloxy)-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-pyrrolidina-2 (1,4)-cyclohexanacyclooctaphan-21-en-6-one (2.60 g, 1.0 equiv., 5.20 mmol) in MeOH (300 mL) was added Pd/C (1.11 g, 10% Wt, 0.2 equiv., 1.04 mmol) at nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 3 hr under hydrogen atmosphere using a hydrogen balloon. The resulting solution was filtered through a Celite pad; the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford (21R, 24R, 52S, 53R)-53-hydroxy-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-pyrrolidina-2 (1,4)-cyclohexanacyclooctaphan-6-one (1.98 g, 3.95 mmol, 75.8%) as an oil. LCMS (ESI): m/z [M+H]+=502.

To a solution of (21S, 24S, 52R, 53S)-53-azido-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-pyrrolidina-2 (1,4)-cyclohexanacyclooctaphan-6-one (1.30 g, 1.0 equiv., 2.47 mmol) in MeOH (400 mL) was added Pd/C (525 mg, 10% Wt, 0.2 equiv., 494 μmol) at nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 1 hr under hydrogen atmosphere using a hydrogen balloon. The resulting solution was filtered through a Celite pad, the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The crude was purified by reverse flash chromatography to afford (21S, 24S, 52R, 53S)-53-amino-11-((2-(trimethylsilyl)ethoxy)methyl)-11H-3,8-dioxa-1 (5,6)-indazola-5 (2,1)-pyrrolidina-2 (1,4)-cyclohexanacyclooctaphan-6-one (1.00 g, 80.9%) as an oil. LCMS (ESI): m/z [M+H]+=501.

T-Rex CHO cells stably overexpressing the human orexin-2 receptor (OX2R) were induced overnight with 1 μg/mL of doxycycline in a T225 flask. 24 hours post induction, cells were lifted with accutase and plated into a 384-well proxy plate at 30,000 cells/well. Cells were then treated with different test compounds in 1× stimulation buffer containing 10 mM Hepes, 1 mM CaCl2), 0.5 mM MgCl2, 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl, pH 7.4, for 1 hr at 37 degrees C. Following incubation, the reaction was terminated by the addition of detection mix, which is composed of IP1-d2 and anti-IP1-cryptate diluted in lysis buffer as well as 1× stimulation buffer. The plates were allowed to incubate for 1 hour at room temperature and were then read in the EnVision® multimode plate reader, measuring inositol phosphate levels.

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

The EC50values reported in Table 2 were obtained according to the human OX2R IP1 assay described above. Data are the mean EC50values ±S.E.M.