Pharmacological correctors of rhodopsin and uses thereof

Abstract

Described herein are pharmacologic correctors of rhodopsin, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in treating disease.

Description

PHARMACOLOGICAL CORRECTORS OF RHODOPSIN AND USES THEREOF CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No.63 / 597,275 filed on November 8, 2023 and U.S. Provisional Patent Application No.63 / 712,969 filed on October 28, 2024, each of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] Autosomal dominant retinitis pigmentosa (adRP) is a progressive blindness disease with over 10,000 patients in the U.S. and Europe alone. Misfolding mutations of Rhodopsin constitute the most common cause of adRP. There is currently no approved pharmacologic treatment for rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP). Therefore, an approved RHO-adRP therapy would address an important unmet medical need. SUMMARY OF THE INVENTION

[0003] In one aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups;each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0004] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):Formula (Ia).

[0005] In another aspect, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y1, Y2, and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; or two R2groups on different carbon atoms are taken together to form a bridge that is -CH2CH2-; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 1, 2, 3, or 4.

[0006] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa):Formula (IIa).

[0007] In another aspect, described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III); wherein: X, Y and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromhalogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0008] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):Formula (IIIa).

[0009] In another aspect, described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromhalogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0010] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):Formula (IVa).

[0011] In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodimentsis a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OH, -OCH3, -CH3, and -CF3. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (I), (Ia), (II), (IIa),(II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0012] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0013] In another aspect, described herein is a method of treating autosomal dominant retinitis pigmentosa (adRP) in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof.

[0014] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled inthe field to provide stable moieties and compounds.

[0015] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0016] Autosomal dominant retinitis pigmentosa (adRP) is a progressive blindness disease with no standard of care or approved therapies. Misfolding mutations of Rhodopsin (RHO) constitute the most common cause of adRP. Mutations have toxic gain-of-function effects and most frequently result in RHO misfolding and mistrafficking. Misfolded RHO accumulationcauses cellular stress, which leads to death of photoreceptor cells (rods) and ultimately loss of central vision (cones).

[0017] Described herein are small molecule correctors which prevent or mitigate RHO misfolding, directly addressing the underlying mechanism of disease to restore Rhodopsin trafficking. Properly folded RHO is trafficked to the rod outer segment preventing photoreceptor cell death and preserving vision. Certain Terminology

[0018] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are fororganizational purposes only and are not to be construed as limiting the subject matter described.

[0019] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0020] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1- C6alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0021] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0022] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0023] The term “alkenyl” refers to a type of alkyl group in which at least one carbon -carbondouble bond is present. In one embodiment, an alkenyl group has the f ormula –C(R)=CR2,wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non- limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and –CH2CH=CH2.

[0024] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3- C≡CCH2CH3, -CH2C≡CH.

[0025] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0026] The term “alkylamine” refers to the –N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0027] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0028] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0029] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending onthe structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0030] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non -aromaticradical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohepty l, cyclooctyl,spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl(i.e., bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7 -dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0031] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0032] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

[0033] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0034] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

[0035] The term “heteroalkylene” refers to a divalent heteroalkyl radical.

[0036] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the provisothat any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 5- azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 8- azabicyclo[3.2.1]octanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoinggroups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0037] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

[0038] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin -2-onyl,pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2- onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0039] The term “oxo” refers to the =O radical.

[0040] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0041] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0042] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independentlyselected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, - CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and - S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0043] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0044] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0045] The term “modulator” as used herein, refers to a molecule that interacts with a targeteither directly or indirectly. The interactions include, but are not limited to, the interactions of acorrector, an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is a corrector.

[0046] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0047] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0048] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0049] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0050] The terms “kit” and “article of manufacture” are used as synonyms.

[0051] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0052] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptoms of the disease orcondition either prophylactically and / or therapeutically. Compounds

[0053] Compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are small molecule correctors of rhodopsin.

[0054] In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein, Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0055] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1, Y2, and Y3are each C(R3). In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1and Y3are C(R3) and Y2is N. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein Y1and Y2are C(R3) and Y3is N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2and Y3are C(R3) and Y1is N.

[0056] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0057] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In someembodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0058] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0059] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0060] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0061] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, - OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0062] In some embodiments, described herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:Formula (Ia); wherein, Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4);R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromhalogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0063] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0064] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0065] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0066] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl,and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0067] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0068] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, - OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compoundof Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 isindependently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In someembodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0069] In some embodiments, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein, Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y1, Y2, and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; or two R2groups on different carbon atoms are taken together to form a bridge that is -CH2CH2-; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 1, 2, 3, or 4.

[0070] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1, Y2, and Y3are each C(R3). In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1and Y3are C(R3) and Y2is N. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein Y1and Y2are C(R3) and Y3is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2and Y3are C(R3) and Y1is N.

[0071] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0072] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0073] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.

[0074] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is-CF3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0075] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solv atethereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0076] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, - OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0077] In some embodiments, described herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIa); wherein, Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl,wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; or two R2groups on different carbon atoms are taken together to form a bridge that is -CH2CH2-; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 1, 2, 3, or 4.

[0078] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0079] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is - CH2OH. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. Insome embodiments is a compound of Formula (IIa), or a pharmaceutically acceptab le salt orsolvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0080] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.

[0081] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. Insome embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0082] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0083] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0084] In some embodiments, described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III); wherein, X, Y and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0085] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X, Y, and Z are each C(R3). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X and Z are C(R3) and Y is N. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X and Y are C(R3) and Z is N. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N and Y and Z are C(R3). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X and Y are N and Z is C(R3).

[0086] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0087] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. Insome embodiments is a compound of Formula (III), or a pharmaceutically accep table salt orsolvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In someembodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0088] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0089] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof , wherein R1 is -OR10,wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OH, -OCH3, -CH3, and -CF3.

[0090] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0091] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, - OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0092] In some embodiments, described herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIa); wherein, Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups;each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0093] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0094] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is - CH2OH. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is - CH2CH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0095] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0096] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0097] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In someembodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0098] In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0099] In some embodiments, described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV); wherein, Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0100] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein J is S. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein J is O.

[0101] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In someembodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

[0102] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0103] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein n is 4. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0104] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OH, -OCH3, -CH3, and -CF3.

[0105] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0106] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, - OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0107] In some embodiments, described herein is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:Formula (IVa); wherein, Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups;R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionallysubstituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0108] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selectedfrom hydrogen, halogen, and -CH3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

[0109] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is - CH2OH. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstitutedC1-6alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0110] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0111] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen C1-6alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments isa compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0112] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0113] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0114] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0115] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:, ,,,

[0116] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

[0117] In some embodiments, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0118] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0119] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosageforms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0120] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0121] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0122] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt."

[0123] In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine,dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0124] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0125] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0126] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0127] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example,increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.

[0128] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0129] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0130] A tautomer refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. The compounds presented herein include all tautomeric forms as well as the appropriate mixtures thereof. Synthesis of Compounds

[0131] Compounds described herein are synthesized using standard synthetic techniques orusing methods known in the art in combination with methods described herein.

[0132] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC,protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0133] Compounds are prepared using standard organic chemistry techniques such as thosedescribed in, for example, March’s Advanced Organic Chemistry, 6 th Edition, John Wiley andSons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0134] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to artic les that describe thepreparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc.Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons,New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, StartingMaterials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0135] In some embodiments, compounds are prepared as described in the Examples. Methods of Treatment

[0136] In some embodiments, described herein is a method of treating retinal degeneration in a subject in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments is a method of treating autosomal dominant retinitis pigmentosa (adRP) in a subject in need thereof comprising administering to the patient a compound of Formula (I), (Ia),(II), (IIa), (II), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof.Pharmaceutical compositions

[0137] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0138] Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.

[0139] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0140] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. Tablets may be made by compression or molding, optionally with one o rmore accessory ingredients. Compressed tablets may be prepared by compressing in a suitablemachine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0141] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0142] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents which increase the so lubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0143] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0144] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprisethe active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0145] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0146] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0147] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0148] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0149] In some embodiments, a compound disclosed herein is formulated in such a manner that delivery of the compound to a particular region of the gastrointestinal tract is achieved. For example, a compound disclosed herein is formulated for oral delivery with bioadhesive polymers, pH-sensitive coatings, time dependent, biodegradable polymers, microflora activated systems, and the like, in order to effect delivering of the compound to a particular region of the gastrointestinal tract.

[0150] In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustainedrelease, prolonged release, pulsatile release, and delayed release profiles. In contrast toimmediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[0151] Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g. such as the colon), include:

[0152] (i) Coating with polymers: The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.

[0153] (ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeteddelivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S 100 are copolymers of methacrylic acid and methyl methacrylate.

[0154] Coating with biodegradable polymers;

[0155] (iv) Embedding in matrices;

[0156] (v) Embedding in biodegradable matrices and hydrogels;

[0157] (vi) Embedding in pH-sensitive matrices;

[0158] (vii) Timed release systems;

[0159] (viii) Redox-sensitive polymers;

[0160] (ix) Bioadhesive systems;

[0161] (x) Coating with microparticles;

[0162] (xi) Osmotic controlled drug delivery;

[0163] Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.

[0164] Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Sci.2003 Jan-Apr;6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst.2007;24(2):147-202. Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv.2008 Jul;5(3):186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv.2006 Jan;3(1):111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech.2015 Aug; 16(4): 731–741.

[0165] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Methods of Dosing and Treatment Regimens

[0166] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of a small molecule corrector of rhodopsin. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0167] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeuticapplications, the compositions are administered to a patient already suffering from a disease orcondition, in an amount sufficient to cure or at least partially arrest at least one of the symptomsof the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0168] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0169] In certain embodiments, wherein the patient’s condition does not improve, upon the doctor’s discretion, the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwisecontrol or limit the symptoms of the patient’s disease or condition.

[0170] In certain embodiments, wherein a patient’s status does improve, the dose of drug beingadministered is temporarily reduced or temporarily suspended for a certain length of time ( i.e., a“drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0171] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which theimproved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0172] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0173] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0174] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies areused in formulating the therapeutically effective daily dosage range and / or the therap euticallyeffective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0175] In any of the aforementioned aspects are further embodiments in which the eff ectiveamount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non- systemically or locally to the mammal. EXAMPLES

[0176] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0177] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:Example 1: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3,4-dihydro-1,4-methanoisoquinolin- 2(1H)-yl)methanonetry

[0178] Step A: To a solution of 1,2,3,4-tetrahydro-1,4-methanoisoquinoline (50.0 mg, 0.275 mmol) in DMF (1.00 mL) was added 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (54.1 mg, 0.275 mmol), DIEA (71.1 mg, 0.550 mmol) and HATU (52.3 mg, 0.138 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were washed with brine (1.00 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by prep-HPLC (Phenomenex Luna C18 column (100 × 40 mm, 5 um); flow rate: 25 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(3,4-dihydro-1,4- methanoisoquinolin-2(1H)-yl)methanone. LC-MS: 324.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.96 – 10.06 (m, 1H), 7.47 – 7.29 (m, 4H), 7.24 – 7.07 (m, 3H), 5.80 – 3.00 (m, 4H), 2.21 – 2.05 (m, 2H). Example 2: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3-cyclohexyl-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0179] The title compound was prepared from 3-cyclohexyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 384.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 15.02 – 14.16 (m, 1H), 7.87 – 7.62 (m, 1H), 7.50 – 7.31 (m, 2H), 5.83 – 3.97 (m, 6H), 3.02 – 2.74 (m, 1H), 2.03 – 1.31 (m, 11H). Example 3: (4-Chloro-1H-benzimidazol-2-yl)-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7- yl)methanone

[0180] Step A: To a solution of 4-chloro-1H-benzimidazole-2-carboxylic acid (70.0 mg, 0.356 mmol) in DCM (2.00 mL) was added BOP-Cl (136 mg, 0.534 mmol) and TEA (149 μL, 1.10mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. Then 5,6,7,8 -tetrahydroimidazo[1,5-a]pyrazine (43.8 mg, 0.356 mmol) was added to the above solution and stirred at 20 °C for 12 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in DMF (2.0 mL), and purified by preparative-HPLC (Phenomenex Luna C18 column 100× 40mm× 5um); flow rate: 25 mL / min; gradient: 1% – 30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (4-chloro-1H- benzimidazol-2-yl)-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl)methanone. LC-MS: 302.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.19 (br d, J = 4.50 Hz, 1 H), 7.52 – 7.69 (m, 2 H), 7.24 – 7.47 (m, 2 H), 5.79 (s, 1 H), 5.03 (s, 1 H), 4.89 (br t, J=4.63 Hz, 1 H), 4.36 – 4.58 (m, 2 H), 4.18 (br d, J=4.63 Hz, 1 H). Example 4: rac-(7-Chloro-1H-benzo[d]imidazol-2-yl)((1S,4R)-1,2,3,4-tetrahydro-1,4- (epiminomethano)naphthalen-10-yl)methanone

[0181] The title compound was prepared from rac-(1S,4R)-1,2,3,4-tetrahydro-1,4- (epiminomethano)naphthalene and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 338.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.61 – 13.21 (m, 1H), 7.57 – 7.20 (m, 7H), 7.05 – 5.69 (m, 1H), 4.37 – 3.46 (m, 2H), 3.27 – 3.18 (m, 1H), 2.34 – 1.98 (m, 2H), 1.65 – 1.40 (m, 2H). Examples 4A and 4B: (4-Chloro-1H-benzo[d]imidazol-2-yl)((1S,4R)-1,2,3,4-tetrahydro-1,4- (epiminomethano)naphthalen-10-yl)methanone and (4-Chloro-1H-benzo[d]imidazol-2- yl)((1R,4S)-1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalen-10-yl)methanone

[0182] Step A: rac-(7-Chloro-1H-benzo[d]imidazol-2-yl)((1S,4R)-1,2,3,4-tetrahydro-1,4- (epiminomethano)naphthalen-10-yl)methanone (Example 4) (39.5 mg, 0.117 mmol) was separated by SFC separation (Phenomenex-DAICEL CHIRALPAK AD (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient:50% B over 14 min; mobile phase A: heptane, mobile phase B: EtOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. Firsteluted compound (Example 4A): LC-MS: 338.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.54 – 10.13 (m, 1H), 8.03 – 7.29 (m, 7H), 7.25 – 5.89 (m, 1H), 4.66 – 3.26 (m, 3H), 2.43 – 2.01 (m, 2H), 1.81 – 1.65 (m, 2H). Second eluted compound (Example 4B): LC-MS: 338.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.60 – 10.17 (m, 1H), 7.96 – 7.28 (m, 8H), 4.62 – 3.41 (m, 3H), 2.40 – 1.99 (m, 2H), 1.81 – 1.65 (m, 2H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 5: (4-Chloro-1H-benzimidazol-2-yl)-(3-methyl-6,8-dihydro-5H-imidazo[1,5- a]pyrazin-7-yl)methanone

[0183] The title compound was prepared from 3-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine and 4-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 3, Step A. LC-MS: 316.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.46 – 7.60 (m, 2 H), 7.27 – 7.44 (m, 2 H), 5.78 (s, 1 H), 5.00 (s, 1 H), 4.92 (br t, J=4.82 Hz, 1 H), 4.37 (br t, J=5.25 Hz, 1 H), 4.10 – 4.30 (m, 2 H), 2.54 – 2.62 (m, 3 H). Example 6: (1-Bromo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4- chloro-1H-benzo[d]imidazol-2-yl)methanone

[0184] The title compound was prepared from 1-bromo-3-(trifluoromethyl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 450.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.64 – 10.20 (m, 1H), 7.90 – 7.45 (m, 1H), 7.44 – 7.38 (m, 1H), 7.37 – 7.28 (m, 1H), 6.13 – 4.26 (m, 6H). Example 7: (1H-Imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone

[0185] Step A: To a solution of 1H-imidazo[4,5-b]pyridine-2-carboxylic acid (10.0 mg, 0.061 mmol) and 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (9.08 mg, 0.057 mmol) in DMF (1.00 mL) was added EDCI (14.1 mg, 0.735 mmol), TEA (18.6 mg, 0.184 mmol) and HOBt (9.94 mg,0.073 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (5.00 mL) and washed with EtOAc (3.00 mL x 3). The combined organic layers were driedover Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified bypreparative HPLC (Phenomenex Gemini C18 column (80× 30 mm, 3 µm); flow rate: 25 mL / min; gradient: 1% – 20% B over 8 min; mobile phase A: HCl: 0.04%, mobile phase B: acetonitrile) to afford (1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone. LC-MS: 294.1 [M+H]+. Example 8: (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0186] Step A: A mixture of 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (1.40 g, 9.45 mmol), 7-chloro-1H-benzimidazole-2-carboxylic acid (2.22 g, 4.34 mmol), HATU (1.80 g, 4.7 mmol) and DIEA (3.60 g, 28.0 mmol) in DMF (35.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (30.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Waters Xbridge C18 (150 × 50 mm, 10 μm); flow rate: [H2O (10mM NH4HCO3)-ACN]; gradient: 20% – 50% B over 8 min; mobile phase A: 10mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (7-chloro- 1H-benzimidazol-2-yl)-(5-methyl-7,8-dihydro-5H-1,6-naphthyridin-6-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.49 – 8.30 (m, 1H), 7.85 – 7.74 (m, 1H), 7.86 – 7.47 (m, 1H), 7.40 – 7.28 (m, 3H), 5.82 (br d, J = 6.4 Hz, 1H), 3.90 – 3.34 (m, 2H), 3.22 – 2.78 (m, 2H), 1.79 – 1.65 (m, 3H).

[0187] Step B: (7-Chloro-1H-benzimidazol-2-yl)-(5-methyl-7,8-dihydro-5H-1,6- naphthyridin-6-yl)methanone (1.4 g, 4.0 mmol) was further separated by SFC separation ((s,s) ChiralPak IH (250 × 30 mm, 10 μm); flow rate: 70 mL / min; gradient: 15-30% B over 12 min; mobile phase A: heptane, mobile phase B: EtOH(0.1%NH3H2O)) to afford (S)-(7-chloro-1H- benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (second eluent). LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 8.45– 8.30 (m, 1H), 7.83– 7.47 (m, 2H), 7.41– 7.19 (m, 3H), 5.87– 5.45 (m, 1H), 4.89 (br s, 1H), 3.84 – 3.65 (m, 1H), 3.84 – 3.33 (m, 1H), 3.17 – 2.98 (m, 1H), 1.80 – 1.60 (m, 3H). Example 9: (R)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0188] Step A: A mixture of (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (890 mg, 4.65 mmol), 7-chloro-1H-benzimidazole-2-carboxylic acid (1.10 g, 5.58 mmol), HATU (885 mg, 2.30 mmol) and DIEA (1.80 g, 14.0 mmol) in DMF (15.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Waters Xbridge C18 (150 × 50 mm, 10 μm); flow rate: [H2O (10mM NH4HCO3)-ACN]; gradient: 20% – 50% B over 8 min; mobile phase A: 10mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (R)-(7- chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 8.48 – 8.30 (m, 1H), 7.84 – 7.50 (m, 2H), 7.41 – 7.16 (m, 3H), 5.81 (br d, J = 6.8 Hz, 1H), 4.89 (br s, 1H), 3.81 – 3.32 (m, 2H), 3.17 – 2.99 (m, 1H), 1.80 – 1.63 (m, 3H). Example 10: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0189] Step A: To a solution of 6-methylpyrazine-2-carbaldehyde (1.80 g, 14.7 mmol) in EtOH (45.0 mL) was added NH2OH.HCl (1.23 g, 17.7 mmol) and NaOAc (1.63 g, 19.9 mmol) in H2O (25.0 mL). The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under vacuum to give (E)-6-methylpyrazine-2-carbaldehyde oxime. LC-MS: 138.3 [M+H]+.

[0190] Step B: To a solution of (E)-6-methylpyrazine-2-carbaldehyde oxime (1.70 g, 12.4 mmol) in MeOH (50.0 mL) was added palladium on carbon (2.00 g, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen and repeated three times. The mixture was stirred at 20 °C for 12 h under a hydrogen (15 Psi) atmosphere. The suspension was filtered through a pad of Celite and the pad was washed with MeOH (10.0 mL ×3). The combined filtrates were concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 3 to afford 6-methylpyrazin-2-yl)methanamine. LC-MS: 124.3 [M+H]+.

[0191] Step C: To a solution of (6-methylpyrazin-2-yl)methanamine (410 mg, 3.33 mmol) in DCM (10.0 mL) was added TFAA (0.50 mL, 3.99 mmol) at -10 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 3 to afford 2,2,2-trifluoro-N-((6-methylpyrazin-2-yl)methyl)acetamide. LC-MS: 220.2 [M+H]+.

[0192] Step D: A solution of 2,2,2-trifluoro-N-((6-methylpyrazin-2-yl)methyl)acetamide (370 mg, 1.69 mmol) in POCl3(6.91 g, 451 mmol) was stirred at 130 °C for 5 h. The mixture was concentrated under vacuum to give a residue and then poured into ice-water (5.00 mL), treated with saturated Na2CO3aqueous (5.00 mL) to pH = 8, and extracted with EtOAc (5.00 mL x 2). The combined organic phase was washed with H2O (2.00 mL x 2) and brine (2.00 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 0 to afford 5-methyl-3- (trifluoromethyl)imidazo[1,5-a]pyrazine. LC-MS: 202.2 [M+H]+.

[0193] Step E: To a solution of 5-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine (35.0 mg, 0.174 mmol) in 2,2,2-trifluoroethanol (1.00 mL) was added palladium on carbon (185 mg, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen and repeated three times. The mixture was stirred at 20 °C for 6 h under a hydrogen (15 Psi.) atmosphere. The suspension was filtered through a pad of Celite and the cake was washed with 2,2,2-trifluoroethanol (2.00 mL × 3). The combined filtrates were concentrated under vacuum to give 5-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. LC-MS: 206.2 [M+H]+.

[0194] Step F: To a solution of 5-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine (30.0 mg, 0.146 mmol), 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (28.7 mg, 0.146 mmol), HATU (16.7 mg, 0.044 mmol) in DMF (1.00 mL) was added DIEA (0.051 mL, 0.292 mmol). The mixture was stirred at 25oC for 1 h. The mixture was poured into H2O (1.00 mL) and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A: 0.04% aqueous HCl mobile phase B: acetonitrile). The relevant fractions were lyophilized to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone. LC-MS: 384.1[M+H]+.1H NMR (400 MHz, CD3OD) δ 7.65 – 7.56 (m, 1H), 7.43 – 7.30 (m, 2H), 7.17 – 7.07 (m, 1H), 6.20 (br d, J = 13.8 Hz, 1H), 5.10 (br d, J = 17.3 Hz, 1H), 5.01– 4.93 (m, 1H), 4.70 – 4.60 (m, 1H), 3.96 – 3.58 (m, 1H), 1.66 – 1.51 (m, 3H). Examples 10A and 10B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7- Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0195] Step A: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (15.7 mg, 0.037 mmol) was separated by SFC separation ((DAICEL CHIRALCEL IG (250 × 30 mm, 10 μm); flow rate: 64 mL / min; gradient: 25% B over 4 min; mobile phase A: CO2, mobile phase B: MeOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 10A): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.71 – 7.55 (m, 1H), 7.44 – 7.29 (m, 2H), 7.11 – 7.01 (m, 1H), 6.94 – 6.65 (m, 1H), 5.68 – 5.10 (m, 1H), 5.03 – 4.48 (m, 2H), 3.91 – 3.39 (m, 1H), 1.66 – 1.46 (m, 3H). Second eluted compound (Example 10B): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.66 – 7.46 (m, 1H), 7.40 – 7.21 (m, 2H), 7.07 – 6.94 (m, 1H), 6.90 – 6.53 (m, 1H), 5.58 – 5.03 (m, 1H), 4.96 – 4.46 (m, 2H), 3.81 – 3.38 (m, 1H), 1.55 – 1.42 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 11: (4-Chloro-1H-benzo[d]imidazol-2-yl)(1-methyl-3,4-dihydro-2,6-naphthyridin- 2(1H)-yl)methanone

[0196] Step A: To a solution of 1-(3-bromopyridin-4-yl)ethan-1-ol (5.00 g, 26.9 mmol) in THF (50.0 mL) was added MeMgBr (3M, 26.9 mL, 26.9 mmol) at -65 °C. The mixture was stirred at 0 °C for 3 h. The mixture was poured into NH4Cl (70.0 mL) and extracted with EtOAc(70.0 mL x 3). The combined organic layers were concentrated under reduced pressure to give 1 -(3-bromopyridin-4-yl)ethan-1-ol. LC-MS: 202.2 [M+H]+.

[0197] Step B: To a mixture of 1-(3-bromopyridin-4-yl)ethan-1-ol (2.60 g, 12.9 mmol) in DCM (26.0 mL) was added DHP (1.76 mL, 19.3 mmol) and TsOH ( 102 mg, 0.594 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was poured into NaHCO3(26.0 mL) and extracted with DCM (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gelchromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 10 to afford 3-bromo-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine. LC-MS: 286.1 [M+H]+.

[0198] Step C: A solution of 3-bromo-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine (750 mg, 2.62 mmol), (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (724 mg, 2.88 mmol), Pd(dppf)Cl2(62.5 mg, 0.085 mmol), Cs2CO3(2.31 g, 7.08 mmol) in toluene (21.0 mL) and H2O (7.00 mL) was degassed and purged with nitrogen for 3 times. The resulting mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was poured into H2O (25.0 mL) and extracted with EtOAc (25.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flashsilica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 2 to affordtert-butyl (2-(4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridin-3-yl)ethyl)carbamate. LC-MS: 351.1 [M+H]+.

[0199] Step D: To a mixture of tert-butyl (2-(4-(1-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)pyridin-3-yl)ethyl)carbamate (430 mg, 1.23 mmol) in MeOH (3.00 mL) was addedTsOH (317 mg, 1.84 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was poured into NaHCO3(2.00 mL) and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 5 to afford tert-butyl (2-(4-(1-hydroxyethyl)pyridin-3-yl)ethyl)carbamate. LC-MS: 267.2 [M+H]+.

[0200] Step E: To a solution of tert-butyl (2-(4-(1-hydroxyethyl)pyridin-3-yl)ethyl)carbamate (50.0 mg, 0.188 mmol) in DCM (2.00 mL) was added TEA (28.5 mg, 0.281 mmol), followed byMsCl (27.9 mg, 0.244 mmol) at 0 °C. The mixture was stirred at 0 °C under nitrogenatmosphere. The mixture was poured into NaHCO3(5.00 mL) and extracted with DCM (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 1-[3-[2-(tert-butoxycarbonylamino)ethyl]-4-pyridyl]ethyl methanesulfonate.1H NMR (400 MHz, CDCl3) δ 8.79 – 8.64 (m, 2H), 8.10 – 8.00 (m, 1H), 6.42 – 6.28 (m, 1H), 5.24 – 5.05 (m, 1H), 3.69 (s, 3H), 3.55 – 3.49 (m, 1H), 3.39 – 3.32 (m, 1H), 1.44 (s, 3H), 1.41 (s, 9H).

[0201] Step F: To a solution of 1-(3-(2-((tert-butoxycarbonyl)amino)ethyl)pyridin-4-yl)ethyl methanesulfonate (50.0 mg, 0.145 mmol) in DMF (1.00 mL) was added KI (2.41 mg, 0.014 mmol), followed by t-BuONa (27.9 mg, 0.290 mmol). The mixture was stirred at 100 °C for 30 min. The reaction mixture was allowed to cool to room temperature, poured into NaHCO3(5.00 mL) and extracted with Petroleum ether (2.00 mL x 2). The aqueous phase was adjusted to pH 4 with HCl (1M aqueous) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4filtered, and concentrated under vacuum to give a residue which waspurified by preparative TLC (Petroleum ether : Ethyl acetate= 1 / 1, R f = 0.5) to afford tert-butyl1-methyl-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate. LC-MS: 249.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.45 – 8.34 (m, 2H), 7.10 – 7.01 (m, 1H), 5.33 – 5.07 (m, 1H), 4.39 – 4.06 (m, 1H), 3.28 – 3.03 (m, 1H), 2.90 – 2.83 (m, 1H), 2.81 – 2.71 (m, 1H), 1.50 (s, 10H), 1.45 (d, J = 6.9 Hz, 3H).

[0202] Step G: To a solution of tert-butyl 1-methyl-3,4-dihydro-2,6-naphthyridine-2(1H)- carboxylate (20.0 mg, 0.080 mmol) in EtOAc (0.50 mL) was added HCl / EtOAc (4M, 0.4 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum to give 1- methyl-1,2,3,4-tetrahydro-2,6-naphthyridine. LC-MS: 149.2 [M+H]+.

[0203] Step H: A mixture of 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid (13.0 mg, 0.067 mmol), 1-methyl-1,2,3,4-tetrahydro-2,6-naphthyridine (10.0 mg, 0.067 mmol), HATU (25.7 mg, 0.067 mmol) and DIEA (17.4 mg, 0.135 mmol) in DMF (1.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (1.00 mL) and extracted with EtOAc (0.50mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge C18 column (150 × 50 mm, 10 μm); flow rate: 60 mL / min; gradient: 25% – 55% B over 8 min; mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile) to afford (4-chloro-1H-benzo[d]imidazol-2- yl)(1-methyl-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.54 – 10.42 (m, 1H), 7.81 – 7.74 (m, 1H), 7.42 (br s, 2H), 7.35 – 7.28 (m, 2H), 6.59 – 6.32 (m, 1H), 5.91– 4.96 (m, 1H), 3.76 – 3.55 (m, 1H), 3.35 – 3.24 (m, 1H), 3.21 – 3.01 (m, 2H), 1.67 (br d, J = 6.8 Hz, 3H). Example 12: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5,5-dimethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0204] Step A: To a mixture of methyl 2-bromopyridine-3-carboxylate (1.00 g, 4.63 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.43 g, 9.26 mmol) and K3PO4(2.95 g, 13.9 mmol) in THF (20.0 mL) and H2O (4.00 mL) was added Pd(dppf)Cl2(677 mg, 0.926 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, poured into water (20.0 mL) and extracted with EtOAc (20.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford methyl 2-vinylnicotinate. LC-MS: 164.2 [M+H]+.

[0205] Step B: A solution of methyl 2-vinylnicotinate (400 mg, 2.46 mmol) and phenylmethanamine (1.31 g, 12.3 mmol) in DMF (8.00 mL) was stirred at 150 °C for 2 h under microwave. The reaction mixture was allowed to cool to room temperature, poured into water (10.0 mL) and extracted with EtOAc (10.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford 6-benzyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one. LC-MS: 286.1 [M+H]+.

[0206] Step C: To a solution of 6-benzyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (300 mg, 1.26 mmol) in THF (6.00 mL) was added ZrCl4(382 mg, 1.64 mmol). The mixture was degassedand purged with nitrogen three times and stirred at -10 °C for 0.5 h under a nitrogen atmosphere. Then MeMgBr (3M, 3.37 mL) was added and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with NH4Cl (aqueous 10.0 mL) and extracted with EtOAc (3 x 3.00 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford 6-benzyl-5,5-dimethyl-5,6,7,8-tetrahydro- 1,6-naphthyridine. LC-MS: 253.2 [M+H]+.

[0207] Step D: To a solution of palladium on carbon (10%, contains 67% water, 211 mg, 0.198 mmol) in MeOH (5.00 mL) was added 6-benzyl-5,5-dimethyl-5,6,7,8-tetrahydro-1,6- naphthyridine (50.0 mg, 0.198 mmol) and Boc2O (47.6 mg, 0.218 mmol). The mixture was degassed and purged with hydrogen three times and stirred at 50 °C for 1 h under hydrogen (50 Psi). The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc / petroleum ether = 1 / 3, Rf = 0.55) to afford tert-butyl 5,5-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate. LC-MS: 253.2 [M+H]+.

[0208] Step E: To a solution of tert-butyl 5,5-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate (20.0 mg, 0.076 mmol) in EtOAc (1.00 mL) was added HCl / EtOAc (4M, 4.00 mL). The resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30 °C to give 5,5-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine. LC-MS: 163.1 [M+H]+.

[0209] Step F: A mixture of 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (9.89 mg, 0.050 mmol), 5,5-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine (10.0 mg, 0.050 mmol), HATU (9.57 mg, 0.025 mmol) and DIEA (19.5 mg, 0.151 mmol) in DMF (0.50 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 5% – 35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-chloro-1H- benzo[d]imidazol-2-yl)(5,5-dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC- MS: 241.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.78 – 8.54 (m, 2H), 7.91 – 7.79 (m, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.42 – 7.23 (m, 2H), 4.21 (br d, J = 5.1 Hz, 2H), 3.34 (br t, J = 4.8 Hz, 2H), 1.93 (s, 6H). Example 13: (4-Chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-5,8-dihydro-1,7-naphthyridin- 7(6H)-yl)methanone

[0210] Step A: 1-(3-Bromopyridin-2-yl)ethan-1-one (200 mg, 1.00 mmol), (2-((tert- butoxycarbonyl)amino)ethyl)trifluoroborate (301 mg, 1.20 mmol) were dissolved in H2O (3.00 mL) and toluene (9.00 mL) at room temperature under nitrogen. Pd(dppf)Cl2(20.0 mg, 0.027 mmol) and then Cs2CO3(977 mg, 3.00 mmol) were added. The mixture was heated at 80 °C for 5 h and then cooled to room temperature. The reaction mixture was poured into H2O (10.0 mL)and extracted with EtOAc (10.0 mL x 2). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give a residue which was purified by flash chromatography on silica gel using a gradient of EtOAc / petroleum ether from 0 / 100 to 1 / 10 to afford tert-butyl (2-(2-acetylpyridin-3-yl)ethyl)carbamate. LC-MS: 265.3 [M+H]+.

[0211] Step B: tert-Butyl (2-(2-acetylpyridin-3-yl)ethyl)carbamate (80.0 mg, 0.303 mmol) was dissolved in EtOAc (1.00 mL) and then HCl / EtOAc (4M, 1.00 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give 8-methyl-5,6-dihydro-1,7-naphthyridine. LC-MS: 147.2 [M+H]+.

[0212] Step C: 8-Methyl-5,6-dihydro-1,7-naphthyridine (40.0 mg, 0.274 mmol) was dissolved in MeOH (2.00 mL) and then NaBH3CN (25.8 mg, 0.410 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into H2O (2.00 mL) andextracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give 8-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine. LC-MS: 149.2 [M+H]+.

[0213] Step D: 8-Methyl-5,6,7,8-tetrahydro-1,7-naphthyridine (20.0 mg, 0.135 mmol), 4- chloro-1H-benzo[d]imidazole-2-carboxylic acid (26.5 mg, 0.135 mmol), HATU (25.7 mg, 0.0675 mmol) and DIEA (24.0 μL, 0.135 mmol) were dissolved in DMF (1.00 mL) and stirred at room temperature for 1 h. The reaction mixture was poured into H2O (1.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 40 mm, 5 μm); flow rate: 60 mL / min; gradient: 10% –40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). Therelevant fractions were lyophilized to afford (4-chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.50 (br s, 1H), 8.47 (br dd, J = 3.9, 17.9 Hz, 1H), 7.78 - 7.65 (m, 1H), 7.59 - 7.46 (m, 1H), 7.42 - 7.36 (m, 1H), 7.35 - 7.26 (m, 2H), 5.68 - 5.39 (m, 1H), 3.29 (br d, J = 5.0 Hz, 2H), 3.02 (br s, 2H), 1.73 (br d, J = 6.8 Hz, 3H). Example 14: (4-Fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0214] Step A: A solution of 3-fluorobenzene-1,2-diamine (1.00 g, 7.93 mmol) and methyl 2,2,2-trichloroacetimidate (1.40 g, 7.93 mmol) in AcOH (8.00 mL) was stirred at 25 °C for 3 h. The reaction mixture was filtered and the filter cake was washed with H2O (5.00 mL) and dried in vacuum to give 4-fluoro-2-(trichloromethyl)-1H-benzo [d]imidazole which was used in the next step without any further purification. LC-MS: 253.0 [M+H]+.

[0215] Step B: A solution of 4-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole (2.00 g, 7.90 mmol) in NaOH aqueous (2M, 40 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (25.0 mL), extracted with MTBE (20.0 mL x 2). The combined organic layers were discarded. The water phase was adjusted pH 7 by using HCl aqueous (1M) and lyophilized further to give a residue The residue was washed with DCM (10.0 mL x 2) and filtered. The combined filtrates layers were dried over Na2SO4and concentrated under vacuum to give 4- fluoro-1H-benzo[d]imidazole-2-carboxylic acid which was used in the next step without any further purification. LC-MS: 181.2 [M+H]+.

[0216] Step C: To a solution of 4-fluoro-1H-benzo[d]imidazole-2-carboxylic acid (20.0 mg, 0.111 mmol) and 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (16.5 mg, 0.111 mmol) in DMF (1.00 mL) was added HATU (42.2 mg, 0.111 mmol) and DIEA (14.3 mg, 0.111 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into H2O (1.00 mL) and extracted with EtOAc (1.00 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 × 30 mm, 10 μm); flow rate: 25 mL / min; gradient: 25% – 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (4-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone. LC-MS: 311.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 10.51 (br s, 1H), 8.57 –8.46 (m, 1H), 7.78 – 7.60 (m, 1H), 7.33 (br s, 2H), 7.14 – 7.01 (m, 1H), 6.55 – 5.84 (m, 1H), 3.87 – 3.68 (m, 1H), 3.48 – 3.18 (m, 3H), 1.90 – 1.67 (m, 3H). Example 15: (6-Chloro-7-methyl-1H-benzimidazol-2-yl)-(5-methyl-7,8-dihydro-5H-1,6- naphthyridin-6-yl)methanone

[0217] The title compound was prepared from 4-chloro-3-methylbenzene-1,2-diamine according to the procedure of Example 14, Steps A, B, and C. LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.64 – 10.29 (m, 1H), 8.55 – 8.42 (m, 1H), 7.65 – 7.53 (m, 1H), 7.38 – 7.28 (m, 1H), 7.27 – 7.18 (m, 2H), 6.50 – 4.77 (m, 1H), 3.76 (dt, J = 3.8, 13.0 Hz, 1H), 3.53 – 3.06 (m, 3H), 2.81 – 2.53 (m, 3H), 1.79 (br dd, J = 6.4, 12.5 Hz, 1H), 1.65 (s, 2H). Examples 15A and 15B: (R)-(6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone and (S)-(6-Chloro-7-methyl-1H- benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

[0218] Step A: (6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (40.0 mg, 0.120 mmol) was separated by SFC separation (Phenomenex-CHIRALPAK IH (250 × 30 mm, 10 µm); flow rate: 30 mL / min; gradient: 42% B over 14 min; mobile phase A: heptane, mobile phase B: EtOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 15B): LC- MS: 340.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.22 (br dd, J = 4.4, 7.6 Hz, 1H), 8.51 – 8.23 (m, 1H), 7.59 – 7.21 (m, 3H), 7.16 – 7.08 (m, 1H), 6.44 – 5.67 (m, 1H), 5.09 – 3.59 (m, 1H), 3.45 – 2.91 (m, 3H), 2.72 – 2.40 (m, 3H), 1.73 – 1.55 (m, 3H). Second eluted compound (Example 15A): LC-MS: 340.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.52 – 10.21 (m, 1H), 8.55 – 8.42 (m, 1H), 7.69 – 7.29 (m, 3H), 727 – 7.15 (m, 1H), 6.53 – 5.75 (m, 1H), 5.09 – 3.67 (m, 1H), 3.53 – 3.01 (m, 3H), 2.79 – 2.52 (m, 3H), 1.84 – 1.63 (m, 3H). Example 16: (7-Chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0219] Step A: To a solution of diisopropylamine (1.17 g, 11.6 mmol) in THF (7.00 mL) was added dropwise n-BuLi (2.5 M in THF, 1.39 mL) at -78 °C over 0.5 h under nitrogen. Then a solution of 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine (650 mg, 2.90 mmol) in THF (14.0 mL) was added dropwise. After stirring for 1 h, MeI (6.17 g, 43.5 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. Dropped 2.00 mL of MeOH into the system, then the reaction mixture was poured into H2O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 100 to 1 / 4 to afford 6-benzyl-8-methyl-5,6,7,8- tetrahydro-1,6-naphthyridine. LC-MS: 239.1 [M+H]+.

[0220] Step B: To a solution of 6-benzyl-8-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (400 mg, 1.68 mmol) in MeOH (20.0 mL) was added palladium on carbon (10%, contains 67% water, 1.79 g) and Boc2O (203 mg, 1.85 mmol). The mixture was stirred at 25 °C for 2 h under hydrogen (50 Psi). The mixture was filtered through Celite pad, then the solvent was removed to give tert-butyl 8-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. LC-MS: 249.3 [M+H]+.

[0221] Step C: To a solution of tert-butyl 8-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate (350 mg, 1.41 mmol) in EtOAc (2.00 mL) was added HCl / EtOAc (4M, 10.0 mL).The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum to give 8 -methyl-5,6,7,8-tetrahydro-1,6-naphthyridine. LC-MS: 149.1 [M+H]+.

[0222] Step D: To a solution of 8-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (8.00 mg, 0.043 mmol), 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (8.52 mg, 0.043 mmol) in DMF (0.50 mL) was added DIEA (11.2 mg, 0.087 mmol) and HATU (8.24 mg, 0.022 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was treated with H2O (2.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75× 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 10% –40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) for second time to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.73 (br d, J = 4.5 Hz, 1H), 8.62 – 8.44 (m, 1H), 8.07 – 7.87 (m, 1H), 7.59 (br d, J = 7.9 Hz, 1H), 7.43 – 7.27 (m, 2H), 6.52 – 5.31 (m, 2H), 4.63 – 4.30 (m, 1H), 4.06 – 3.49 (m, 2H), 1.60 – 1.49 (m, 3H). Example 17: (7-Chloro-1H-benzimidazol-2-yl)-(7-methyl-7,8-dihydro-5H-1,6-naphthyridin- 6-yl)methanone

[0223] Step A: To a solution of 2-methylnicotinic acid (2.00 g, 14.6 mmol) and phenylmethanamine (1.56 g, 14.6 mmol) in DMF (10.0 mL) was added DIEA (5.65 g, 43.7 mmol) and HATU (11.1 g, 29.2 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was treated with H2O (15.0 mL) and extracted with EtOAc (15.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 2 / 5 to afford N-benzyl-2-methyl-pyridine-3-carboxamide. LC-MS: 227.1 [M+H]+.

[0224] Step B: To a solution of N-benzyl-2-methyl-pyridine-3-carboxamide (500 mg, 2.21 mmol) in THF (5.50 mL) was added dropwise BH3.THF (1M, 11.0 mL) at 0 °C. The mixture was stirred at 70 °C for 2 h. To the mixture was added MeOH dropwise at 0 °C and then refluxed for 1 h. The resulting mixture was concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 2 to afford N-benzyl-1-(2-methylpyridin-3-yl)methanamine. LC-MS: 213.3 [M+H]+.

[0225] Step C: A mixture of diisopropylamine (357 mg, 3.53 mmol) in THF (10.0 mL) was degassed and purged with nitrogen for 3 times, and then n-BuLi (1.5 M, 1.88 mL) was added at -70 °C during a period of 10 min. N-benzyl-1-(2-methylpyridin-3-yl)methanamine (250 mg, 1.18 mmol) in THF (2.50 mL) was then added into the solution dropwise at -70 °C for 1h. Then acetaldehyde (5M, 1.18 mL) was added. The mixture was stirred at -70 °C for 1 h under nitrogen atmosphere. The reaction mixture was poured into saturated NH4Cl aqueous (5.00 ml), extractedwith EtOAc (10.0 ml x 3). The combined organic layers were dried over Na 2SO4, filtered andconcentrated under vacuum to give a residue, which was purified by flash silica gelchromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 2 to afford 1-(3-((benzylamino)methyl)pyridin-2-yl)propan-2-ol. LC-MS: 257.3 [M+H]+.

[0226] Step D: To a solution of 1-(3-((benzylamino)methyl)pyridin-2-yl)propan-2-ol (50.0 mg, 0.195 mmol) in CHCl3(0.50 mL) was added SOCl2(69.0 mg, 0.585 mmol) at 0 °C. Then the mixture was stirred at 70 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3(5.00ml) and extracted with DCM (5.00 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give N-benzyl-1-(2-(2- chloropropyl)pyridin-3-yl)methanamine. LC-MS: 275.3 [M+H]+.

[0227] Steps E, F, and G: The title compound was prepared from N-benzyl-1-(2-(2- chloropropyl)pyridin-3-yl)methanamine according to the procedure of Example 16, Steps B, C, and D. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.69 – 10.31 (m, 1H), 8.51 (br t, J = 5.6 Hz, 1H), 7.82 – 7.52 (m, 1H), 7.48 – 7.28 (m, 2H), 7.24 – 7.16 (m, 1H), 6.91 – 6.63 (m, 1H), 5.55 – 5.35 (m, 1H), 5.06 – 4.45 (m, 1H), 3.64 – 3.29 (m, 1H), 3.10 – 2.83 (m, 1H), 1.42 – 1.24 (m, 4H). Example 18: (7-Chloro-1H-benzo[d]imidazol-2-yl)(1-methyl-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)-yl)methanone

[0228] The title compound was prepared from 1-methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine and 7-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 315.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 7.9 Hz, 1H), 7.44 – 7.33 (m, 3H), 6.39 – 6.05 (m, 1H), 5.81 (br d, J = 6.4 Hz, 1H), 5.32 (br d, J = 14.0 Hz, 1H), 4.14 (br d, J = 5.5 Hz, 2H), 3.92 – 3.55 (m, 2H), 1.59 (br d, J = 6.0 Hz, 3H). Example 19: (7-Chloro-1H-benzo[d]imidazol-2-yl)(1,6-dimethyl-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)-yl)methanone

[0229] The title compound was prepared from 1,6-dimethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine and 7-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 329.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.74 – 13.32 (m, 1H), 7.67 – 7.50 (m, 1H), 7.44 – 7.24 (m, 2H), 5.93 – 5.58 (m, 3H), 4.16 – 3.95 (m, 1H), 3.92 – 3.67 (m, 2H), 3.58 – 3.38 (m, 1H), 2.14 (s, 3H), 1.69 – 1.41 (m, 3H). Example 20: (7-Chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-5,6-dihydroimidazo[1,2- a]pyrazin-7(8H)-yl)methanone

[0230] The title compound was prepared from 8-methyl-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine and 7-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 316.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.60 (br s, 1H), 7.54 (br s, 1H), 7.44 – 7.29 (m, 2H), 7.19 – 7.06 (m, 1H), 6.94 – 6.72 (m, 1H), 5.68 (q, J = 6.8 Hz, 1H), 4.31 – 3.96 (m, 2H), 3.91 – 3.48 (m, 1H), 3.33 (s, 2H), 1.74 – 1.49 (m, 3H). Example 21: (7-Methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0231] Step A: A solution of 4-methylpyridine-2,3-diamine (200 mg, 1.62 mmol) in 2- hydroxyacetic acid (247 mg, 3.25 mmol) was stirred at 150 °C for 3 h. The mixture was cooled down to room temperature, then treated with NaHCO3solution until some solid appeared. The mixture was filtered and the filter cake was dried in vacuum to give (7-methyl-1H-imidazo[4,5- b]pyridin-2-yl)methanol. LC-MS: 162.2 [M+H]+.

[0232] Step B: A solution of KMnO4(58.0 mg, 0.367 mmol) in H2O (4.00 mL) was stirred at 100 °C. Then a mixture of (7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)methanol (40.0 mg, 0.245 mmol) and Na2CO3(19.0 mg, 179 mmol) in H2O (4.00 mL) was added. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was acidified to pH 2 – 3 with (1MHCl). The resulting precipitate was filtered off and the cake was dried in vacuum to afford 7- methyl-1H-imidazo[4,5-b]pyridine-2-carboxylic acid. LC-MS: 176.1 [M+H]+.

[0233] Step C: A mixture of 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (12.0 mg, 0.084 mmol), 7-methyl-1H-imidazo[4,5-b]pyridine-2-carboxylic acid (15.0 mg, 0.084 mmol), HATU (16.0 mg, 0.042 mmol) and DIEA (32.0 mg, 0.254 mmol) in DMF (0.500 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (5.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column 100 × 40 mm× 5 µm); flow rate: 25 mL / min; gradient: 1% – 18% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-methyl-1H-imidazo[4,5- b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 308.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.70 (m, 1H), 8.63 – 8.34 (m, 2H), 7.99 – 7.75 (m, 1H), 7.59 – 7.34 (m, 1H), 6.52 – 5.85 (m, 1H), 5.44 – 4.63 (m, 1H), 3.79 – 3.11 (m, 3H), 2.82 – 2.60 (m, 3H), 1.86 – 1.52 (m, 3H). Example 22: (7-Methyl-1H-imidazo[4,5-c]pyridin-2-yl)(1-methyl-3,4-dihydro-2,6- naphthyridin-2(1H)-yl)methanone

[0234] The title compound was prepared from 5-methylpyridine-3,4-diamine according to the procedure of Example 21, Steps A, B, and C. LC-MS: 308.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.75 – 10.54 (m, 1H), 9.09 (br s, 1H), 8.56 – 8.27 (m, 2H), 7.62 – 7.51 (m, 1H), 7.24 – 7.12 (m, 1H), 6.50 – 5.73 (m, 1H), 5.12 – 3.68 (m, 1H), 3.60 – 2.89 (m, 3H), 2.80 – 2.42 (m, 3H), 1.84 – 1.63 (m, 3H). Example 23: (4-Methyl-3H-imidazo[4,5-c]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0235] Step A: A solution of 2-methyl-3-nitropyridin-4-amine (800 mg, 5.22 mmol) and Raney Ni (306 mg) in MeOH (8.00 mL) was degassed and purged with hydrogen for three times. The mixture was stirred at 20 °C for 1 h under hydrogen (15 psi). The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (2.00 mL × 3). The combined filtrates were concentrated under vacuum to give 2-methylpyridine-3,4-diamine. LC- MS: 124.2 [M+H]+.

[0236] Steps B, C, and D: The title compound was prepared from 2-methylpyridine-3,4- diamine according to the procedure of Example 21, Steps A, B, and C. LC-MS: 308.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.57 – 8.33 (m, 1H), 7.64 – 7.43 (m, 1H), 7.37 – 7.28 (m, 1H), 7.26 – 7.02 (m, 3H), 3.35 – 2.79 (m, 4H), 2.33 – 2.08 (m, 1H), 1.88 – 1.57 (m, 3H), 1.48 – 0.73 (m, 3H). Examples 24A and 24B: (S)-(4-Methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone (Example 24A) and (R)-(4-methyl-1H- benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (Example 24B)

[0237] Step A: Racemic (4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone was prepared from 5-methyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 4-methyl-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 307.3 [M+H]+.

[0238] Step B: Racemic (4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (36.7 mg, 0.120 mmol) was separated by SFC separation ((Phenomenex-Cellulose-2(250 × 30 mm, 10 μm); flow rate: 70 mL / min; gradient: 45 – 45% B over 11 min; mobile phase A: CO2, mobile phase B: IPA(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 24A): LC-MS: 307.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.61 (br s, 1H), 8.56 – 8.35 (m, 1H), 7.73 – 7.51(m, 1H), 7.41 – 7.27 (m, 1H), 7.26 – 6.99 (m, 3H), 6.61 – 4.89 (m, 2H), 3.88 – 2.98 (m, 3H), 2.78 – 2.48 (m, 3H), 1.81 – 1.63 (m, 3H). Second eluted compound (Example 24B): LC-MS: 307.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.38 (br d, J = 5.1 Hz, 1H), 8.61 – 8.32 (m, 1H), 7.82 – 7.47 (m, 1H), 7.43 – 7.28 (m, 1H), 7.26 – 7.06 (m, 3H), 6.65 – 4.81 (m, 2H), 3.83 – 3.05 (m, 3H), 2.80 – 2.46 (m, 3H), 1.89 – 1.60 (m, 3H). Example 25: (7-Chloro-1H-benzo[d]imidazol-2-yl)(8-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0239] The title compound was prepared from 4-chloro-3-methylbenzene-1,2-diamine according to the procedure of Example 10, Steps C, D, E, and F. LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.77 – 10.40 (m, 1H), 7.81 – 7.29 (m, 3H), 7.08 – 7.00 (m, 1H), 6.83 – 6.58 (m, 1H), 6.14 – 5.02 (m, 1H), 4.57 – 3.42 (m, 3H), 1.90 – 1.61 (m, 3H). Example 26: (7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0240] The title compound was prepared from (5-methylpyrazin-2-yl)methanamine according to the procedure of Example 10, Steps C, D, E, and F. LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.65 - 7.50 (m, 1H), 7.46 - 7.31 (m, 2H), 7.20 - 6.97 (m, 1H), 5.51 - 5.31 (m, 1H), 4.52 - 4.25 (m, 2H), 3.92 - 3.75 (m, 1H), 3.37 (s, 2H), 1.37 (d, J = 6.8 Hz, 3H). Examples 26A and 26B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0241] (7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (7.90 g, 20.6 mmol) was separated by SFC separation (DAICEL CHIRALCEL OD (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient:38% B over 14 min; mobile phase A: heptane, mobile phase B: CO2- MeOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 26A): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.64 (br s, 1H), 7.45 – 7.38 (m, 1H), 7.37 – 7.29 (m, 1H), 7.11 (br d, J = 5.8 Hz, 1H), 7.07 – 6.72 (m, 1H), 5.53 – 4.59 (m, 2H), 4.47 – 4.21 (m, 2H), 1.43 – 1.37 (m, 3H). Second eluted compound (Example 26B): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.74 – 7.60 (m, 1H), 7.48 – 7.39 (m, 1H), 7.38 – 7.31 (m, 1H), 7.12 (br d, J = 5.1 Hz, 1H), 7.09 – 6.71 (m, 1H), 5.57 – 4.60 (m, 2H), 4.53 – 4.17 (m, 2H), 1.48 – 1.37 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 27: (7-Chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)methanone

[0242] Step A: To a solution of 1-(1H-pyrazol-5-yl)ethan-1-one (500 mg, 4.54 mmol), 2- aminoethan-1-ol (277 mg, 4.54 mmol) in MeOH (8.00 mL) was added NaBH3CN (571 mg, 9.08 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was poured into H2O (8.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4and concentrated under vacuum to give 2-((1-(1H-pyrazol-5-yl)ethyl)amino)ethan-1-ol. LC-MS: 156.2 [M+H]+.

[0243] Step B: To a solution of 2-((1-(1H-pyrazol-5-yl)ethyl)amino)ethan-1-ol (500 mg, 3.22 mmol) in MeOH (10.0 mL) and H2O (3.00 mL) was added (Boc)2O (703 mg, 3.22 mmol) andK2CO3(891 mg, 6.44 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was poured into H2O (15.0 mL) and extracted with EtOAc (6.00 mL x 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of Petroleum ether / (Ethanol / Ethyl acetate = 3 / 1 ether from 1 / 100 to 1 / 2 to afford tert-butyl (1-(1H-pyrazol-5-yl)ethyl)(2-hydroxyethyl)carbamate. LC-MS: 256.2 [M+H]+.

[0244] Step C: To a solution of tert-butyl (1-(1H-pyrazol-5-yl)ethyl)(2- hydroxyethyl)carbamate (100 mg, 0.392 mmol) in DCM (1.00 mL) was added TEA (59.5 mg, 0.587 mmol), followed by MsCl (89.7 mg, 0.784 mmol) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 12 h. The mixture was poured into saturated NaHCO3aqueous (1.00 mL)and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (Petroleum ether / Ethyl acetate = 1 / 1, Rf= 0.4) to afford 2-((1-(1H-pyrazol-5-yl)ethyl)(tert- butoxycarbonyl)amino)ethyl methanesulfonate. LC-MS: 234.1 [M+H]+.

[0245] Step D: To a solution of 2-((1-(1H-pyrazol-5-yl)ethyl)(tert- butoxycarbonyl)amino)ethyl methanesulfonate (25.0 mg, 0.075 mmol) in DMF (1.50 mL) wasadded NaH (9.00 mg, 0.224 mmol, 60% purity). The mixture was stirred at 20 °C for 12 h. Themixture was poured into H2O (2.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined filtrates layers were dried over Na2SO4and concentrated under vacuum to give tert-butyl 4- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate. LC-MS: 238.2 [M+H]+.

[0246] Step E: To a solution of tert-butyl 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (12.0 mg, 0.050 mmol) in EtOAc (0.50 mL) was added HCl / EtOAc (4M, 0.50 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give the 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0247] Step F: To a solution of 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (11.0 mg, 0.080 mmol, HCl salt) and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (15.8 mg, 0.080 mmol) in DMF (1.00 mL) was added HATU (30.5 mg, 0.080 mmol) and DIEA (20.7 mg, 0.160 mmol). The mixture was stirred at 20 °C for 3 h. The mixture was poured into H2O (1.00 mL) and extracted with EtOAc (1.00 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna C18 (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 25% – 55% B over 8 min; mobile phase A: 0.04% aqueous HCl mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- yl)methanone. LC-MS: 315.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.61 – 7.52 (m, 1H),7.51 – 7.42 (m, 1H), 7.38 (s, 1H), 7.36 – 7.29 (m, 1H), 6.78 – 6.55 (m, 1H), 6.29 – 6.19 (m, 1H), 6.02 – 5.88 (m, 1H), 5.87 – 5.77 (m, 1H), 4.89 – 4.31 (m, 1H), 4.27 – 4.04 (m, 1H), 3.96 – 3.51 (m, 1H), 1.75 – 1.46 (m, 3H). Examples 27A and 27B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone and (R) or (S)-(7-Chloro-1H- benzo[d]imidazol-2-yl)(4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone

[0248] ((7-Chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)methanone (12 mg, 0.035 mmol) was further separation by SFC separation((DAICEL CHIRALCEL OZ (250 × 30 mm, 10 μm); flow rate: 64 mL / min; gradient: 30% B over 4 min; mobile phase A: CO2, mobile phase B: IPA(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 27A): LC-MS: 316.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.59 (br s, 1H), 7.66 – 7.49 (m, 1H), 7.48 – 7.42 (m, 1H), 7.40 – 7.36 (m, 1H), 7.35 – 7.28 (m, 2H), 6.78 – 6.16 (m, 1H), 6.06 – 5.77 (m, 1H), 4.91 – 4.29 (m, 1H), 4.25 – 4.02 (m, 1H), 3.95 – 3.52 (m, 1H), 1.75 – 1.46 (m, 3H). Second eluted compound (Example 27B): LC-MS: 316.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.68 – 13.49 (m, 1H), 7.56 – 7.48 (m, 1H), 7.44 (br s, 1H), 7.41 – 7.36 (m, 1H), 7.33 – 7.30 (m, 2H), 6.82 – 6.16 (m, 1H), 6.11 – 5.73 (m, 1H), 4.94 – 4.29 (m, 1H), 4.26 – 4.00 (m, 1H), 3.94 – 3.50 (m, 1H), 1.77 – 1.44 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Examples 28A and 28B: (R) or (S)-(6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5- methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0249] Step A: Racemic (6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone was prepared from 5- methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine and 6-chloro-7-methyl-1H- benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 398.1 [M+H]+.

[0250] Step B: Racemic (6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (20.0 mg, HCl salt) was purified by SFC separation ((DAICEL CHIRALPAK AD (250 × 30 mm, 10 μm); flow rate: 64 mL / min; gradient: 38% B over 15 min; mobile phase A: CO2, mobile phase B: EtOH (0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 28A): LC-MS: 398.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.54 – 10.04 (m, 1H), 7.70 (d, J = 3.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.11 – 6.62 (m, 2H), 5.63 – 5.05 (m, 1H), 4.58 (br d, J = 17.5 Hz, 2H), 3.89 – 3.44 (m, 1H), 2.75 (s, 3H), 1.67 – 1.51 (m, 3H). Second eluted compound (Example 28B): LC-MS: 398.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.42 – 10.08 (m, 1H), 7.70 – 7.30 (m, 2H), 7.10 – 6.65 (m, 2H), 5.64 – 5.06 (m, 1H), 4.96 – 4.52 (m, 2H), 3.89 – 3.42 (m, 1H), 2.80 – 2.53 (m, 3H), 1.64 – 1.51 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Examples 29A and 29B: (R) or (S)-(7-Methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7- Methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0251] Step A: Racemic (7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone was prepared from 5-methyl-3- (trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine and 7-methyl-1H-benzo[d]imidazole- 2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 364.1 [M+H]+.

[0252] Step B: Racemic (7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (10.0 mg, 0.0275 mmol, HCl salt) was further separated by SFC separation ((DAICEL CHIRALCEL OZ (250 × 25 mm, 10 μm); flow rate: 64 mL / min; gradient: 35% B over 4 min; mobile phase A: CO2, mobile phase B: MeOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 29A): LC-MS: 364.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.37 – 10.12 (m, 1H), 7.77 – 7.28 (m, 2H), 7.23 – 6.74 (m, 3H), 5.71 – 5.05 (m, 1H), 4.98 – 4.47 (m, 2H), 3.89 – 3.43 (m, 1H), 2.80 – 2.50 (m, 3H), 1.62 – 1.56 (m, 3H). Second eluted compound (Example 29B): LC-MS: 364.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 10.45 – 10.12 (m, 1H), 7.76 – 7.20 (m, 2H), 7.16 – 6.61 (m, 3H), 5.68 – 4.95 (m, 1H), 4.93 – 4.43 (m, 2H), 3.81 – 3.28 (m, 1H), 2.71 – 2.40 (m, 3H), 1.49 (br s, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 30: (R)-(4-Chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0253] Step A: A mixture of 3-chloro-5-fluorobenzene-1,2-diamine (200 mg, 1.26 mmol) and methyl 2,2,2-trichloroethanimidate (219 mg,1.25 mmol) in AcOH (2.00 mL) was stirred at 20 °Cfor 2 h. The reaction mixture was filtered and the filter cake was washed with 10.0 mL wa ter,dried in vacuum to give 7-chloro-5-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole. LC-MS: 288.9 [M+H]+.

[0254] Step B: A mixture of 7-chloro-5-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole (360 mg, 1.25 mmol) in NaOH (2M in aqueous, 4.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (5.0 mL) and extracted with MTBE (5.00 mL x 2). The aqueous phase was adjusted to pH 4 by adding HCl (1M aqueous) and extracted with DCM (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 7-chloro-5-fluoro-1H-benzo[d]imidazole-2-carboxylic acid. LC-MS: 213.1 [M+H]+.

[0255] Step C: A mixture of 7-chloro-5-fluoro-1H-benzo[d]imidazole-2-carboxylic acid (30.0 mg, 0.140 mmol), (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (21.0 mg, 0.112 mmol), HATU (27.0 mg, 0.070 mmol) and DIEA (54.0 mg, 0.419 mmol) in DMF (2.00 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column 75× 30mm× 3um); flow rate:25 mL / min; gradient: 15% – 40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (R)-(4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 344.9 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.77 – 8.48 (m, 2H), 8.01 – 7.86 (m, 1H), 7.36 – 6.97 (m, 2H), 6.09 – 5.88 (m, 1H), 4.97 (br dd, J = 4.6, 13.2 Hz, 1H), 3.84 – 3.31 (m, 3H), 1.96 – 1.64 (m, 3H). Example 31: (R)-(4-Chloro-6-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0256] (R)-(4-Chloro-6-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone was prepared from 3-chloro-5-methylbenzene-1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.83 – 8.70 (m, 1H), 8.67 – 8.47 (m, 1H), 8.00 – 7.83 (m, 1H), 7.43 – 7.17 (m, 2H), 6.84 – 5.87 (m, 1H), 5.86 – 4.58 (m, 1H), 3.53 – 3.22 (m, 3H), 2.43 (s, 3H), 1.83 – 1.56 (m, 3H). Example 32: (R)-(6-Fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0257] (R)-(6-Fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone was prepared from 5-fluoro-3-methylbenzene-1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 344.9 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.77 – 8.48 (m, 2H), 8.01 – 7.86 (m, 1H), 7.36 – 6.97 (m, 2H), 6.09 – 5.88 (m, 1H), 4.97 (br dd, J = 4.6, 13.2 Hz, 1H), 3.84 – 3.31 (m, 3H), 1.96 – 1.64 (m, 3H). Example 33: (R)-2-(5-Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1H- benzo[d]imidazole-7-carbonitrile

[0258] (R)-2-(5-Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1H- benzo[d]imidazole-7-carbonitrile was prepared from 2,3-diaminobenzonitrile according to the procedure of Example 30, Steps A, B, and C. LC-MS: 318.0 [M+H]+.1H NMR (400 MHz,CDCl3) δ 11.85 – 11.12 (m, 1H), 8.52 – 8.10 (m, 1H), 7.83 – 7.69 (m, 2H), 7.64 – 7.38 (m, 2H), 7.21 (br dd, J = 4.9, 7.4 Hz, 1H), 6.54 – 4.92 (m, 2H), 3.90 – 3.43 (m, 1H), 3.42 – 3.09 (m, 2H), 1.86 – 1.65 (m, 3H). Example 34: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3-(trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone

[0259] The title compound was prepared from 3-(trifluoromethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine and 7-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 370.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.68 – 13.55 (m, 1H), 7.60 – 7.25 (m, 3H), 6.17 – 5.10 (m, 2H), 5.07 – 4.37 (m, 2H), 4.31 – 4.15 (m, 2H). Example 35: (7-Methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0260] Step A: A solution of 4-methylpyridine-2,3-diamine (200 mg, 1.62 mmol) in 2- hydroxyacetic acid (266 mg, 3.51 mmol) was stirred at 140 °C for 3 h. The reaction mixture was allowed to cool to room temperature and treated with saturated NaHCO3aqueous (5.0 mL). The resulting precipitates are filtered and the cake was dried in vacuum to give 7 -methyl-2-(trichloromethyl)-1H-imidazo[4,5-b]pyridine. LC-MS: 162.1 [M+H]+.

[0261] Step B: A solution of KMnO4(261 mg, 1.65 mmol) in H2O (18.0 mL) was stirred at 100 °C. Then (7-methyl-1H-imidazo [4,5-b]pyridin-2-yl)methanol (180 mg, 1.10 mmol) and Na2CO3(85.3 mg, 0.805 mmol) in H2O (18.0 mL) was added. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was allowed to cool to room temperature, acidified to pH 2-3 with HCl (12M). The resulting precipitate was filtered and the cake was dried in vacuum to give 7-methyl-1H-imidazo[4,5-b]pyridine-2-carboxylic acid. LC-MS: 176.1 [M+H]+.

[0262] Step C: To a solution of 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (10.4 mg, 0.056 mmol) in DMF (0.50 mL) was added 7-methyl-1H-imidazo[4,5-b]pyridine-2-carboxylic acid (10.0 mg, 0.056 mmol), DIEA (21.9 mg, 0.169 mmol) and HATU (10.7 mg, 0.028 mmol).The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (5.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150× 40 mm, 10 μm); flow rate: 60 mL / min; gradient: 43% – 73% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone. LC-MS: 308.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.61 (br d, J = 7.1 Hz, 1H), 8.48 – 8.25 (m, 2H), 7.85 – 7.61 (m, 1H), 7.35 – 7.06 (m, 2H), 6.47 – 5.64 (m, 1H), 5.51 – 4.68 (m, 1H), 3.75 – 3.38 (m, 1H), 3.23 – 2.90 (m, 2H), 2.60 (br s, 3H), 1.81 – 1.49 (m, 3H). Examples 36A and 36B: (R) or (S)-2-(7-Chloro-1H-benzo[d]imidazole-2-carbonyl)-1- methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile and (R) or (S)-2-(7-Chloro- 1H-benzo[d]imidazole-2-carbonyl)-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carbonitrile

[0263] Step A: Racemic 2-(7-chloro-1H-benzo[d]imidazole-2-carbonyl)-1-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile was prepared from 1-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile and 4-chloro-1H-benzo[d]imidazole-2- carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 339.9 [M+H]+.

[0264] Step B: Racemic 2-(7-Chloro-1H-benzo[d]imidazole-2-carbonyl)-1-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile (40.0 mg, 0.120 mmol) was separated by SFC separation (Phenomenex-CHIRALPAK IH (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient: 60% B over 14 min; mobile phase A: heptane, mobile phase B: EtOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 36A): LC-MS: 339.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.42 – 10.08 (m, 1H), 7.73 – 7.20 (m, 3H), 6.91 – 6.41 (m, 1H), 6.06 – 4.89 (m, 1H), 4.38 – 3.37 (m, 2H), 2.10 (s, 2H), 1.74 – 1.52 (m, 2H), 1.28 – 0.41 (m, 2H). Second eluted compound (Example 36B): LC-MS:339.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.53 – 10.23 (m, 1H), 7.72 – 7.19 (m, 3H), 6.79 – 6.50 (m, 1H), 6.06 – 4.91 (m, 1H), 4.37 – 3.36 (m, 2H), 2.10 (s, 2H), 1.75 – 1.51 (m, 2H), 1.28 – 0.48 (m, 2H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 37: (R)-(4-(Difluoromethyl)-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0265] Step A: A solution of 3-bromobenzene-1,2-diamine (2 g, 10.7 mmol) and methyl 2,2,2-trichloroethanimidate (1.89 g, 10.7 mmol) in AcOH (20.0 mL) was stirred at 20 °C for 1 hr. Themixture was concentrated to give 7-bromo-2-(trichloromethyl)-1H-benzimidazole. LC-MS: 312.9 [M+H]+.

[0266] Step B: A solution of Na2CO3(809 mg, 7.63 mmol) in H2O (8.00 mL) was added to a solution of 7-bromo-2-(trichloromethyl)-1H-benzimidazole (2.40 g, 7.63 mmol) in MeOH (100 mL). The solution was stirred at 100 °C for 24 h. The reaction mixture was allowed to cool to room temperature and half of the solvent was removed in vacuum. The solution was then added to well-stirred water (5.00 mL) over 10 min. The solution was extracted with EtOAc (5.00 mL x 3). The combined organic phases were washed with brine (2.00 mL), dried over Na2SO4,filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford methyl 7- bromo-1H-benzimidazole-2-carboxylate. LC-MS: 256.9 [M+H]+.

[0267] Step C: To a solution of methyl 7-bromo-1H-benzimidazole-2-carboxylate (500 mg, 1.96 mmol) in DMF (8.00 mL) was added NaH (157 mg, 3.92 mmol, 60% purity). The mixture was stirred at 0 °C for 30 min, then SEM-Cl (392 mg, 2.35 mmol) was added. The mixture wasstirred at 20 °C for 12 h. The reaction mixture was poured into H2O (5.00ml), then extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 10 to afford methyl 7- bromo-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-carboxylate. LC-MS: 385.2 [M+H]+.

[0268] Step D: A mixture of methyl 7-bromo-1-(2-trimethylsilylethoxymethyl)benzimidazole- 2-carboxylate (70.0 mg, 0.182 mmol), Pd(dppf)Cl2(33.2 mg, 0.045 mmol), TES (83.3 mg, 0.363 mmol) and Na2CO3(19.3 mg, 0.182 mmol) in DMF (2.00 mL) was degassed and purged with CO for 3 times, and then the mixture was stirred at 70 °C for 24 h under CO (50 Psi) atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was purified via preparative TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf= 0.3) to afford methyl 7- formyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-carboxylate. LC-MS: 335.2 [M+H]+.

[0269] Step E: To a solution of methyl 7-formyl-1-(2- trimethylsilylethoxymethyl)benzimidazole-2-carboxylate (30.0 mg, 0.089 mmol) in DCM (1.00 mL) was added DAST (145 mg, 0.897 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with DCM (2.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified via preparative TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf= 0.7) to afford methyl 7-(difluoromethyl)-1-(2- trimethylsilylethoxymethyl)benzimidazole-2-carboxylate. LC-MS: 357.2 [M+H]+.

[0270] Step F: A solution of methyl 7-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-benzo[d]imidazole-2-carboxylate (15.0 mg, 0.042 mmol) in EtOH (0.600 mL) and HCl (0.200 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was allowed to cool to room temperature, poured into saturated NaHCO3aqueous (1.00 mL) and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na2SO4,filtered, and concentrated under vacuum to give methyl 7-(difluoromethyl)-1H-benzo[d]imidazole-2-carboxylate. LC-MS: 227.1 [M+H]+.

[0271] Step G: To a solution of methyl 7-(difluoromethyl)-1H-benzo[d]imidazole-2- carboxylate (10.0 mg, 0.044 mmol) in THF (0.050 mL) and EtOH (0.050 mL) was added NaOH aqueous (2M, 0.221 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum at 20oC to give 7-(difluoromethyl)-1H-benzo[d]imidazole-2- carboxylic acid. LC-MS: 213.0 [M+H]+.

[0272] Step H: To a solution of 7-(difluoromethyl)-1H-benzo[d]imidazole-2-carboxylic acid (8.00 mg, 0.037 mmol , HCl salt) and (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (13.1mg, 0.070 mmol) in DMF (0.500 mL) was added DIEA (18.3 mg, 0.141 mmol) and HATU (13.4 mg, 0.035 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (2.00 mL) and extracted with EtOAc (1.00 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 × 30 mm, 3 μm); flow rate: 30 mL / min; gradient: 1% – 30% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (R)-(4-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 343.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.76 – 8.67 (m, 1H), 8.50 – 8.29 (m, 1H), 7.90 – 7.72 (m, 2H), 7.60 – 7.34 (m, 3H), 5.94 – 5.66 (m, 1H), 3.73 (br s, 1H), 3.45 – 3.38 (m, 1H), 3.26 – 3.25 (m, 1H), 3.23 – 3.16 (m, 2H), 1.83 – 1.73 (m, 1H), 1.76 (d, J = 6.8 Hz, 2H). Example 38: (7-Chloro-1H-benzo[d]imidazol-2-yl)(1-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0273] Step A: A solution of MeMgBr (3M, 10.9 mL) was added into a solution of pyrazine-2- carbonitrile (3.00 g, 28.5 mmol) in THF (30.0 mL) at 0 °C. The mixture was warmed to 25 °C slowly, further stirred for 0.5 h, and followed by adding MeOH (60.0 mL) and NaBH4(2.16 g, 57.1 mmol) in portions. The mixture was stirred at 25 °C for 10 h. The mixture was poured into water (100 mL) and NaOH (2M aqueous, 100 mL), extracted with EtOAc (100 mL×3). The combined organic layers were washed in turn with water (80.0 mL×3) and brine (80.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 1-(pyrazin-2-yl)ethan-1-amine. LC-MS: 124.0 [M+H]+.

[0274] Step B: To a solution of 1-(pyrazin-2-yl)ethan-1-amine (1.27 g, 10.3 mmol) in DCM (10.0 mL) was added TFAA (4.33 g, 20.6 mmol). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated under vacuum to give 2,2,2-trifluoro-N-(1-(pyrazin-2- yl)ethyl)acetamide. LC-MS: 220.2 [M+H]+.

[0275] Step C: To a solution of 2,2,2-trifluoro-N-(1-(pyrazin-2-yl)ethyl)acetamide (750 mg, 3.42 mmol) in POCl3(10.0 mL) was added P2O5(607 mg, 4.28 mmol). The resulting mixture was stirred at 100 °C for 12 h. The mixture was concentrated under vacuum to give a residue which was poured into ice-water (20.0 mL), basified with Na2CO3(solid) to pH 8, and extracted with EtOAc (20.0 mL x 2). The combined organic phase was washed with water (10.0 mL x 2) and brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford 1-methyl-3-(trifluoromethyl)imidazo[1,5- a]pyrazine. LC-MS: 202.2 [M+H]+.

[0276] Step D: To a solution of 1-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine (300 mg, 1.49 mmol) in 2,2,2-trifluoroethanol (6.00 mL) was added palladium on carbon (10% purity, 317mg) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen andrepeated two times. The mixture was stirred at 20 °C for 3 h under a hydrogen atmosphere. Thesuspension was filtered through a pad of Celite and the pad was washed with 2,2,2 -trifluoroethanol (6.00 mL × 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by HPLC (Phenomenex Luna C18 (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 1% – 5% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford 1-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. LC-MS: 206.1 [M+H]+.

[0277] Step E: A mixture of 1-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine (100 mg, 0.487 mmol), 7-chloro-1H-benzimidazole-2-carboxylic acid (95.8 mg, 0.487 mmol), HATU (185 mg, 0.487 mmol) and DIEA (189 mg, 1.46 mmol) in DMF (3.00 mL) was stirred at 25 °C for 1 h. The mixture was poured into H2O (3.00 mL) at 0 °C, and extracted with EtOAc (3.00 mL x 2). The combined organic phase was washed with brine (4.00 mL), dried over Na2SO4, filtered, and concentrated to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 10 μm); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(1-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone. LC-MS: 384.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.61 – 10.30 (m, 1H), 7.85 – 7.29 (m, 3H), 6.12 – 5.12 (m, 2H), 4.99 (s, 1H), 4.49 – 4.13 (m, 3H), 2.32 – 2.22 (m, 3H). Example 39: (R)-(7-Cyclohexyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0278] Step A: To a solution of methyl 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-2-carboxylate (product of Example 37, step C) (150 mg, 0.389 mmol) and 2- (cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (162 mg, 0.779 mmol) in THF (5.00 mL) and H2O (1.00 mL) was added K3PO4(248 mg, 1.17 mmol) and Pd(dppf)Cl2(57.0 mg, 0.779 mmol) under nitrogen atmosphere. The mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into H2O (5.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 3 to afford methyl 7-(cyclohex-1-en-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carboxylate. LC-MS: 387.3 [M+H]+.

[0279] Step B: A solution of methyl 7-cyclohexyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d] imidazole-2-carboxylate (150 mg, 0.388 mmol) and 10% palladium on carbon (150 mg) in EtOAc (20.0 mL) was degassed and purged with hydrogen for three times. The mixture was stirred at 20 °C for 1 h under hydrogen (15 psi). The suspension was filtered through a pad of Celite, and the filter cake was extracted with EtOAc (2.00 mL x 3). The combined filtrates were concentrated under vacuum to give methyl 7-cyclohexyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carboxylate. LC-MS: 389.3 [M+H]+.

[0280] Step C: To a solution of methyl 7-cyclohexyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-2-carboxylate (100 mg, 0.257 mmol) in EtOH (4.80 mL) was added conc. HCl (1.60 mL). The mixture was stirred at 80 °C for 30 min. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.00 mL) and extracted with MTBE (5.00 mL x 2). The aqueous layer was acidified to pH 5 with 1M HCl. The product was extracted with DCM (3.00 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 7-cyclohexyl-1H-benzo[d]imidazole-2-carboxylic acid which was used in the next step without any further purification. LC-MS: 245.2 [M+H]+.

[0281] Step D: To a solution of 7-cyclohexyl-1H-benzo[d]imidazole-2-carboxylic acid (40.0 mg, 0.819 mmol and (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (30.2 mg, 0.819 mmol) in DCM (3.00 mL) was added TEA (24.9 mg, 0.246 mmol) and T4P (118 mg, 0.164 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was poured into H2O (5.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 × 50 mm, 10 µm); flow rate: 25 mL / min; gradient: 50% – 85% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (R)-(7-cyclohexyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone. LC-MS: 375.2 [M+H]+. Example 40: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3-(difluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0282] The title compound was prepared from 3-(difluoromethyl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 352.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.61 – 7.50 (m, 1H), 7.43 – 7.29 (m, 2H), 7.28 – 7.08 (m, 1H), 7.07 – 6.93 (m, 1H), 5.77 – 5.64 (m, 1H), 5.07 – 4.95 (m, 1H), 4.99 (s, 2H), 4.40 – 4.29 (m, 2H), 4.14 (br d, J = 4.5 Hz, 1H). Example 41: (R)-(6-Chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone

[0283] The title compound was prepared from 5-chloro-4-methylpyridine-2,3-diamine according to the procedure of Example 35, Steps A, B, and C. LC-MS: 342.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.81 – 8.68 (m, 1H), 8.56 (br d, J = 7.1 Hz, 1H), 8.51 – 8.42 (m, 1H), 8.00 – 7.74 (m, 1H), 6.67 – 5.83 (m, 1H), 5.56 – 4.74 (m, 2H), 3.88 – 3.03 (m, 3H), 2.66 (s, 3H), 1.93 – 1.48 (m, 3H).Example 42: (R)-(4-Fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0284] Step A: A solution of 3-fluoro-6-methyl-2-nitroaniline (500 mg, 6.25 mmol) and 10% palladium on carbon (500 mg) in EtOAc (100 mL) was degassed and purged with hydrogen for three times. The mixture was stirred at 20 °C for 1 h under hydrogen (15 psi). The suspension was filtered through a pad of Celite, and the cake was washed with EtOAc (20.0 mL×3). The combined filtrates were concentrated under vacuum to give 3-fluoro-6-methylbenzene-1,2- diamine. LC-MS: 141.3 [M+H]+.

[0285] Steps B, C, and D: The title compound was prepared from 3-fluoro-6-methylbenzene- 1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 325.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.61 (br t, J = 5.8 Hz, 1H), 8.33 – 8.15 (m, 1H), 7.82 – 7.58 (m, 1H), 7.14 – 6.96 (m, 2H), 6.70 – 6.52 (m, 1H), 6.15 – 5.06 (m, 1H), 4.03 – 3.27 (m, 3H), 2.57 (d, J = 8.8 Hz, 3H), 1.88 – 1.71 (m, 3H). Example 43: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3,5-dimethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0286] Step A: To a solution of LiHMDS (52.6 mL, 52.6 mmol, 1M) in THF (30.0 mL) was added acetonitrile (2.16 g, 52.6 mmol) at –78 °C dropwise under nitrogen. The mixture was stirred at –78 °C for 1 h. And then 3-bromo-2-fluoro-5-methylpyridine (5.00 g, 26.3 mmol) in THF (30.0 mL) was added at –78 °C dropwise. The mixture was stirred at same temperature for 2 h and then stirred at 20 °C for 12 h under nitrogen. The reaction mixture was poured into H2O (80.0 mL) and washed with EtOAc (100 mL x 3). The combined organic layers were dried overNa2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flashsilica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford 2-(3-bromo-5-methylpyridin-2-yl)acetonitrile. LC-MS: 211.0 [M+H]+.

[0287] Step B: To a solution of Raney Ni (2.20 g) in MeOH (220 mL) was added 2-(3-bromo- 5-methylpyridin-2-yl)acetonitrile (2.20 g, 10.4 mmol) and Boc2O (11.4 g, 52.1 mmol). The mixture was stirred at 20 °C for 6 h under hydrogen. The mixture was filtered through Celite pad, filtered, and concentrated under vacuum to give a residue which was purified by flash silicagel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford tert-butyl (2-(3-bromo-5-methylpyridin-2-yl)ethyl)carbamate. LC-MS: 315.2 [M+H]+.

[0288] Step C: A mixture of tert-butyl (2-(3-bromo-5-methylpyridin-2-yl)ethyl)carbamate (1.48 g, 4.70 mmol), tributyl(1-ethoxyvinyl)stannane (3.90 g, 10.8 mmol) and Pd(PPh3)2Cl2(264 mg, 0.376 mmol) in dioxane (30.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 2 h under nitrogen. The reaction mixture was poured into H2O (30.0 mL) and washed with EtOAc (30.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford tert-Butyl (2-(3-(1-ethoxyvinyl)-5-methylpyridin-2-yl)ethyl)carbamate. LC-MS: 307.3 [M+H]+.

[0289] Step D: To a mixture of tert-butyl (2-(3-(1-ethoxyvinyl)-5-methylpyridin-2- yl)ethyl)carbamate (1.29 g, 4.21 mmol) in EtOAc (1.00 mL) was added HCl / EtOAc (4M, 12.9 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum to give 3,5-dimethyl-7,8-dihydro-1,6-naphthyridine. LC-MS:161.2 [M+H]+.

[0290] Step E: To a solution of 3,5-dimethyl-7,8-dihydro-1,6-naphthyridine (200 mg, 1.25 mmol) in MeOH (4.00 mL) was added NaBH4(104 mg, 2.75 mmol) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (5.00 mL) andwashed with DCM (5.00 mL x 3). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give 3,5-dimethyl-5,6,7,8-tetrahydro-1,6- naphthyridine. LC-MS: 163.3 [M+H]+.

[0291] Step F: To a solution of 3,5-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine (60.0 mg, 0.370 mmol) and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (72.7 mg, 0.370 mmol) in DMF (2.00 mL) was added DIEA (143 mg, 1.11 mmol) and HATU (141 mg, 0.370 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and washed with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparativeHPLC (Phenomenex Gemini C18 column (75 × 30 mm, 3 μm); flow rate: 60 mL / min; gradient: 5% – 35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(3,5-dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone. LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.87 – 8.59 (m, 1H), 8.53 – 8.24 (m, 1H), 7.70 – 7.47 (m, 1H), 7.43 – 7.28 (m, 2H), 6.69 – 5.81 (m, 1H), 5.77 – 4.72 (m, 2H), 3.81 – 3.07 (m, 3H), 2.48 – 2.35 (m, 3H), 1.85 – 1.55 (m, 3H). Example 44: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3-(trifluoromethyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methanone

[0292] Step A: To a solution of tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (2.00 g, 8.96 mmol) in toluene (40.0 mL) and DMF (10.0 mL) was added NIS (2.12 g, 9.41 mmol). The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was poured into H2O (50.0 mL) and extracted with EtOAc (50.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford tert-butyl 3-iodo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate. LC- MS: 350.2 [M+H]+.

[0293] Step B: A mixture of tert-butyl 3-iodo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (800 mg, 2.29 mmol), methyl 2,2-difluoro-2-fluorosulfonyl-acetate (3.74 g, 19.5 mmol), CuI (3.71 g, 19.5 mmol) in DMF (15.0 mL) was degassed and purged with nitrogen for 3times, and then the mixture was stirred at 60 °C for 12 h under a nitrogen atmosphere. Thereaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (30.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford tert-butyl 3-(trifluoromethyl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate. LC-MS: 292.2 [M+H]+.

[0294] Step C: A solution of tert-butyl 3-(trifluoromethyl)-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (200 mg, 0.687 mmol) in HCl / EtOAc (4M, 2.00 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give a residue which was purifiedby preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25mL / min; gradient: 1% – 10% B over 8 min; mobile phase A: 0.1% aqueous HCl, mobile phase B: acetonitrile) to afford 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine. LC-MS: 192.2 [M+H]+.

[0295] Step D: A mixture of 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (100 mg, 0.523 mmol), 7-chloro-1H-benzimidazole-2-carboxylic acid (103 mg, 0.523 mmol), HATU (199 mg, 0.523 mmol) and DIEA (203 mg, 1.57 mmol) in DMF (2.00 mL) was stirred at 25 °C for 1 h. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (2.00 ml) and extracted with EtOAc (2.00 ml × 3). The combine organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 0.04% aqueous HCl mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(3-(trifluoromethyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methanone. LC-MS: 370.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.75 - 7.63 (m, 2H), 7.36 (br s, 2H), 5.70 - 5.16 (m, 4H), 4.64 (br s, 2H). Example 45: (7-Chloro-1H-benzo[d]imidazol-2-yl)(2,5-dimethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0296] The title compound was prepared from 3-bromo-2-fluoro-6-methylpyridine according to the procedure of Example 43, Steps A, B, C, D, E, and F. LC-MS: 342.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.60 – 8.29 (m, 1H), 7.88 – 7.68 (m, 1H), 7.62 – 7.50 (m, 1H), 7.45 – 7.26 (m, 2H), 6.71 – 5.83 (m, 1H), 5.78 – 4.73 (m, 2H), 3.76 – 3.16 (m, 3H), 2.84 – 2.65 (m, 3H), 1.85 – 1.44 (m, 3H). Example 46: (6-Chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(7-methyl-1H- benzo[d]imida zol-2-yl)methanone

[0297] Step A: A mixture of 6-chloro-1,2,3,4-tetrahydro-2,7-naphthyridine (35.0 mg, 0.207 mmol), 7-methyl-1H-benzimidazole-2-carboxylic acid (36.0 mg, 0.207 mmol), TEA (63.0 mg, 0.622 mmol) and T4P (249 mg, 0.415 mmol, 50% purity) in DCM (1.00 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30oC to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column 75× 30mm× 3um); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(7-methyl-1H- benzo[d]imidazol-2-yl)methanone. LC-MS: 327.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.30 – 8.09 (m, 1H), 7.75 – 7.61 (m, 1H), 7.44 – 7.27 (m, 2H), 7.18 – 7.06 (m, 1H), 5.62 – 5.32 (m, 1H), 4.75 – 4.43 (m, 1H), 4.31 – 4.07 (m, 1H), 4.00 – 3.70 (m, 1H), 3.18 – 3.01 (m, 1H), 2.99 – 2.82 (m, 1H), 2.73 – 2.63 (m, 3H). Example 47: (R)-(7-(Difluoromethyl)-1H-indol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0298] Step A: To a solution of ethyl 7-bromo-1H-indole-2-carboxylate (5.00 g, 18.7 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.18 g, 46.6 mmol) in dioxane (100 mL) and H2O (10.0 mL) was added Na2CO3(4.55 mg, 42.9 mmol) and Pd(dppf)Cl2(1.52 g, 1.86 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 80 °C for 10 h under nitrogen. The reaction mixture was allowed to cool to room temperature, poured into water (100 mL) and extracted with EtOAc (80.0 mL x 2). The combined organic layers were dried over Na2SO4,filtered, and concentrated under vacuum to give a residue which was purifiedby flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 20 to afford ethyl 7-vinyl-1H-indole-2-carboxylate. LC-MS: 216.1[M+H]+.

[0299] Step B: A mixture of ethyl 7-vinyl-1H-indole-2-carboxylate (850 mg, 3.95 mmol) in NMP (12.0 mL) at 0 °C was degassed and purged with nitrogen. To the mixture was added NaH (316 mg, 7.95 mmol, 60% purity) and the resulting mixture was stirred at 0 °C for 0.5 h, followed by SEM-Cl (658 mg, 3.95 mmol) and purged with nitrogen three times, then stirred at 20 °C for 1 h under nitrogen. The mixture was poured into water (12.0 mL) and extracted with EtOAc (12.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 20 to afford ethyl 1- ((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indole-2-carboxylate. LC-MS: 228.1 [M+H]+.

[0300] Step C: A mixture of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indole-2- carboxylate (440 mg, 1.27 mmol) in THF (1.00 mL) and H2O (1.00 mL) was cooled to 0 °C. Themixture was degassed and purged with nitrogen three times. To the mixture was added OsO 4(1.25 g, 0.255 mmol) and the resulting mixture was stirred at 0 °C for 1 h. To the mixture was added NaIO4(1.36 g, 6.37 mmol) and purged with nitrogen three times, then stirred at 20 °C for 12 h under nitrogen. The mixture was poured into water (50.0 mL) and extracted with EtOAc (50.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 20 to afford ethyl 7-formyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate. LC-MS: 230.1 [M+H]+.

[0301] Steps D, E, F, and G: (R)-(7-(Difluoromethyl)-1H-indol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone was prepared from ethyl 7-formyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate according to the procedure of Example 37, Steps E, F, G, and H. LC-MS: 342.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 9.49 (br s, 1H), 8.62 (br d, J = 3.8 Hz, 1H), 8.21 (br d, J = 7.0 Hz, 1H), 7.96 – 7.66 (m, 2H), 7.38 (d, J = 7.0 Hz, 1H), 7.26 – 7.19 (m, 1H), 7.12 – 6.71 (m, 2H), 5.97 (q, J = 6.5 Hz, 1H), 4.97 (br d, J = 7.6 Hz, 1H), 4.14 – 3.88 (m, 1H), 3.80 – 3.45 (m, 2H), 1.75 (br d, J = 5.5 Hz, 3H). Example 48: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-ethyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0302] Step A: To a mixture of methyl 2-bromonicotinate (1.80 g, 8.33 mmol) and potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (2.30 g, 9.17 mmol) in H2O (15.0 mL) and toluene (45.0 mL) was added Pd(dppf)Cl2(610 mg, 0.833 mmol) and Cs2CO3(8.14 g, 25.0 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (40.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gelchromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 7 to afford methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)nicotinate. LC-MS: 281.3 [M+H]+.

[0303] Step B: To a solution of methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)nicotinate (1.45 g, 5.17 mmol) in dioxane (10.0 mL) was added NaOH aqueous (2M, 1.5 mL), then the mixture was stirred at 25 °C for 1 h. The reaction mixture was added to H2O (15.0 mL) and extracted with MTBE (5.00 mL x 3). The aqueous phase was neutralized to pH 5 - 4 using 1M HCl and then the precipitate was filtered .The reaction mixture was filtered and the filter cake was washed with H2O (1.00 mL x 2), dried in vacuum to give 2-(2-((tert- butoxycarbonyl)amino)ethyl)nicotinic acid. LC-MS: 267.2 [M+H]+.

[0304] Step C: A mixture of 2-(2-((tert-butoxycarbonyl)amino)ethyl)nicotinic acid (1.15 g, 4.32 mmol), N-methoxymethanamine (463 mg, 4.75 mmol, HCl salt), HATU (821 mg, 2.16 mmol) and DIEA (1.50 mL, 8.64 mmol) in DMF (20.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (20.0 mL) and extracted with DCM (10.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient ofEtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford tert-butyl (2-(3- (methoxy(methyl)carbamoyl)pyridin-2-yl)ethyl)carbamate. LC-MS: 310.2 [M+H]+.

[0305] Step D: To a solution of tert-butyl (2-(3-(methoxy(methyl)carbamoyl)pyridin-2- yl)ethyl)carbamate (400 mg, 1.29 mmol) in THF (15.0 mL) was added EtMgBr (3 M, 1.30 mL) at 0 °C. The mixture was stirred at 20 °C for 5 h. The reaction mixture was poured into H2O (15.0 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 1 to afford tert-butyl (2-(3-propionylpyridin-2-yl)ethyl)carbamate. LC-MS: 279.3 [M+H]+.

[0306] Step E: To a solution of tert-butyl (2-(3-propionylpyridin-2-yl)ethyl)carbamate (70.0 mg, 0.251 mmol) in MeOH (2.00 mL) was added NaBH4(14.3 mg, 0.377 mmol) at 0°C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (2.00 mL) andextracted with EtOAc (1.00 mL x 3). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give tert-butyl (2-(3-(1-hydroxypropyl)pyridin-2- yl)ethyl)carbamate. LC-MS: 281.2 [M+H]+.

[0307] Step F: To a solution of tert-butyl (2-(3-(1-hydroxypropyl)pyridin-2- yl)ethyl)carbamate (80.0 mg,0.285 mmol) in DCM (2.00 mL) was added TEA (59.6 μL, 0.428 mmol), followed by MsCl (65.4 mg, 0.571 mmol) at 0 °C under a Nitrogen atmosphere. The resulting reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by preparative TLC (EtOAc, Rf = 0.4 and 0.3) to afford tert-butyl (2-(3-(1-chloropropyl)pyridin-2- yl)ethyl)carbamate. LC-MS: 299.2 [M+H]+.

[0308] Step G: To a solution of tert-butyl (2-(3-(1-chloropropyl)pyridin-2-yl)ethyl)carbamate (20.0 mg, 0.067 mmol) in DMF (0.50 mL) was added t-BuONa (12.9 mg, 0.134 mmol) and KI (1.11 mg, 0.007 mmol). The mixture was stirred at 100 °C for 0.5 h. The reaction mixture was poured into H2O (1.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 5- ethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. LC-MS: 263.3 [M+H]+.

[0309] Step H: To a solution of tert-butyl 5-ethyl-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate (45.0 mg,0.172 mmol) in EtOAc (0.50 mL) was added HCl / EtOAc (4M, 1.00 mL). The resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum to give 5-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridine. LC-MS: 163.3 [M+H]+.

[0310] Step I: A mixture of 5-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridine (30.0 mg, 0.151 mmol, HCl salt), 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (29.7 mg, 0.151 mmol), HATU (28.7 mg, 0.075 mmol) and DIEA (0.039 mL, 0.226 mmol) in DMF (1.00 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 10% – 40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(5-ethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.84 – 8.69 (m, 1H), 8.64 – 8.45 (m, 1H), 7.97 – 7.82 (m, 1H), 7.62 – 7.50 (m, 1H), 7.45 – 7.29 (m, 2H), 6.96 – 5.86 (m, 1H), 5.81 – 4.70 (m, 1H), 3.79 – 3.65 (m, 1H), 3.34 – 3.22 (m, 2H), 2.07 – 1.91 (m, 2H), 1.07 – 0.93 (m, 3H). Example 48A: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-ethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (single enantiomer)

[0311] Step A: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-ethyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone (8.00 mg, 0.024 mmol) was separated by SFC separation((DAICEL CHIRALCEL OZ (250 × 30 mm, 10 μm); flow rate: 64 mL / min; gradient: 45% B over 4 min; mobile phase A: CO2, mobile phase B: MeOH(0.1%NH3H2O)) to afford (R) or (S)-(7-chloro-1H- benzo[d]imidazol-2-yl)(5-ethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (first eluent). LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 11.05 – 10.41 (m, 1H), 8.49 (br d, J = 0.8 Hz, 1H), 7.85 – 7.30 (m, 3H), 7.23 (br d, J = 5.3 Hz, 1H), 5.83 (br t, J = 7.3 Hz, 1H), 5.11 – 2.99 (m, 3H), 2.01 (dt, J = 7.0, 14.1 Hz, 2H), 1.35 – 0.92 (m, 5H). The absolute stereochemistry of Example 48A was not determined. Examples 49A and 49B: (R) or (S)-(6-Chloro-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5- methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(6-Chloro-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-3-(trifluoromethyl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0312] Step A: Racemic (6-chloro-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone was prepared from 5- methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine and 6-chloro-7-methyl-1H- imidazo[4,5-b]pyridine-2-carboxylic acid according to the procedure of Example 1, Step A. LC- MS: 399.2 [M+H]+.

[0313] Step B: Racemic (6-Chloro-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (71.0 mg, 0.178 mmol) was further purified by SFC separation((Phenomenex-Cellulose-2 (250 × 30 mm, 10 μm); flow rate: 70 mL / min; gradient: 30 – 30% B over 11 min; mobile phase A: CO2, mobile phase B: EtOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 49A): LC-MS: 399.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 14.13 – 13.84 (m, 1H), 8.46 (s, 1H), 7.27 – 6.90 (m, 1H), 6.43 – 5.66 (m, 1H), 5.54 – 4.42 (m, 3H), 3.95 – 3.50 (m, 1H), 2.88 – 2.55 (m, 3H), 1.54 – 1.32 (m, 3H). Second eluted compound (Example 49B): LC-MS: 399.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.23 – 6.82 (m, 1H), 6.20 – 5.54 (m, 1H), 5.46 – 4.49 (m, 3H), 3.85 – 3.44 (m, 1H), 2.60 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 50: (R)-2-(5-Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1H- benzo[d]imidazole-7-carbonitrile

[0314] (R)-2-(5-Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1H- benzo[d]imidazole-7-carbonitrile was prepared from 2-(trichloromethyl)-3H-benzimidazole-4- carbonitrile according to the procedure of Example 30, Steps B and C. LC-MS: 318.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.56 – 13.97 (m, 1 H), 8.36 – 8.48 (m, 1 H), 7.92 (br d, J =7.75 Hz, 1 H), 7.61 – 7.85 (m, 2 H), 7.41 – 7.55 (m, 1 H), 7.18 – 7.34 (m, 1 H), 5.66 – 6.42 (m, 1 H), 4.58 – 5.55 (m, 1 H), 3.40 – 3.79 (m, 1 H), 3.12 – 3.25 (m, 1 H), 2.94 – 3.01 (m, 1 H), 1.47 – 1.78 (m, 3 H). Example 51: (S)-(6-Chloro-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone

[0315] The title compound was prepared from 3-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine and 4-chloro-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 3, Step A. LC-MS: 342.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 – 8.67 (m, 2 H), 8.00 – 8.22 (m,1 H), 7.46 – 7.62 (m,1 H), 5.76 – 6.52 (m, 1 H), 4.71 – 5.48 (m, 1 H), 3.24 – 3.86 (m, 2 H), 3.06 – 3.17 (m, 1 H), 2.66 (s, 3 H), 1.57 – 1.78 (m, 3 H). Examples 52A and 52B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(2,5-dimethyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone and (R) or (S)-(7-Chloro-1H- benzo[d]imidazol-2-yl)(2,5-dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

[0316] Step A: Racemic (7-chloro-1H-benzo[d]imidazol-2-yl)(2,5-dimethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone was prepared from 2,5-dimethyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 341.2 [M+H]+.

[0317] Step B: Racemic (7-chloro-1H-benzo[d]imidazol-2-yl)(2,5-dimethyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (170 mg) was purified by SFC separation ((Phenomenex- Cellulose-2(250 × 30 mm, 10 μm); flow rate: 70 mL / min; gradient: 40 – 40% B over 11 min; mobile phase A: CO2, mobile phase B: EtOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 52A): LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.78 – 13.17 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (br d, J = 7.9 Hz, 1H), 7.42 – 7.25 (m, 2H), 7.19 – 7.01 (m, 1H), 6.52 – 5.46 (m, 1H), 3.82 – 3.33 (m, 2H),3.22 – 2.82 (m, 2H), 2.46 – 2.36 (m, 3H), 1.72 – 1.48 (m, 3H). Second eluted compound (Example 52B): LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.70 – 13.34 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 (br d, J = 7.9 Hz, 1H), 7.42 – 7.27 (m, 2H), 7.20 – 7.03 (m, 1H), 6.55 – 5.47 (m, 1H), 3.69 (br d, J = 1.0 Hz, 2H), 3.26 – 2.83 (m, 2H), 2.47 – 2.36 (m, 3H), 1.74 – 1.41 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 53: 2-(7-Chloro-1H-benzo[d]imidazole-2-carbonyl)-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine-6-carbonitrile

[0318] Step A: To a solution of tert-butyl 6-formyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2- carboxylate (300 mg, 1.20 mmol) in H2O (2.00 mL) and EtOH (2.00 mL) was added NH2OSO3H (135 mg, 1.20 mmol). The mixture was stirred at 80 °C for 1 h. The solvent was removed in vacuum to give a residue, which was dissolved in DMF (5.00 mL), and the resulting solution was purified by prep-HPLC (column: Phenomenex luna C1880 × 40mm×3 um; mobile phase: [H2O (0.1% TFA)-ACN];gradient:1% - 5% B over 8.0 min ) to afford 1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine-6-carbonitrile. LC-MS: 148.3 [M+H]+.

[0319] Step B: To a solution of 7-chloro-1H-benzimidazole-2-carboxylic acid (80.1 mg, 0.407 mmol) in DCM (2.00 mL) were added TEA (123 mg, 1.20 mmol) and BOP-Cl (155 mg, 0.611 mmol) at 0 °C and the resulting mixture was stirred at 0 °C for 1h, then 1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile (60.0 mg, 0.407 mmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The solvent was removed in vacuum to give a residue, which was dissolved in DMF (5.00 mL), and the resulting solution was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18100×30mm×10um; mobile phase: [H2O (10mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min ) to afford 2-(7-chloro-1H- benzimidazole-2-carbonyl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-6-carbonitrile. LC-MS: 326.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.55 (br d, J = 8.13 Hz, 1 H), 7.26 – 7.35 (m, 2 H), 6.96 – 7.02 (m, 1 H), 6.00 – 6.29 (m, 1 H),5.65 (s, 1 H), 4.72 – 5.06 (m, 3 H), 4.14 – 4.28 (m, 3 H). Example 54: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)methanone

[0320] Step A: 2,2,6,6-Tetramethylpiperidine (9.18 g, 65.0 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. n-BuLi (2.5 M, 25.0 mL) was added dropwise to keep the temperature below -70 °C. The mixture was stirred at -78 °C for 30 min under N2atmosphere.2- Chloropyrazine (5.73 g, 50.0 mmol) was added dropwise and the mixture was stirred for 1 h. After this time, acetaldehyde (5M, 20.0 mL) was added and the mixture was allowed to warm to 20 °C and stirred for another 4 h under N2atmosphere. The reaction mixture was poured into H2O (50.0 mL) and extracted with DCM (50.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified byflash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 3 toafford 1-(3-chloropyrazin-2-yl)ethan-1-ol.1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 5.28 – 5.11 (m, 1H), 1.53 (d, J = 6.5 Hz, 3H).

[0321] Steps B, C, D, E, F, G, and H: (7-Chloro-1H-benzimidazol-2-yl)-(5-methyl-7,8- dihydro-5H-pyrido[3,4-b]pyrazin-6-yl)methanone was prepared from 1-(3-chloropyrazin-2- yl)ethan-1-ol according to the procedure of Example 11, Steps B, C, D, E, F, G, and H. LC-MS: 328.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.60 – 8.40 (m, 2H), 7.75 – 7.29 (m, 3H), 6.53 – 4.97 (m, 2H), 3.79 – 3.15 (m, 3H), 1.92 – 1.70 (m, 3H). Examples 54A and 54B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone and (R) or (S)-(7-Chloro-1H- benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanone

[0322] Step A: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydropyrido[3,4- b]pyrazin-6 (5H)-yl)methanone (50.0 mg, 0.153 mmol) was further separated by SFC separation (Phenomenex-DAICEL CHIRALPAK AD (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient:50% B over 14 min; mobile phase A: heptane, mobile phase B: EtOH (0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 54A): LC-MS: 328.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.88 – 10.33 (m, 1H), 8.61 – 8.33 (m, 2H), 7.84 – 7.28 (m, 3H), 6.68 – 6.36 (m, 1H), 5.98 – 4.93 (m, 1H), 3.82 – 3.02 (m, 3H), 2.00 – 1.68 (m, 3H). Second eluted compound (Example 54B): LC-MS: 328.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.76 – 10.29 (m, 1H), 8.56 – 8.35 (m, 2H), 7.86 – 7.28 (m, 3H), 6.64 – 6.30 (m, 1H), 6.07 – 4.88 (m, 1H), 3.92 – 2.93 (m, 3H), 1.95 – 1.68 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 55: 2-(7-Chloro-1H-benzo[d]imidazole-2-carbonyl)-4-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile

[0323] Step A: To a solution of 4-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (800 mg, 5.33 mmol) in THF (32.0 mL) was added LAH (2.5M in THF). The mixture was degassed and purged with nitrogen three times and stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to 0 °C, the reaction mixture was quenched by addition of 0.60 mL of H2O, followed by 0.60 mL of 10% aqueous NaOH and 1.80 mL of H2O. After being stirred at 20 °C for 5 min, then added MgSO4, the mixture was filtered through Celite pad, then was concentrated in vacuum to give 4-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine. LC- MS: 137.2 [M+H]+.

[0324] Step B: To a solution of 4-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (800 mg, 5.87 mmol) in DCM (10.0 mL) was added Boc2O (1.41 g, 6.46 mmol) and TEA (594 mg, 5.87 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (20.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were driedover Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified byflash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 toafford tert-butyl 4-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. LC-MS: 237.3 [M+H]+.

[0325] Step C: To a solution of tert-butyl 4-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate (300 mg, 1.27 mmol) in DCM (20.0 mL) was added sulfurisocyanatidic chloride (198 mg, 1.40 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 0 °C for 1 h under a nitrogen atmosphere. Then DMF (928 mg, 12.7 mmol) was added dropwise to the mixture, cooled to -10 °C. The resulting mixture was stirred at 20 °C for 5 h. The reaction mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 3 to afford tert-butyl 6-cyano-4-methyl-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.1H NMR (400 MHz, DMSO d6) δ 6.96 (d, J = 4.0 Hz, 1H), 6.05 (d, J = 4.0 Hz, 1H), 5.06 – 4.69 (m, 1H), 4.51 – 4.11 (m, 2H), 3.54 – 3.35 (m, 1H), 1.43 (s, 9H), 1.32 (br d, J = 6.4 Hz, 3H).

[0326] Step D: To a solution of tert-butyl 6-cyano-4-methyl-3,4-dihydropyrrolo[1,2- a]pyrazine-2(1H)-carboxylate (180 mg, 0.689 mmol) in EtOAc (2.00 mL) was added HCl / EtOAc (4M, 10.0 mL). The resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30 °C to give 4-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile. LC-MS: 162.1 [M+H]+.

[0327] Step E: A mixture of 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (49.7 mg, 0.253 mmol), 4-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile (50.0 mg, 0.253 mmol), HATU (48.1 mg, 0.126 mmol) and DIEA (98.1 mg, 0.759 mmol) in DMF (1.00 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 5% – 35% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford 2-(7- chloro-1H-benzo[d]imidazole-2-carbonyl)-4-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carbonitrile. LC-MS: 340.1 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 7.56 (br d, J = 8.0 Hz, 1H), 7.47 – 7.26 (m, 2H), 7.07 – 6.96 (m, 1H), 6.40 - 6.08 (m, 1H), 5.45 – 4.91 (m, 1H), 4.76 – 4.44 (m, 2H), 4.01 (br dd, J = 3.7, 13.9 Hz, 2H), 1.42 (dd, J = 3.8, 6.3 Hz, 3H). Example 56: (6-Chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)(2,5-dimethyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone

[0328] The title compound was prepared from 2,5-dimethyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 356.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.55 – 8.30 (m, 2H), 7.85 – 7.66 (m, 1H), 6.58 – 5.79 (m, 1H), 5.53 – 4.68 (m, 1H), 3.53 – 3.06 (m, 3H), 2.76 – 2.68 (m, 3H), 2.67 – 2.61 (m, 3H), 1.75 (d, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 2H). Example 57: (R)-(5-Chloro-4,6-dimethyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone

[0329] The title compound was prepared from (R)-5-methyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 5-chloro-4,6-dimethyl-1H-benzimidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 355.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.60 (br d, J = 3.4 Hz, 1H), 8.31 – 8.07 (m, 1H), 7.88 – 7.69 (m, 1H), 7.40 (br d, J = 15.4 Hz, 1H), 6.04 (br d, J = 7.3 Hz, 1H), 5.19 – 3.19 (m, 4H), 2.71 – 2.50 (m, 6H), 1.85 (br d, J = 6.6 Hz, 1H), 1.70 (br d, J = 6.9 Hz, 2H). Example 58: (2,5-Dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluoro-7-methyl-1H- benzo[d]imidazol-2-yl)methanone

[0330] The title compound was prepared from 2,5-dimethyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 7-fluoro-4-methyl-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 339.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.54 – 8.33 (m, 1H), 7.88 – 7.67 (m, 1H), 7.13 – 6.91 (m, 2H), 6.61 – 5.82 (m, 1H), 5.62 – 4.72 (m, 1H), 4.93 – 4.63 (m, 1H), 3.98 – 3.54 (m, 2H), 3.48 – 2.99 (m, 3H), 2.71 (br s, 3H), 1.84 – 1.51 (m, 3H). Examples 58A and 58B: (R) or (S)-(2,5-Dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)(4-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)methanone and (R) or (S)-(2,5-Dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluoro-7-methyl-1H-benzo[d]imidazol-2- yl)methanone

[0331] Step A: (2,5-Dimethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluoro-7-methyl-1H- benzo[d]imidazol-2-yl)methanone (20.0 mg, 0.059 mmol) was separated by SFC separation(ChiralPak IH (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient:50% B over 14 min;mobile phase A: heptane, mobile phase B: CO2- EtOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 58A): LC-MS: 339.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.71 – 10.27 (m, 1H), 7.87 – 7.59 (m, 1H), 7.22 – 6.85 (m, 3H), 6.58 – 4.94 (m, 2H), 3.74 – 3.32 (m, 3H), 2.76 – 2.50 (m, 6H), 1.80 (br s, 1H), 1.63 (br d, J = 6.6 Hz, 2H). Second eluted compound (Example 58B): LC-MS: 339.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.86 – 10.50 (m, 1H), 7.61 – 7.40 (m, 1H), 7.22 – 6.88 (m, 3H), 6.49 – 4.93 (m, 2H), 3.87 – 3.11 (m, 3H), 2.74 – 2.45 (m, 6H), 1.77 (br d, J = 6.6 Hz, 2H), 1.61 (br d, J = 6.6 Hz, 1H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 59: (4-Chloro-1H-benzo[d]imidazol-2-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)- yl)methanone

[0332] The title compound was prepared from 1-methyl-1,2,3,4-tetrahydroisoquinoline and 4- chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 326.1 [M+H]+. Example 60: (4-Chloro-1H-benzo[d]imidazol-2-yl)(2-chloro-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0333] The title compound was prepared from 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 347.2 [M+H]+.1H NMR (400 MHz,CDCl3) δ 7.89 – 7.69 (m, 1H), 7.58 – 7.44(m, 1H), 7.40 – 7.36 (m, 1H), 7.31 (br d, J = 6.9 Hz, 1H), 7.23 (dd, J = 4.7, 8.0 Hz, 1H), 6.05 – 5.73 (m, 1H), 5.11 – 4.88 (m, 2H), 4.18 (t, J = 6.2 Hz, 1H), 3.34 – 3.01 (m, 2H). Example 61: (4-Chloro-1H-benzo[d]imidazol-2-yl)(7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone

[0334] The title compound was prepared from 5,6,7,8-tetrahydro-1,6-naphthyridine and 4- chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 313.3 [M+H]+. Example 62: (3-Bromo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-chloro-1H- benzo[d]imidazol-2-yl)methanone

[0335] The title compound was prepared from 3-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 393.2 [M+H]+. Example 63: (4-Chloro-1H-benzo[d]imidazol-2-yl)(6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)methanone

[0336] The title compound was prepared from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 302.1 [M+H]+. Example 64: (4-Chloro-1H-benzo[d]imidazol-2-yl)(7-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)methanone

[0337] The title compound was prepared from (S)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 316.1 [M+H]+. Example 65: 2-(4-Chloro-1H-benzo[d]imidazole-2-carbonyl)-1-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carbonitrile

[0338] The title compound was prepared from 1-methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine-6-carbonitrile and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 340.1 [M+H]+. Example 66: (S)-(4-Fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0339] The title compound was prepared from (S)-5-methyl-5,6,7,8-tetrahydro-1,6- naphthyridine and 4-fluoro-7-methyl-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 325.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.83 – 8.43 (m, 2H), 8.00 – 7.72 (m, 1H), 7.21 – 6.88 (m, 2H), 6.64 – 5.84 (m, 1H), 5.63 – 4.74 (m, 3H), 3.79 – 3.14 (m, 4H), 1.81 – 1.60 (m, 3H). Example 67: 4-Chloro-1H-benzo[d]imidazol-2-yl)(3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0340] The title compound was prepared from 3-(trifluoromethyl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 370.0 [M+H]+. Example 68: (4-Methyl-1H-benzimidazol-2-yl)-(5-methyl-7,8-dihydro-5H-1,6- naphthyridin-6-yl)methanone

[0341] The title compound was prepared from 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine and 4-methyl-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 306.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.49 (br d, J = 4.6 Hz, 1H), 7.77 – 7.52 (m, 1H), 7.42 – 7.29 (m, 1H), 7.26 – 7.07 (m, 2H), 6.71 – 6.31 (m, 1H), 6.01 – 4.85 (m, 1H), 3.98 – 3.06 (m, 1H), 3.53 – 3.05 (m, 1H), 2.79 – 2.38 (m, 3H), 1.92 – 1.52 (m, 4H). Example 69: (4-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0342] The title compound was prepared from 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine and 4-chloro-1H-benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 1, Step A. LC-MS: 336.2 [M+H]+. Example 70: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-isopropyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0343] Step A: To a solution of LiHMDS (56.8 mL, 56.8 mmol, 1M) in THF (30.0 mL) was added dropwise acetonitrile (2.34 g, 56.8 mmol) at – 78 °C under nitrogen, and the mixture was stirred at – 78 °C for 1 h. Then 3-bromo-2-fluoropyridine (5.00 g, 28.4 mmol) in THF (30.0 mL) was added dropwise at – 78 °C. The mixture was stirred at same temperature for 2 h then stirred at 20 °C for 12 h under nitrogen. The reaction mixture was poured into H2O (80.0 mL) andwashed with EtOAc (100 mL x 3). The combined organic layers were dried over Na 2SO4,filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford 2-(3- bromopyridin-2-yl)acetonitrile. LC-MS: 197.1 [M+H]+.

[0344] Step B: To a solution of Raney Ni (4.20 g, 49.0 mmol) in MeOH (420 mL) was added 2-(3-bromopyridin-2-yl)acetonitrile (4.20 g, 21.3 mmol) and Boc2O (23.3 g, 107 mmol). The mixture was stirred at 20 °C for 2 h under hydrogen. The mixture was filtered through Celite pad, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5 to afford tert- butyl (2-(3-bromopyridin-2-yl)ethyl)carbamate. LC-MS: 301.1 [M+H]+.

[0345] Step C: To a solution of tert-butyl (2-(3-bromopyridin-2-yl)ethyl)carbamate (2.25 g, 7.47 mmol) in THF (40.0 mL) was added n-BuLi (5.98 mL, 14.9 mmol, 2.5M) at – 78 °C for 1 h under nitrogen. Then isobutyraldehyde (5.39 g, 74.7 mmol) in THF (40.0 mL) was added at – 78°C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into H 2O (100mL) and washed with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flashsilica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 3 to affordtert-butyl (2-(3-(1-hydroxy-2-methylpropyl)pyridin-2-yl)ethyl)carbamate. LC-MS: 295.3 [M+H]+.

[0346] Steps D, E, F, and G: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-isopropyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone was prepared from tert-butyl (2-(3-(1-hydroxy-2- methylpropyl)pyridin-2-yl)ethyl)carbamate according to the procedure of Example 11, Steps E, F, G, and H. LC-MS: 355.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.87 – 8.66 (m, 1H), 8.60 – 8.19 (m, 1H), 7.96 – 7.78 (m, 1H), 7.58 – 7.49 (m, 1H), 7.40 – 7.29 (m, 2H), 5.64 (br d, J = 9.4 Hz, 1H), 3.90 – 3.23 (m, 4H), 2.37 – 2.21 (m, 1H), 1.17 – 0.95 (m, 6H). Examples 70A and 70B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-isopropyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone and (R) or (S)-(7-Chloro-1H- benzo[d]imidazol-2-yl)(5-isopropyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

[0347] Step A: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-isopropyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (10.0 mg, 0.028 mmol) was separated by SFC separation ((Phenomenex-Cellulose-2 (250 × 30 mm, 10 μm); flow rate: 70 mL / min; gradient: 33 – 33% Bover 11 min; mobile phase A: CO2, mobile phase B: EtOH (0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 70A): LC- MS: 355.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.50 – 8.35 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.57 – 7.48 (m, 1H), 7.40 – 7.20 (m, 3H), 5.60 – 5.31 (m, 1H), 3.96 – 3.49 (m, 1H), 3.20 – 2.92 (m, 3H), 2.31 – 2.17 (m, 1H), 1.08 – 0.97 (m, 6H). Second eluted compound (Example 70B): LC-MS: 355.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.65 – 8.27 (m, 1H), 7.84 – 7.66 (m, 1H), 7.60 – 7.44 (m, 1H), 7.37 – 7.19 (m, 3H), 5.41 (d, J = 9.1 Hz, 1H), 4.04 – 3.68 (m, 1H), 3.18 – 2.99 (m, 3H), 2.28 – 2.11 (m, 1H), 1.08 – 0.97 (m, 6H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 71: (R)-(7-Methoxy-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0348] (R)-(7-Methoxy-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone was prepared from 3-methoxybenzene-1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 323.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.24 – 12.87 (m, 1H), 8.55 – 8.27 (m, 1H), 7.89 – 7.54 (m, 1H), 7.41 – 6.97 (m, 3H), 6.83 – 6.63 (m, 1H), 5.90 - 5.60 (m, 1H), 3.96 (s, 3H), 3.75 - 3.62 (m, 2H), 3.04 – 2.88 (m, 2H), 1.72 – 1.47 (m, 3H). Example 72: (R)-(5,7-Dichloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0349] (R)-(5,7-Dichloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone was prepared from 3,5-dichlorobenzene-1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 361.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.76 – 8.52 (m, 2H), 8.03 – 7.88 (m, 1H), 7.67 – 7.35 (m, 2H), 7.09 – 5.98 (m, 1H), 5.97 – 4.94 (m, 1H), 3.85 – 3.32 (m, 3H), 1.94 – 1.68 (m, 3H). Example 73: (R)-(5,7-Dimethyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0350] (R)-(5,7-Dimethyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone was prepared from 3,5-dimethylbenzene-1,2-diamine according to the procedure of Example 30, Steps A, B, and C. LC-MS: 321.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.75 (d, J = 5.8 Hz, 1H), 8.68 – 8.37 (m, 1H), 7.99 (br s, 1H), 7.51 – 7.18 (m, 2H), 6.04 (q, J = 6.8 Hz, 1H), 4.72 – 4.52 (m, 1H), 4.01 – 3.44 (m, 2H), 3.29 – 3.12 (m, 1H), 2.72 – 2.35 (m, 6H), 1.77 (d, J = 6.9 Hz, 3H). Examples 74A and 74B: rac-(7-Chloro-1H-benzo[d]imidazol-2-yl)((cis)-8-methoxy-5- methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone and rac-(7-Chloro-1H- benzo[d]imidazol-2-yl)((trans)-8-methoxy-5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone

[0351] Step A: To a solution of tert-butyl 5-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate (5.00 g, 20.0 mmol) in DCM (50.0 mL) was added m-CPBA (8.00 g, 40.0 mmol,85% purity). The mixture was stirred at 25 °C for 2 h. The residue was diluted with sat.aq Na2SO3(200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 6-(tert-butoxycarbonyl)-5-methyl-5,6,7,8- tetrahydro-1,6-naphthyridine 1-oxide. LC-MS: 265.2 [M+H]+.

[0352] Step B: To a solution of 6-(tert-butoxycarbonyl)-5-methyl-5,6,7,8-tetrahydro-1,6- naphthyridine 1-oxide (4.00 g, 15.0 mmol) in DMF (40.0 mL) was added TFAA (13.0 g, 61.0 mmol) at 0 °C. The mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with Na2CO3(60.0 mL) and extracted with EtOAc (80.0 mL x 3). The combined organic layers were washed with sat.aq LiCl (80.0 mL x 5), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography using a gradient of Dichloromethane / Methanol from 95 / 5 to 91 / 9 to afford tert-butyl 8-hydroxy-5-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. LC-MS: 265.2 [M+H]+.

[0353] Step C: To a solution of tert-butyl...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl,C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):Formula (Ia).

3. A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y1, Y2, and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; or two R2groups on different carbon atoms are taken together to form a bridge that is -CH2CH2-; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups;each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 1, 2, 3, or 4.

4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa):Formula (IIa).

5. A compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III); wherein: X, Y and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups;each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):Formula (IIIa).

7. A compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups;each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):Formula (IVa).

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, - N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

20. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4).

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

31. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:, , , , , ,,, and .

32. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:, , ,, , ,.

33. A pharmaceutical composition comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

34. A method of treating autosomal dominant retinitis pigmentosa (adRP) in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-32,or a pharmaceutically acceptable salt or solvate.

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