Amide prodrugs and uses thereof

Abstract

Described herein are amide prodrugs, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in treating a CNS disease or disorder.

Description

AMIDE PRODRUGS AND USES THEREOF CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No.63 / 536,004 filed on August 31, 2023, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] The blood-brain barrier is composed of tightly linked endothelial cells that limit the passage of pathogens and specific types of small and large molecules from the blood into the brain. This critical protective function also restricts the diffusion of therapeutics into the brain representing a major challenge to the development of new medicines for CNS diseases. SUMMARY OF THE INVENTION

[0003] In one aspect, described herein is a compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein: X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2arecombined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R3is phenyl substituted with R3a, R3b, R3c, R3d, and R3e; R3ais selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; or R3aand R3bare combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10;R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 from 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 p 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, wherein R3ais selected from -OR10, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from halogen, C1- 6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis selected from hydrogen, halogen, -CN, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3c, R3d, and R3eare hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from-C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

[0005] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

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

[0007] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):

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

[0009] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0010] In another aspect, described herein is a compound that has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein: ring A and ring B are each independently selected from 6-membered heteroaryl and phenyl, wherein at least one of ring A and ring B is 6-membered heteroaryl; X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

[0011] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is phenyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl and ring B is pyridyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is pyridyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and unsubstituted C3-6cycloalkyl and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. 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 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from - C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

[0012] In another aspect, described herein is a compound that has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein:ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl;each R7and each R8are independently selected from hydrogen and C1-C6alkyl; 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

[0013] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):

[0014] In another aspect, described herein is a compound that has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:wherein: ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH;R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0015] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):

[0016] In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, - CN, -OR10, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from C1-6haloalkyl. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from -OR10and each R3is C1-6alkyl. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is1. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R1)(R2). In some embodiments is a compound of Formula (III), (IIIa), (IV), or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0017] In another aspect, described herein is a compound that has the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y is selected from -O-, -N(R9)-, -S-, -S(O)-, -S(O)2-, -C(R7)(R8)-, and -C(O)-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; R3is selected from C3-C8alkyl, C3-C8alkenyl, and C3-C8alkynyl, wherein C3-C8alkyl, C3- C8alkenyl, and C3-C8alkynyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)R13, and -S(O)2R13;each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 m is 0, 1, 2, 3, or 4.

[0018] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R9)-, -S-, and -C(R7)(R8)-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), - C(O)R13, and -S(O)2R13. In some embodiments is a compound of Formula (V), or apharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted C3-C8alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0019] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1- 6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected fromhalogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, - N(R10)(R11), and -S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2-C9heterocycloalkyl.

[0020] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0021] In another aspect, described herein is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments described herein is a method oftreating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from a neurodegenerative disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, epilepsy, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, neurodegeneration, and neuropathic pain.

[0022] 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.

[0023] 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

[0024] Spingosine-1-phospate is a pleiotropic signaling factor that mediates diverse biological responses through interactions with members of the endothelial cell differentiation gene family (EDG receptors) of plasma membrane-localized G protein-coupled receptors. Five members of this family have been identified across a variety of cell types, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8). The receptor subtypes S1P1, S1P2 and S1P3 are expressed widely in both peripheral tissues and in the central nervous system (CNS) and play key roles in cardiovascular regulation, lymphocyte trafficking and neurogenesis. The S1P4 receptor is expressed mainly in the immune and hematopoietic systems and mediates immunecell proliferation and cytokine production typically in the presence of high concentrations of S1P. The S1P5 receptor expression is notably more restricted and predominantly expressed in oligodendrocytes in the CNS, where it is believed to play a key role in myelin biology, and on natural killer cells and other lymphocytes in the spleen where it is thought to mediate cellular trafficking. S1P5 is also thought to be important in regulating blood-brain barrier permeability and integrity. Oligodendrocyte precursor cells (OPCs), pre-oligodendrocytes, and fully differentiated mature oligodendrocyte cells all express S1P5 receptors at high levels. Activation of the S1P5 receptor can promote the survival of OPCs and drives pre-oligodendrocytes to mature into myelinating oligodendrocytes. Indeed, preclinical models in mice and xenopus tadpoles have shown evidence of S1P5-mediated remyelination. Additionally, administration of selective S1P5 agonists have been reported to normalize proteinopathies and improve clinical scores in several animal models of neurodegenerative disease. These data support the use of S1P5 agonists in the treatment of a variety of neurological disorders including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Neiman Pick Type-C and others.

[0025] In certain embodiments, selectively modulating S1P1 and S1P5 receptors simultaneously within the brain tissue of patients with nervous system diseases should provide neuroprotective and remyelinating benefits. S1P1 / 5 receptors are expressed on astrocytes, microglia, neurons and oligodendroglia and have been shown to modulate processes relevant to demyelinating neuropathologies, including astrocyte activation, microglial activation, oligodendrocyte precursor cell migration and maturation, and oligodendroglial cell survival. Studies in EAE mouse models of MS have shown that genetic deletion or pharmacological functional antagonism of S1P1 reduces demyelination, axonal loss, and astrogliosis. S1P5 is highly expressed on myelin-forming oligodendrocytes and S1P5 stimulation / modulation has been shown to promote survival of mature oligodendrocytes. Use of a dual S1P1 / S1P5 agonist or a selective S1P5 agonist in a conditional demyelination Xenopus tadpole model, resulted in an increase in myelinated internodes compared with controls - use of a selective S1P1 agonist did not result in the same phenotype. On the other hand, expression of S1P1 compared to S1P5 is higher on astrocytes, microglia and endothelial cells and has been linked to reduced cytokine release and inflammatory signaling and improved BBB integrity. Together these data suggest that modulation of both receptor subtypes concurrently may lead to improvements in the treatment of multiple neurological disorders including epilepsy, multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Neiman Pick Type-C and others.

[0026] Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids and can hydrolyze select amide prodrugs. FAAH is highly conserved between species and is expressed in many tissues, including the central nervous system (CNS), to varying degrees. Select carboxylic acids can be converted to more permeable amide prodrugs which are then capable of passing through the blood brain barrier where they can be converted to active molecules through the action of FAAH upon the prodrug. This results in the delivery of higher amounts of the parent carboxylic acid to the CNS as compared to dosing the parent alone. However, peripherally expressed FAAH simultaneously hydrolyzes the prodrug resulting in a considerable amount of non-productive prodrug conversion. Co-administration of a peripherally restricted FAAH inhibitor with a CNS permeable FAAH convertible prodrug increases the selectivity of prodrug delivery to the CNS. It also results in lower exposures of the parent molecule in plasma and peripheral tissue than what is observed when dosing the prodrug alone. Certain Terminology

[0027] 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 for organizational purposes only and are not to be construed as limiting the subject matter described.

[0028] 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.

[0029] 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.

[0030] 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-C4 alkylene). 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-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2 alkylene). 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.

[0031] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0032] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –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.

[0033] 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.

[0034] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0035] The term “alkylamine” refers to the –N(alkyl)xHy group, 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.

[0036] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ 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.

[0037] 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.

[0038] 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 on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0039] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, 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, cycloheptyl, 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.

[0040] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The term “heteroalkylene” refers to a divalent heteroalkyl radical.

[0045] 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 proviso that 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 foregoing groups 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 oneof the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0046] 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.

[0047] 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.

[0048] The term “oxo” refers to the =O radical.

[0049] 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.

[0050] 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.

[0051] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected 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).

[0052] 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.

[0053] 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.

[0054] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0055] 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 theart 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0060] The terms “kit” and “article of manufacture” are used as synonyms.

[0061] 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.

[0062] 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 a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. Compounds

[0063] In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are selective S1P5 receptor agonists. In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are amide prodrugs of selective S1P5 receptor agonists.

[0064] In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are dual S1P1 and S1P5 receptor agonists. In some embodiments, the compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are amide prodrugs of dual S1P1 and S1P5 receptor agonists.

[0065] In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein,X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-;R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R3is phenyl substituted with R3a, R3b, R3c, R3d, and R3e; R3ais selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; or R3aand R3bare combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; 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 from 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 p is 0, 1, 2, 3, or 4.

[0066] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from - C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, -C(R7)(R8)S-, -SC(R7)(R8)-, - C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, and -N(R9)C(R7)(R8)-. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)O-, and -OC(R7)(R8)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OC(R7)(R8)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)-.

[0067] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OCH2-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2CH2-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-.

[0068] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from -OR10, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais C1-6haloalkyl. In someembodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais -CF3.

[0069] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis selected from hydrogen, halogen, -CN, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis -CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis -CF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3c, R3d, and R3eare hydrogen.

[0070] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0071] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 4.

[0072] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0073] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are independently selected from C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are - CH3.

[0074] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0075] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0076] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0077] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0078] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, - OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2- C9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0079] In some embodiments, described herein is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof:wherein, R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R3ais selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R3bis selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; or R3aand R3bare combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 groupsselected 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 from 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 p is 0, 1, 2, 3, or 4.

[0080] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from -OR10, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais halogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais -Cl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais C1-6alkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais - CH3. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais -CF3.

[0081] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis selected from hydrogen, halogen, -CN, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis hydrogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis halogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof,wherein R3bis -Cl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis -CN. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis -CF3.

[0082] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0083] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 4.

[0084] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0085] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0086] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, - N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0087] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0088] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, - N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, - N(R10)(R11), and -S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In someembodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0089] In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2-C9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0090] In some embodiments, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:wherein: ring A and ring B are each independently selected from 6-membered heteroaryl and phenyl, wherein at least one of ring A and ring B is 6-membered heteroaryl; X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionallysubstituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 areoptionally 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

[0091] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is phenyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl and ring B is pyridyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is pyridyl.

[0092] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, - C(O)C(R7)(R8)-, -C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, and -N(R9)C(R7)(R8)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from - C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)O-, and -OC(R7)(R8)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OC(R7)(R8)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)-.

[0093] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2O-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -OCH2-. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2CH2-. In someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-.

[0094] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and unsubstituted C3-6cycloalkyl and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl and unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -Cl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CN. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CF3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independentlyselected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independently selected from C1-6alkyl.

[0095] 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 1.

[0096] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0097] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0098] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is C1-C6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are independently selected from C1-C6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are -CH3.

[0099] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0100] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0101] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0102] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. Insome embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0103] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, - OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2- C9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0104] In some embodiments, described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein: ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

[0105] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):

[0106] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and unsubstituted C3-6cycloalkyl and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl and unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -Cl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CN. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6alkyl. In someembodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CH3. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CF3. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independently selected from C1- 6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independently selected from C1-6alkyl.

[0107] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0108] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0109] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0110] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is C1-C6alkyl. In some embodiments is a compound of Formula(III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is -CH3. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are independently selected from C1-C6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are -CH3.

[0111] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0112] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R1)(R2).

[0113] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0114] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0115] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0116] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0117] In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2- C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2-C9heterocycloalkyl. In some embodiments is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0118] In some embodiments, described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV); wherein: ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 groupsselected 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; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0119] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):

[0120] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and unsubstituted C3-6cycloalkyl and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl and unsubstituted C3-6cycloalkyl.In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from -CN and -OR10and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -Cl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CN. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CH3. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -CF3. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is -OR10and each R10is independently selected from C1-6alkyl.

[0121] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0122] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0123] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

[0124] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is C1-C6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is -CH3. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are independently selected from C1-C6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are -CH3.

[0125] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

[0126] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R1)(R2).

[0127] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0128] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2isC1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0129] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0130] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0131] In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2- C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (IV) or (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2-C9heterocycloalkyl. In some embodiments is a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0132] In some embodiments, described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:wherein, Y is selected from -O-, -N(R9)-, -S-, -S(O)-, -S(O)2-, -C(R7)(R8)-, and -C(O)-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; R3is selected from C3-C8alkyl, C3-C8alkenyl, and C3-C8alkynyl, wherein C3-C8alkyl, C3- C8alkenyl, and C3-C8alkynyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)R13, and -S(O)2R13; each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; 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 m is 0, 1, 2, 3, or 4.

[0133] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R9)-, -S-, and -C(R7)(R8)-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R9)-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(H)-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -S-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -C(R7)(R8)-. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2-.

[0134] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)R13, and -S(O)2R13. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted C3-C8alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)2CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)2CH(CH3)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)3CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)3CH(CH3)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)4CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)4CH(CH3)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)5CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)5CH(CH3)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)6CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is –(CH2)7CH3.

[0135] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -Cl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is -CF3.

[0136] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 4.

[0137] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0138] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is C1-C6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is hydrogen and R6is -CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are independently selected from C1-C6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are -CH3.

[0139] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3.

[0140] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

[0141] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, - OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted cyclopropyl.

[0142] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13, wherein C1- 9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridazinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrimidinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazinyl.

[0143] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, - OR10, -N(R10)(R11), and -S(O)2R13. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from C1-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2- C9heterocycloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted azetidinyl.

[0144] 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.

[0145] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

[0146] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

[0147] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

[00] n some emo ments s a compoun, or a parmaceutca y accepta e sat or solvate thereof, selected from:,

[0149] 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.

[0150] “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.

[0151] 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 dosage forms. 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 moleculecan be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0152] 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.

[0153] 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.

[0154] 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."

[0155] 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.

[0156] 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.

[0157] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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. Synthesis of Compounds

[0163] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0164] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0165] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, 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.

[0166] 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, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., NewYork; 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, Starting Materials", 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.

[0167] In some embodiments, compounds are prepared as described in the Examples. Methods of Treatment

[0168] In some embodiments, described herein is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from a neurodegenerative disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, epilepsy, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome,schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, neurodegeneration, and neuropathic pain. In some embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis. In some embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X-linked adrenoleukodystrophy.

[0169] In some embodiments, described herein is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments is a method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IIIa), (IV), (IVa), or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from a neurodegenerative disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, epilepsy, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, neurodegeneration, and neuropathic pain, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

[0170] In some embodiments of the methods described herein, the peripherally restricted FAAH inhibitor is ASP-3652. Pharmaceutical compositions

[0171] 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. Properformulation 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.

[0172] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. In some embodiments disclosed herein, the pharmaceutical composition further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the pharmaceutical composition further comprises a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0173] 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.

[0174] 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.

[0175] 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 as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine 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. Moldedtablets 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.

[0176] 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.

[0177] 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 viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0178] 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.

[0179] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0180] 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.

[0181] 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 instillation 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate 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.

[0186] Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g. such as the colon), include:

[0187] (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.

[0188] (ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeted delivery 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.

[0189] (iii) Coating with biodegradable polymers;

[0190] (iv) Embedding in matrices;

[0191] (v) Embedding in biodegradable matrices and hydrogels;

[0192] (vi) Embedding in pH-sensitive matrices;

[0193] (vii) Timed release systems;

[0194] (viii) Redox-sensitive polymers;

[0195] (ix) Bioadhesive systems;

[0196] (x) Coating with microparticles;

[0197] (xi) Osmotic controlled drug delivery;

[0198] 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.

[0199] 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 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.

[0200] 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

[0201] 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 selective S1P5 receptor agonist or a dual S1P1 and S1P5 receptor agonist. 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.

[0202] In some embodiments disclosed herein, are methods of administering a dual S1P1 and S1P5 receptor agonist in combination with an additional therapeutic agent. In some embodiments are methods of administering a dual S1P1 and S1P5 receptor agonist in combination with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments are methods of administering a dual S1P1 and S1P5 receptor agonist incombination with a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0203] In some embodiments disclosed herein, are methods of administering an S1P5 receptor agonist in combination with an additional therapeutic agent. In some embodiments are methods of administering an S1P5 receptor agonist in combination with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments are methods of administering an S1P5 receptor agonist in combination with a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0204] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of 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.

[0205] 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.

[0206] 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 otherwise control or limit the symptoms of the patient’s disease or condition.

[0207] In certain embodiments, wherein a patient’s status does improve, the dose of drug being administered 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 2days 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%.

[0208] 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 the improved 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.

[0209] 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.

[0210] 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.

[0211] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0212] 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 LD50 and 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 therapeutically effective 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 ED50 with 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.

[0213] In any of the aforementioned aspects are further embodiments in which the effective amount 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.

[0214] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[0215] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0216] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0217] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0218] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0219] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0220] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and / or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0221] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0222] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co- administered with one or more other therapeutic agents, the compound provided herein isadministered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0223] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0224] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years. EXAMPLES

[0225] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0226] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH acetic acid Ac acetyl BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Bn benzyl BOC or Boc tert-butyl carbamate t-Bu tert-butyl Cy cyclohexylDBA or dba dibenzylideneacetone DCE dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMSO dimethylsulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq equivalent(s) Et ethyl Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HMPA hexamethylphosphoramide HPLC high performance liquid chromatography KHMDS potassium bis(trimethylsilyl)amide NaHMDS sodium bis(trimethylsilyl)amide LiHMDS lithium bis(trimethylsilyl)amide LAH lithium aluminum anhydride LCMS liquid chromatography mass spectrometry Me methyl MeOH methanol MS mass spectroscopy Ms mesyl NBS N-bromosuccinimide NMM N-methyl-morpholine NMP N-methyl-pyrrolidin-2-one NMR nuclear magnetic resonance PCC pyridinium chlorochromate Ph phenylPPTS pyridium p-toluenesulfonate iPr / i-Pr iso-propyl TBS tert-butyldimethylsilyl RP-HPLC reverse phase-high pressure liquid chromatography TFA trifluoroacetic acid TEA triethylamine THF tetrahydrofuran TLC thin layer chromatography Example 1: Synthesis of 1-(2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3- carboxylic acid

[0227] Step 1: To a solution of 2-bromo-4-hydroxybenzoic acid (2.50 g, 11.5 mmol) in THF (10 mL) at 0oC was added borane-tetrahydrofuran complex (1 M, 23 mL) under N2 atmosphere. The mixture was stirred at rt for 16 h, quenched with water (50 mL*2), and extracted with DCM (50 mL*2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 3-bromo-4-(hydroxymethyl)phenol (1.80 g, 77.0% yield) as a colorless oil.

[0228] Step 2: To a solution of 3-bromo-4-(hydroxymethyl)phenol (1.80 g, 8.87 mmol) in THF (18 mL) was added manganese dioxide (7.71 g, 88.7 mmol). The resulting mixture was stirred at rt for 16 h then filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography to afford 2-bromo-4-hydroxybenzaldehyde (1.00 g, 56.1% yield) as a yellow solid.

[0229] Step 3: To a solution of 2-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL) was added 1,2-dichloro-4-(chloromethyl)benzene (972 mg, 4.97 mmol) and potassium carbonate (2.06 g, 14.9 mmol). The mixture was stirred at 60oC for 4 h, diluted with water (50 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, concentrated in vacuo to afford 2-bromo-4-((3,4- dichlorobenzyl)oxy)benzaldehyde (1.70 g, 94.9% yield) as a yellow solid.

[0230] Step 4: To a solution of 2-bromo-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (1.70 g, 4.72 mmol) and cyclopropylboronic acid (1.22 g, 14.2 mmol) in toluene (10 mL) and water (2 mL) was added potassium carbonate (1.96 g, 14.2 mmol) and Pd(dppf)Cl2(383 mg, 472 µmol).The resulting mixture was stirred at 80oC for 6 h, filtered, diluted with water (50 mL,) and extracted with DCM (50 mL*3). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford 2- cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (400 mg, 26.4% yield) as a colorless oil.

[0231] Step 5: To a solution of 2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzaldehyde (300 mg, 934 µmol) in MeOH (2 mL) was added acetic acid (0.2 mL) and azetidine-3-carboxylic acid (94.4 mg, 934 µmol). The mixture was stirred at rt for 0.5 h, then sodium cyanoborohydride (23.5 mg, 374 µmol) was added. The reaction was stirred at rt for 16 h, diluted with water (50 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with brine (20 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-(2-cyclopropyl-4-((3,4-dichlorobenzyl)oxy)benzyl)azetidine-3- carboxylic acid (40.0 mg, 10.5% yield) as a white solid. LCMS: 406.0 [M+1]+. Example 2: Synthesis of 1-(4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzyl)azetidine- 3-carboxylic acid

[0232] Step 1: To a solution of 3,4-dichlorobenzaldehyde (732 mg, 4.18 mmol) in MeOH (6 mL) was added methyl 4-amino-2-ethylbenzoate (625 mg, 3.49 mmol) and acetic acid (20 µL, 349 µmol). The resulting mixture was stirred at rt for 4 h. Sodium cyanoborohydride (131 mg, 2.09 mmol) was added and the reaction was stirred at rt for 4 h, quenched with water (10 mL), and extracted with EtOAc (10 mL*3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, concentrated in vacuo, and purified by prep- TLC followed by prep-HPLC to afford methyl 4-((3,4-dichlorobenzyl)amino)-2-ethylbenzoate (800 mg, 67.8% yield) as a white solid.

[0233] Step 2: To a solution of 4-((3,4-dichlorobenzyl)amino)-2-ethylbenzoate (1.00 g, 2.96 mmol) in MeOH (10 mL) was added formaldehyde (3 mL, 29.6 mmol) and acetic acid (16.9 µL, 296 µmol). The resulting mixture was stirred at 30oC for 16 h. Sodium cyanoborohydride (111 mg, 1.77 mmol) was added and the reaction was stirred at rt for 4 h, quenched with water (10 mL), and extracted with EtOAc (10 mL*3). The combined organic extracts were washed with water (10 mL) and brine (10 ml), dried over Na2SO4, concentrated in vacuo, and purified byprep-TLC to afford methyl 4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzoate (900 mg, 86.4% yield) as a yellow solid.

[0234] Step 3: To a solution of methyl 4-((3,4-dichlorobenzyl)(methyl)amino)-2- ethylbenzoate (900 mg, 2.55 mmol) in THF (10 mL) at 0oC was added lithium aluminum hydride (145 mg, 3.83 mmol). The resulting mixture was stirred at rt for 2 h, quenched with aqueous potassium sodium tartrate (10 mL), and extracted with EtOAc (10 mL*3). The combined organic extracts were washed with water (10 mL*2) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to afford (4-((3,4-dichlorobenzyl)(methyl)amino)-2- ethylphenyl)methanol (400 mg, 43.5% yield) as a colorless oil.

[0235] Step 4: To a solution of (4-((3,4-dichlorobenzyl)(methyl)amino)-2- ethylphenyl)methanol (360 mg, 1.11 mmol) in DCM (6 mL) was added Dess-Martin periodinane (706 mg, 1.67 mmol). The mixture was stirred at rt for 16 h, quenched with water (20 mL), and extracted with EtOAc (10 mL*2). The combined organic extracts were washed with water (20 mL*2) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-((3,4-dichlorobenzyl)(methyl)amino)-2- ethylbenzaldehyde (200 mg, 55.9% yield) as a colorless oil.

[0236] Step 5: To a solution of 4-((3,4-dichlorobenzyl)(methyl)amino)-2-ethylbenzaldehyde (120 mg, 372 µmol) and azetidine-3-carboxylic acid (45.2 mg, 447 µmol) in MeOH (5 mL) was added acetic acid (2.13 µL, 37.2 µmol). The mixture was stirred at rt for 3 h and then sodium cyanoborohydride (14.0 mg, 223 µmol) was added. After stirring for 16 h, the reaction mixture was purified by reverse phase chromatography to afford 1-(4-((3,4- dichlorobenzyl)(methyl)amino)-2-ethylbenzyl)azetidine-3-carboxylic acid (50.0 mg, 32.8% yield) as a white solid. LCMS: 405.05 [M-1].

[0237] Examples 3 and 4 in the table below were prepared using the procedure above, but instead employing the designated reagents.Example 5: Synthesis of 1-(4-(((4-(trifluoromethyl)pyridin-2- yl)methyl)amino)benzyl)azetidine-3-carboxylic acid

[0238] Step 1: A solution of 4-(trifluoromethyl)pyridine-2-carbaldehyde (280 mg, 1.60 mmol) and methyl 4-aminobenzoate (242 mg, 1.60 mmol) in MeOH (10 mL) and acetic acid (1 mL) was stirred at rt for 16 h. Sodium cyanoborohydride (121 mg, 1.92 mmol) was added and the mixture was stirred at rt for 3 h, diluted with water (50 mL), and extracted with EtOAc (50 mL*3). The combined organic extracts were washed with brine (50 mL*3), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford methyl 4-(((4- (trifluoromethyl)pyridin-2-yl)methyl)amino)benzoate (260 mg, 52.4% yield) as a white solid.

[0239] Step 2: To a solution of methyl 4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}amino)benzoate (100 mg, 322 µmol) in THF (5 mL) at 0oC was added diisobutylaluminum hydride (1.0 N in hexane, 1.13 mL, 1.13 mmol). The reaction mixture was stirred at rt for 16 h, quenched with water (50 mL), and extracted with EtOAc (50 mL*3). The combined organic extracts were washed with brine (50 mL*3), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford [4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}amino)phenyl]methanol (50.0 mg, 55.0% yield) as a white solid.

[0240] Step 3: To a solution of [4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}amino)phenyl]methanol (140 mg, 496 µmol) in THF (3 mL) at 0oC was added Dess- Martin periodinane (316 mg, 744 µmol). The resulting mixture was stirred at 0oC for 3 h, diluted with water (50 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with brine (50 mL*3), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford 4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}amino)benzaldehyde (80.0 mg, 57.6% yield) as a yellow solid.

[0241] Step 4: A solution of 4-({[4-(trifluoromethyl)pyridin-2-yl]methyl}amino)benzaldehyde (70.0 mg, 250 µmol) and azetidine-3-carboxylic acid (25.3 mg, 250 µmol) in MeOH (3 mL) and acetic acid (0.2 mL) was stirred at rt for 16 h. Sodium cyanoborohydride (25.6 mg, 408 µmol) was added and the mixture was stirred at rt for 3 h, diluted with water (50 mL), neutralized to pH = 5-6 with 1 N HCl, and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with brine (50 mL*3), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-{[4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}amino)phenyl]methyl}azetidine-3-carboxylic acid (20.0 mg, 21.6% yield) as a yellow oil. LCMS: 364.0 [M-1].Example 6: Synthesis of 1-(4-((methyl(6-(trifluoromethyl)pyridin-2- yl)amino)methyl)benzyl)azetidine-3-carboxylic acid

[0242] Step 1: A mixture of 6-(trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol), methyl 4-formylbenzoate (1.22 g, 7.40 mmol), and acetic acid (37.0 mg, 617 µmol) in MeOH (10 mL) was stirred at 35oC for 16 h. Sodium cyanoborohydride (1.16 g, 18.5 mmol) was added, and the mixture was stirred at 35oC for 4 h, then poured into water and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*3) and brine (20 mL) and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford methyl 4-({[6-(trifluoromethyl)pyridin-2-yl]amino}methyl)benzoate (1.50 g, 78.2% yield) as a white solid.

[0243] Step 2: To a mixture of methyl 4-({[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)benzoate (1.50 g, 4.83 mmol) in DMF (10 mL) at 0oC was added sodium hydride (60% in mineral oil, 370 mg, 9.67 mmol) and the mixture was stirred at 0oC for 1 h. Iodomethane (1.37 g, 9.67 mmol) was added and the mixture was stirred at rt for 4 h, poured into water and extracted with EtOAc (30 mL*3). The combined organic extracts were washed with water (30 mL*3) and brine (40 mL) and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford methyl 4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)benzoate (740 mg, 47.2% yield) as a white solid.

[0244] Step 3: To a mixture of methyl 4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)benzoate (740 mg, 2.28 mmol) in THF (10 mL) at 0oC was added lithium aluminum hydride (173 mg, 4.56 mmol). The resulting mixture was stirred at rt for 4 h, quenched with water, and filtered. The filtrate was extracted with EtOAc (20 mL*3) and the combined organic extracts were washed with water (20 mL*3) and brine (20 mL), dried over Na2SO4,and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford [4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)phenyl]methanol (650 mg, 96.1% yield) as a white solid.

[0245] Step 4: To a solution of [4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)phenyl]methanol (650 mg, 2.19 mmol) in chloroform (10 mL) was added manganese dioxide (1.91 g, 21.9 mmol). The resulting mixture was stirred at 80oC for 16 h,filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)benzaldehyde (440 mg, 1.50 mmol) as a white solid.

[0246] Step 5: A mixture of 4-({methyl[6-(trifluoromethyl)pyridin-2- yl]amino}methyl)benzaldehyde (100 mg, 340 µmol), azetidine-3-carboxylic acid (51.5 mg, 510 µmol) and acetic acid (2.04 mg, 34 µmol) in MeOH (10 mL) was stirred at 35oC for 16 h. Sodium cyanoborohydride (64.1 mg, 1.02 mmol) was added, and the mixture was stirred at 35oC for 4 h, then poured into water and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*3) and brine (20 mL) and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford 1-{[4-({methyl[6- (trifluoromethyl)pyridin-2-yl]amino}methyl)phenyl]methyl}azetidine-3-carboxylic acid (40.0 mg, 105 µmol) as a white solid. LCMS: 380.1 [M+1]+.

[0247] Example 7 in the table below was prepared using the procedure above, but instead employing the designated reagents.Example 8: Synthesis of 1-(4-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)benzyl)azetidine-3-carboxylic acid

[0248] Step 1: A mixture of 6-(trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol), 4- (methoxymethyl)benzaldehyde (1.22 g, 7.40 mmol) and acetic acid (37.0 mg, 617 µmol) in MeOH (10 mL) was stirred at 35oC for 16 h. Sodium cyanoborohydride (1.16 g, 18.5 mmol) was added, and the reaction was stirred at 35oC for 4 h, then poured into water and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*3) and brine (20 mL) and concentrated in vacuo. The crude material was purified by silica gelchromatography to afford methyl 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzoate (1.60 g, 83.6% yield) as a white solid.

[0249] Step 2: To a mixture of methyl 4-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)benzoate (1.00 g, 3.22 mmol) in THF (10 mL) at 0oC was added lithium aluminum hydride (245 mg, 6.45 mmol). The resulting mixture was stirred at rt for 4 h, then poured into water and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*3) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford (4-(((6- (trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)methanol (750 mg, 82.4% yield) as a white solid.

[0250] Step 3: To a solution of (4-(((6-(trifluoromethyl)pyridin-2- yl)amino)methyl)phenyl)methanol (750 mg, 2.66 mmol) in chloroform (20 mL) was added manganese dioxide (2.31 g, 26.6 mmol). The resulting mixture was stirred at 80oC for 16 h, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzaldehyde (650 mg, 82.3%) as a white solid.

[0251] Step 4: A mixture of 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzaldehyde (100 mg, 357 µmol), azetidine-3-carboxylic acid (54.1 mg, 535 µmol) and acetic acid (0.1 mL) in MeOH (10 mL) was stirred at 35oC for 16 h. Sodium cyanoborohydride (67.3 mg, 1.07 mmol) was added, and the reaction was stirred at 35oC for 4 h, then poured into water, neutralized to pH = 5-6 with 2 N HCl, and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*3) and brine (20 mL) and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford 1-(4-(((6- (trifluoromethyl)pyridin-2-yl)amino)methyl)benzyl)azetidine-3-carboxylic acid (50.0 mg, 38.4% yield) as a white solid. LCMS: 366.0 [M-1].

[0252] Example 9 in the table below was prepared using the procedure above, but instead employing the designated reagents.Example 10: Synthesis of 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)benzyl)azetidine-3-carboxylic acid

[0253] Step 1: To a solution of 5-bromo-2-(chloromethyl)-1,3-dimethylbenzene (500 mg, 2.14 mmol) and methyl azetidine-3-carboxylate hydrochloride (389 mg, 2.57 mmol) in DMF (5 mL) was added potassium carbonate (888 mg, 6.42 mmol). The mixture was stirred at 60oC for 16 h, diluted with water (40 mL), and extracted with EtOAc (30 mL*3). The combined organic extracts were washed with water (30 mL*2) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 1-(4-bromo-2,6-dimethylbenzyl)azetidine-3-carboxylate (600 mg, 89.8% yield) as a colorless oil.

[0254] Step 2: To a solution of methyl 1-(4-bromo-2,6-dimethylbenzyl)azetidine-3- carboxylate (500 mg, 2.49 mmol) and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (853 mg, 2.73 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3(228 mg, 249 µmol), RuPhos (116 mg, 249 µmol) and cesium carbonate (2.43 g, 7.46 mmol). The mixture was stirred at 110oC under N2 for 16 h and then filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (80 mL*3). The combined organic extracts were washed with brine (100 mL*2), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford methyl 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)benzyl)azetidine-3-carboxylate (400 mg, 37.2% yield) as a yellow solid.

[0255] Step 3: To a solution of methyl 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)benzyl)azetidine-3-carboxylate (400 mg, 925 µmol) in THF (5 mL) was added LiOH.H2O (77.6 mg, 1.85 mmol) and water (1 mL). The resulting mixture was stirred at rt for 3 h, acidified to pH = 5-6 with 0.5 N HCl, diluted with water (10 mL), and extracted with EtOAc (30 mL*3). The combined organic extracts were washed with brine (20 mL*2), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford 1-(2,6-dimethyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl)benzyl)azetidine-3-carboxylic acid (120 mg, 30.7% yield) as a yellow oil. LCMS: 417.05 [M- 1]. Example 11: Synthesis of 1-(4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl)benzyl)azetidine-3-carboxylic acid

[0256] Step 1: To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (547 mg, 2.30 mmol) in DMF (5 mL) was added 4-fluorobenzaldehyde (272 µL, 2.53 mmol) and potassium carbonate (954 mg, 6.91 mmol). The resulting mixture was stirred at 100oC for 16 h, . diluted with water (50 mL), and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with water (50 mL*2) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-(7- (trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)benzaldehyde (220 mg, 26.5% yield) as a colorless oil.

[0257] Step 2: A solution of 4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)- yl)benzaldehyde (100 mg, 328 µmol) and azetidine-3-carboxylic acid (49.7 mg, 491 µmol) in MeOH (2 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (22.6 mg, 360 µmol) and AcOH (1.88 µL, 32.8 µmol) were added, and the reaction mixture was stirred at rt for 3 h, diluted with water (50 mL), and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-(4-(7-(trifluoromethyl)-3,4- dihydroisoquinolin-2(1H)-yl)benzyl)azetidine-3-carboxylic acid (70.0 mg, 54.7% yield) as a yellow solid. LCMS: 389.2 [M-1].

[0258] Examples 12-15 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 16: Synthesis of 1-(4-((4-cyano-5-isopropoxypyridin-2- yl)ethynyl)benzyl)azetidine-3-carboxylic acid

[0259] Step 1: To a solution of 2-iodopropane (2.90 mL, 29.4 mmol) and 6-chloro-4- iodopyridin-3-ol (5.00 g, 19.6 mmol) in DMF (30 mL) was added cesium carbonate (12.7 g, 39.2 mmol). The resulting mixture was stirred at rt for 16 h, diluted with water (300 mL), and extracted with EtOAc (150 mL*3). The combined organic extracts were washed with water (300 mL*3) and brine (300 mL), dried over Na2SO4, and concentrated in vacuo to afford 2-chloro-4- iodo-5-isopropoxypyridine l (5.10 g, 87.5% yield) as a yellow oil.

[0260] Step 2: To a solution of 2-chloro-4-iodo-5-(propan-2-yloxy)pyridine (5.10 g, 17.1 mmol) in DMF (30 mL) was added copper cyanide (2.30 g, 25.7 mmol). The reaction was microwaved at 140oC for 6 h, filtered, and rinsed with EtOAc. The filtrate was diluted with water (300 mL) and extracted with EtOAc (150 mL*3). The combined organic extracts were washed with water (300 mL*3) and brine (300 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 2-chloro-5- isopropoxyisonicotinonitrile (1.80 g, 53.4% yield) as a white solid.

[0261] Step 3: To a solution of 2-chloro-5-isopropoxyisonicotinonitrile (1.50 g, 7.63 mmol) in MeCN (20 mL) was added bromotrimethylsilane (2.34 g, 15.3 mmol). The resulting mixture was stirred at 80oC for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with water (100 mL*3) and brine (60 mL), dried over Na2SO4, and concentrated in vacuo to afford 2-bromo-5-isopropoxyisonicotinonitrile (1.50 g, 81.6% yield) as a brown solid.

[0262] Step 4: To a solution of 2-bromo-5-isopropoxyisonicotinonitrile (1.00 g, 4.15 mmol) in THF (10 mL) was added 4-ethynylbenzaldehyde (1.08 g, 8.29 mmol), copper iodide (126 mg, 665 µmol), tetrakis(triphenylphosphane) palladium (384 mg, 332 µmol) and triethylamine (841 mg, 8.29 mmol). The resulting mixture was stirred at rt under N2 for 16 h, diluted with water (30 mL), filtered, and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 2-((4-formylphenyl)ethynyl)-5- isopropoxyisonicotinonitrile (430 mg, 35.7% yield) as a yellow solid.

[0263] Step 5: To a solution of 2-((4-formylphenyl)ethynyl)-5-isopropoxyisonicotinonitrile (280 mg, 964 µmol) in MeOH (5 mL) was added azetidine-3-carboxylic acid (117 mg, 1.16 mmol) and acetic acid (0.1 mL). The resulting mixture was stirred at rt for 4 h before addition of sodium cyanoborohydride (121 mg, 1.93 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated in vacuo and purified by reverse phase chromatography followed by prep- HPLC to afford 1-(4-((4-cyano-5-isopropoxypyridin-2-yl)ethynyl)benzyl)azetidine-3-carboxylic acid (200 mg, 55.3% yield) as a yellow solid. LCMS: 374.2 [M-1].

[0264] Example 17 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 18: Synthesis of 1-(4-(2-(4-cyano-5-isopropoxypyridin-2- yl)ethyl)benzyl)azetidine-3-carboxylic acid

[0265] Step 1: To a solution of 1-(4-((4-cyano-5-isopropoxypyridin-2- yl)ethynyl)benzyl)azetidine-3-carboxylic acid (150 mg, 0.400 mmol) in THF (6 mL) was added 10% Pd / C (30 mg). The resulting mixture was stirred at 50oC for 16 h under H2 atmosphere, filtered, and rinsed with MeOH. The filtrate was concentrated in vacuo and purified by prep- HPLC to afford 1-(4-(2-(4-cyano-5-isopropoxypyridin-2-yl)ethyl)benzyl)azetidine-3-carboxylic acid (50.0 mg, 33.0% yield) as a yellow oil. LCMS: 378.2 [M-1].

[0266] Examples 19-21 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 22: Synthesis of 1-(4-(2-(pyridin-3-yl)ethyl)benzyl)azetidine-3-carboxylic acid

[0267] Step 1: To a solution of 3-ethynylpyridine (507 mg, 4.91 mmol) and 4- iodobenzaldehyde (950 mg, 4.09 mmol) in toluene (5 mL) was added copper iodide (39.0 mg, 205 µmol), triethylamine (1.14 mL, 8.19 mmol) and bis(triphenylphosphine)palladium(II) chloride (287 mg, 409 µmol). After stirring at 70oC for 1 h, water was added (30 mL) and the resulting mixture was extracted with EtOAc (10 mL*2). The combined organic extracts were washed with water (30 ml) and brine (30 mL), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford 4-[2-(pyridin-3-yl)ethynyl]benzaldehyde (750 mg, 88.4% yield) as a yellow solid.

[0268] Step 2: To a solution of 4-[2-(pyridin-3-yl)ethynyl]benzaldehyde (700 mg, 3.38 mmol) and azetidine-3-carboxylic acid (342 mg, 3.38 mmol) in MeOH (7 mL) was added acetic acid (19.3 µL, 338 µmol). The mixture was stirred at rt for 3 hours, and sodium cyanoborohydride (127 mg, 2.03 mmol) was added. After stirring at rt for 16 h, water was added (10 mL) and the resulting mixture was extracted with EtOAc (10 mL). The aqueous phase was concentrated in vacuo, dissolved in DCM / MeOH=10 / 1 (10 mL), filtered, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-({4-[2-(pyridin-3- yl)ethynyl]phenyl}methyl)azetidine-3-carboxylic acid (650 mg, 65.8% yield) as a yellow solid.

[0269] Step 3: To a solution of 1-({4-[2-(pyridin-3-yl)ethynyl]phenyl}methyl)azetidine-3- carboxylic acid (710 mg, 2.43 mmol) in THF (9.59 mL, 118 mmol) was added 10% Pd / C (140 mg). The resulting mixture was stirred at 60oC under H2for 16 h, filtered, and purified by prep- HPLC to afford 1-({4-[2-(pyridin-3-yl)ethyl]phenyl}methyl)azetidine-3-carboxylic acid (100 mg, 13.9% yield) as a yellow solid. LCMS: 297.2 [M+1]+. Example 23: Synthesis of 1-(4-(bicyclo[2.2.2]octan-2-ylmethoxy)-2-methylbenzyl)azetidine- 3-carboxylic acid

[0270] Step 1: To a solution of bicyclo[2.2.2]oct-5-en-2-ylmethanol (500 mg, 3.62 mmol) in DCM (8 mL) at 0oC was added triethylamine (1.01 mL, 7.24 mmol) followed by the dropwise addition of methanesulfonyl chloride (280 µL, 3.62 mmol). The resulting mixture was stirred at rt for 1 h, quenched with water (10 mL), and extracted with DCM (10 mL*2). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to afford bicyclo[2.2.2]oct-5-en-2-ylmethyl methanesulfonate (500 mg, 63.9% yield) as a yellow oil.

[0271] Step 2: To a solution of bicyclo[2.2.2]oct-5-en-2-ylmethyl methanesulfonate (235 mg, 1.09 mmol) in DMF (5 mL) was added 4-hydroxy-2-methylbenzaldehyde (296 mg, 2.17 mmol) and cesium carbonate (1.42 g, 4.35 mmol). The resulting mixture was stirred at 80oC for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (20 mL*2) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford 4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2- methylbenzaldehyde (160 mg, 57.5% yield) as a colorless oil.

[0272] Step 3: To a solution of 4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2-methylbenzaldehyde (120 mg, 468 µmol) and azetidine-3-carboxylic acid (56.8 mg, 562 µmol) in MeOH (4 mL) was added acetic acid (2.68 µL, 46.8 µmol). The mixture was stirred at rt 3 h, and then sodium cyanoborohydride (17.6 mg, 281 µmol) was added. After stirring at rt for 16 h, the mixture was filtered to afford 1-(4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2-methylbenzyl)azetidine-3- carboxylic acid (80.0 mg, 50.1% yield) as a white solid.

[0273] Step 4: To a solution of 1-(4-(bicyclo[2.2.2]oct-5-en-2-ylmethoxy)-2- methylbenzyl)azetidine-3-carboxylic acid (80.0 mg, 234 µmol) in MeOH (5 mL) was added 10% Pd / C (20 mg). The resulting mixture was stirred at 30oC under H2 atmosphere for 16 h, filtered, and purified by prep-HPLC to afford 1-(4-(bicyclo[2.2.2]octan-2-ylmethoxy)-2- methylbenzyl)azetidine-3-carboxylic acid (10.0 mg, 12.2% yield) as a white solid. LCMS: 344.2 [M+1]+.

[0274] Examples 24-27 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 28: Synthesis of 1-(4-((3-cyano-4-isopropoxybenzyl)oxy)-2-ethylbenzyl)azetidine- 3-carboxylic acid

[0275] Step 1: To a solution of 2-ethyl-4-hydroxybenzaldehyde (157 mg, 1.05 mmol) and triphenylphosphine (411 mg, 1.57 mmol) in THF (5 mL) at 0oC was added 5-(hydroxymethyl)- 2-(propan-2-yloxy)benzonitrile (200 mg, 1.05 mmol) and diisopropyl azodicarboxylate (309 µL, 1.57 mmol). The resulting mixture was stirred at rt for 10 h, diluted with water (30 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (100 mL*3) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford 5-[(3-ethyl-4-formylphenoxy)methyl]- 2-(propan-2-yloxy)benzonitrile (200 mg, 59.1% yield) as a yellow oil.

[0276] Step 2: To a solution of 5-[(3-ethyl-4-formylphenoxy)methyl]-2-(propan-2- yloxy)benzonitrile (150 mg, 464 µmol) and azetidine-3-carboxylic acid (70.3 mg, 696 µmol) in MeOH (2 mL) was added azetidine-3-carboxylic acid (70.3 mg, 696 µmol). The resulting mixture was stirred for 2 h and AcOH (27.9 mg, 464 µmol) and sodium cyanoborohydride (43.7 mg, 696 µmol) were added. After stirring at rt for 16 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic extracts were dried over Na2SO4 and purified by reverse phase chromatography followed by prep-HPLC to afford 1- (4-((3-cyano-4-isopropoxybenzyl)oxy)-2-ethylbenzyl)azetidine-3-carboxylic acid (40.0 mg, 21.1% yield) as a white solid. LCMS: 409.15 [M+1]+.

[0277] Examples 29-68 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 69: Synthesis of 1-(4-((3-(trifluoromethyl)phenoxy)methyl)benzyl)azetidine-3- carboxylic acid

[0278] Step 1: To a solution of 3-(trifluoromethyl)phenol (1.21 g, 4.63 mmol) in THF (15 mL) at 0oC was added diisopropyl azodicarboxylate (936 mg, 4.63 mmol) and the resulting mixture was stirred at 0oC for 30 min.4-(Hydroxymethyl)benzaldehyde (462 mg, 3.39 mmol) andtriphenylphosphine (500 mg, 3.08 mmol) were added, and the mixture was stirred at rt for 16 h, diluted with water (100 mL), and extracted with DCM (100 mL*3). The combined organic extracts were washed with water (100 mL*3) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford 4-((3-(trifluoromethyl)phenoxy)methyl)benzaldehyde (380 mg, 44.0% yield) as a colorless oil.

[0279] Step 2: To a solution of 4-((3-(trifluoromethyl)phenoxy)methyl)benzaldehyde (380 mg, 1.36 mmol) in MeOH (4 mL) was added azetidine-3-carboxylic acid (206 mg, 2.03 mmol) and AcOH (cat). The reaction was stirred at rt for 3 h, then sodium cyanoborohydride (256 mg, 4.07 mmol) was added. After stirring at rt for 3 h, the reaction was purified by reverse phase chromatography to afford 1-(4-((3-(trifluoromethyl)phenoxy)methyl)benzyl)azetidine-3- carboxylic acid (200 mg, 40.4% yield) as a white solid. LCMS: 366.0 [M+1]+. Example 70: Synthesis of 1-(4-(2-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)ethyl)-3,5-dimet hylbenzyl)azetidine-3-carboxylic acid

[0280] Step 1: A solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (2.00 g, 9.26 mmol), potassium vinyltrifluoroborate (1.49 g, 11.1 mmol), triethylamine (1.56 mL, 11.1 mmol), Pd(dppf)Cl2•CH2Cl2(375 mg, 463 µmol) in EtOH (15.1 mL, 258 mmol) was microwaved at 120oC for 2 h. The resulting mixture was filtered, quenched with water (35 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (15 mL*3) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo to afford 5-chloro-4-(trifluoromethyl)-2- vinylpyridine (1.80 g, 93.6% yield) as a brown oil.

[0281] Step 2: A mixture of 5-chloro-4-(trifluoromethyl)-2-vinylpyridine (2.00 g, 9.63 mmol), 5-bromo-2-iodo-m-xylene (3.60 g, 11.6 mmol), tris(o-tolyl)phosphine (293 mg, 963 µmol), and triethylamine (1.95 g, 19.3 mmol) in DMF (25 mL) was microwaved at 130oC for 2 h then was quenched with water (100 mL) and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (50 mL*3) and brine (50 mL), dried over Na2SO4, andconcentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-[(E)-2- (4-bromo-2,6-xylyl)ethenyl]-5-chloro-4-(trifluoromethyl)pyridine (2.00 g, 53.1% yield) as a white solid.

[0282] Step 3: A mixture of 2-[(E)-2-(4-bromo-2,6-xylyl)ethenyl]-5-chloro-4- (trifluoromethyl)pyridine (5.00 g, 12.8 mmol), palladium bis(acetate) (144 mg, 640 µmol), iron bis[1-(diphenylphosphino)-2,4-cyclopentadien-1-ide] (355 mg, 640 µmol), and triethylamine (3.89 g, 38.4 mmol) in DMF (30 mL) and MeOH (30 mL) was stirred at 100oC under 3 atm CO for 7 h then diluted with water (100 mL) and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with water (100 mL*3) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to afford methyl 4-{(E)-2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethenyl}-3,5-xylenecarboxylate (2.00 g, 42.3% yield) as a yellow solid.

[0283] Step 4: To a mixture of methyl 4-{(E)-2-[5-chloro-4-(trifluoromethyl)-2- pyridyl]ethenyl}-3,5-xylenecarboxylate (2.90 g, 7.84 mmol) in THF (30 mL) was added platinum dioxide (290 mg, 1.28 mmol). The mixture was stirred at rt for 18 h then filtered, concentrated in vacuo, and purified by reverse phase chromatography to afford methyl 4-{2-[5- chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-xylenecarboxylate (2.30 g, 78.9% yield) as a white solid.

[0284] Step 5: To a solution of methyl 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}- 3,5-xylenecarboxylate (1.20 g, 3.23 mmol) in THF (24 mL) at 0oC was added lithium aluminum hydride (147 mg, 3.87 mmol). The mixture was stirred at 0oC for 10 min then quenched with water (50 mL) and extracted with EtOAc (20 mL). The combined organic extracts were washed with water (25 mL*3) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo to afford (4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-xylyl)methanol (700 mg, 63.1% yield) as a white solid.

[0285] Step 6: A mixture of (4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5- xylyl)methanol (600 mg, 1.75 mmol) and Dess Martin periodinane (1.11 g, 2.62 mmol) in DCM (6 mL) was stirred at rt for 18 h then filtered, concentrated in vacuo, and purified by silica gel chromatography to afford 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5- xylenecarbaldehyde (300 mg, 50.3% yield) as a white solid. Step 7: A solution of 4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5- xylenecarbaldehyde (60.0 mg, 176 µmol), 3-azetidinecarboxylic acid (35.5 mg, 351 µmol) in MeOH (2 mL) was stirred at 40oC for 2 h. Sodium cyanoborohydride (21.0 mg, 351 µmol) was added and the result mixture was stirred at 40oC for 2 h. The reaction mixture was purified by reverse phase chromatography to afford 1-[(4-{2-[5-chloro-4-(trifluoromethyl)-2-pyridyl]ethyl}-3,5-xylyl)methyl]-3-azetidinecarboxylic acid (45.0 mg, 59.7% yield) as a white solid. LCMS: 427.10. Example 71: Synthesis of 1-((2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinolin-6-yl)methyl)azetidine-3-carboxylic acid

[0286] Step 1: To a solution of 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline (700 mg, 3.10 mmol) in DMF (20 mL) was added (3,4-dichlorophenyl)boronic acid (1.77 g, 9.29 mmol), copper(II) acetate (927 mg, 4.64 mmol), and pyridine (735 mg, 9.29 mmol). The resulting mixture was stirred at 60oC under O2for 16 h, diluted with aqueous Na2CO3(20 mL), and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with water (20 mL*2) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 6-bromo-2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinoline (350 mg, 30.5% yield) as a yellow solid.

[0287] Step 2: To a solution of 6-bromo-2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinoline (350 mg, 943 µmol) in DMSO (2 mL) and MeOH (2 mL) was added palladium acetate (21.2 mg, 94.3 µmol), triethylamine (286 mg, 2.83 mmol), and 1,3- bis(diphenylphosphino)propane (77.8 mg, 189 µmol). The resulting mixture was stirred at 80oC under CO (1 atm) for 16 h, diluted with water (5 mL), and extracted with EtOAc (5 mL*2). The combined organic extracts were washed with water (5 mL*3) and brine (5 mL), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford methyl 2-(3,4- dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (195 mg, 59.0% yield) as a yellow solid.

[0288] Step 3: To a solution of methyl 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinoline-6-carboxylate (195 mg, 557 µmol) in THF (4 mL) at 0oC was added lithium aluminum hydride (42.3 mg, 1.11 mmol). The resulting mixture was stirred at rt for 1 h, quenched with water (5 mL), and extracted with EtOAc (5 mL*2). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo to afford [2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydro-6-isoquinolyl]methanol (170 mg, 94.8% yield) as a yellow solid.

[0289] Step 4: To a solution of [2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydro-6- isoquinolyl]methanol (170 mg, 528 µmol) in DCM (4 mL) at 0oC was added Dess-Martin periodinane (269 mg, 633 µmol). The resulting mixture was stirred at rt for 1 h, quenched withaqueous NaHCO3 (5 mL), and extracted with DCM (5 mL*2). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, concentrated in vacuo, and purified by prep-TLC to afford 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinoline-6-carbaldehyde (35.0 mg, 20.7% yield) as a red solid.

[0290] Step 5: To a solution of 2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4- tetrahydroisoquinoline-6-carbaldehyde (20.0 mg, 62.5 µmol) in MeOH (2 mL) was added azetidine-3-carboxylic acid (9.47 mg, 93.7 µmol) and acetic acid (20 µL). The resulting mixture was stirred at 40oC for 16 h. Sodium cyanoborohydride (2.24 mg, 37.5 µmol) was added and the mixture was stirred for 1 h then concentrated in vacuo and purified by reverse phase chromatography to afford 1-((2-(3,4-dichlorophenyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)azetidine-3-carboxylic acid (10.0 mg, 39.5% yield) as a white solid. LCMS: 405.1 [M+1]+.

[0291] Example 72 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 73: Synthesis of 1-(4-(3-(difluoromethoxy)phenethyl)benzyl)azetidine-3- carboxylic acid

[0292] Step 1: To a solution of 4-vinylbenzaldehyde (1.00 g, 7.57 mmol) and 1-iodo-3- (trifluoromethoxy)benzene (1.75 mL, 11.3 mmol) in DMF (10 mL) was added Pd(PPh3)2Cl2 (266 mg, 387 ^mol) and cesium carbonate (4.93 g, 15.1 mmol). The resulting mixture was stirred at 120oC under N2 atmosphere for 16 h, diluted with water (50 mL,) and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to afford (E)-4-(3-(trifluoromethoxy)styryl)benzaldehyde (600 mg, 24.4% yield) as a yellow solid.

[0293] Step 2: To a solution of (E)-4-(3-(trifluoromethoxy)styryl)benzaldehyde (350 mg, 1.20 mmol) in MeOH (5 mL) was added N-methylazetidine-3-carboxamide (684 mg, 5.99 mmol) and AcOH (cat). The mixture was stirred at rt for 16 h, then sodium cyanoborohydride (45.2 mg, 719 µmol) was added. After stirring at rt for 2 h, the reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by prep- HPLC to afford methyl (E)-1-(4-(3-(trifluoromethoxy)styryl)benzyl)azetidine-3-carboxylate (180 mg, 30.8% yield) as a yellow oil.

[0294] Step 3: To a solution of (E)-1-(4-(3-(trifluoromethoxy)styryl)benzyl)azetidine-3- carboxylate (2.30 g, 5.88 mmol) in MeOH (10 mL) was added 10% Pd / C (450 mg, 4.23 mmol). The resulting mixture was stirred at 40oC under H2 atmosphere for 16 h, filtered, and purified by reverse phase chromatography to afford methyl 1-(4-(3- (trifluoromethoxy)phenethyl)benzyl)azetidine-3-carboxylate (1.00 g, 43.3% yield) as a yellow oil.

[0295] Step 4: To a solution of methyl 1-(4-(3-(trifluoromethoxy)phenethyl)benzyl)azetidine- 3-carboxylate (1.50 g, 3.05 mmol) in THF (6 mL) and water (10 mL) was added LiOH (256 mg, 6.10 mmol). The mixture was stirred at rt for 2 h, neutralized to pH = 6 with 2 M HCl, and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by prep- HPLC to afford 1-(4-(3-(trifluoromethoxy)phenethyl)benzyl)azetidine-3-carboxylic acid (450 mg, 38.8% yield) as a white solid. LCMS: 380.2 [M+1]+.

[0296] Example 74 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 75: Synthesis of 1-(4-(cyclohexylmethoxy)-3-methylbenzyl) azetidine-3-carboxylic acid

[0297] Step 1: To a solution of cyclohexylmethanol (840 mg, 7.34 mmol) and triphenylphosphine (1.44 g, 5.51 mmol) in THF (10 mL) at 0oC was added 4-hydroxy-3-methylbenzaldehyde (500 mg, 3.67 mmol). The resulting mixture was stirred at 0oC for 30 min, and added diisopropyl azodicarboxylate (1.08 mL, 5.51 mmol) was added. The mixture was stirred at rt for 16 h, quenched with water (50 mL), and extracted with EtOAc (60 mL*2). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-(cyclohexylmethoxy)-3- methylbenzaldehyde (500 mg, 29.3% yield) as a colorless oil.

[0298] Step 2: A mixture of 4-(cyclohexylmethoxy)-3-methylbenzaldehyde (500 mg, 2.15 mmol), methyl azetidine-3-carboxylate hydrochloride (248 mg, 2.15 mmol), diisopropylethylamine (278 mg, 2.15 mmol), and acetic acid (12.9 mg, 215 µmol) in DCE (10 mL) was stirred at 35oC for 16 h. Sodium triacetoxyborohydride (1.37 g, 6.46 mmol) was added, and the mixture was stirred at 35oC for 4 h, diluted with water (50 mL), and extracted with DCM (50 mL*2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford methyl 1-(4-(cyclohexylmethoxy)-3-methylbenzyl) azetidine-3-carboxylate (500 mg, 70.1% yield) as a yellow solid.

[0299] Step 3: To a solution of methyl 1-(4-(cyclohexylmethoxy)-3-methylbenzyl)azetidine-3- carboxylate (500 mg, 1.51 mmol) in THF (5 mL) and H2O (1 mL) was added LiOH (190 mg, 4.53 mmol). The resulting mixture was stirred at rt for 2 h, acidified to pH 6-7 with 2 N HCl, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give 1-{[4-(cyclohexylmethoxy)-3-methylphenyl]methyl}azetidine-3-carboxylic acid (300 mg, 62.7% yield) as a white solid. LCMS: 318.2 [M+1]+.

[0300] Examples 76-87 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 88: Synthesis of 1-(4-((3,4-dichlorophenoxy)methyl)-3,5- dimethylbenzyl)azetidine-3-carboxylic acid

[0301] Step 1: To a solution of (4-bromo-2,6-dimethylphenyl)methanol (1.00 g, 4.65 mmol) in DCM (10 mL) at 0oC was added sulfonyl chloride (506 µL, 6.97 mmol). The mixture was stirred at rt for 2 h, then was concentrated in vacuo to afford 5-bromo-2-(chloromethyl)-1,3- dimethylbenzene (1.08 g, 99.9% yield) as a yellow solid.

[0302] Step 2: To a mixture of 3,4-dichlorophenol (762 mg, 4.68 mmol) and potassium carbonate (1.85 g, 13.4 mmol) in DMF (10 mL) was added 5-bromo-2-(chloromethyl)-1,3- dimethylbenzene (1.04 g, 4.45 mmol). The reaction was stirred at rt for 16 h, diluted with water (100 mL), and extracted with EtOAc (100 mL*2). The combined organic extracts were washedwith water (100 mL*3) and brine (200 mL), dried over Na2SO4, concentrated in vacuo to afford 5-bromo-2-((3,4-dichlorophenoxy)methyl)-1,3-dimethylbenzene (1.48 g, 92.5% yield) as a yellow solid.

[0303] Step 3: To a solution of 5-bromo-2-((3,4-dichlorophenoxy)methyl)-1,3- dimethylbenzene (500 mg, 1.39 mmol) in MeOH (10 mL) was added BINAP (86.5 mg, 139 µmol), diisopropylethyl amine (359 mg, 2.78 mmol), and Pd(dppf)Cl2(56.7 mg, 69.4 µmol). The resulting mixture was stirred at 60oC for 16 h under CO atmosphere (1 atm), diluted with water (50 mL), and extracted with EtOAc (50 mL*2), The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by Prep-TLC to afford methyl 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzoate (417 mg, 88.5% yield) as a white solid.

[0304] Step 4: To a solution of methyl 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzoate (407 mg, 1.20 mmol) in THF (4 mL) at 0oC was added lithium aluminum hydride (54.6 mg, 1.44 mmol). The resulting mixture was stirred at 0oC for 1 h, quenched with water (50 mL), filtered, and the filtrate was extracted with EtOAc (30 mL*2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford (4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylphenyl)methanol (250 mg, 66.9% yield) as a colorless oil.

[0305] Step 5: To a solution of (4-((3,4-dichlorophenoxy)methyl)-3,5- dimethylphenyl)methanol (400 mg, 1.29 mmol) in DCM (8 mL) at 0oC was added Dess-Martin periodinane (654 mg, 1.54 mmol). The mixture was stirred at rt for 3 h under N2, quenched with saturated aqueous Na2S2O3solution (50 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with water (50mL*2) and brine (50 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by Prep-TLC to afford 4-((3,4- dichlorophenoxy)methyl)-3,5-dimethylbenzaldehyde (260 mg, 65.4% yield) as a white solid.

[0306] Step 6: To a solution of 4-((3,4-dichlorophenoxy)methyl)-3,5-dimethylbenzaldehyde (260 mg, 841 µmol) in MeOH (5 mL) was added azetidine-3-carboxylic acid (85.0 mg, 841 µmol) and acetic acid (0.2 mL). The mixture was stirred at rt for 1 h, then sodium cyanoborohydride (79.3 mg, 1.26 mmol) was added. The mixture was stirred at rt for 16 h then purified by reverse phase chromatography to afford 1-(4-((3,4-dichlorophenoxy)methyl)-3,5- dimethylbenzyl)azetidine-3-carboxylic acid (150 mg, 45.2% yield) as a white solid. LCMS: 394.1 [M+1]+. Example 89: Synthesis of 1-((2-(3,4-dichlorophenyl)chroman-6-yl)methyl)azetidine-3- carboxylic acid

[0307] Step 1: To a solution of vinylmagnesium bromide (4.50 g, 34.3 mmol) in THF (50 mL) at -78oC was added 3,4-dichlorobenzaldehyde (5.00 g, 28.6 mmol) dropwise. The reaction mixture was stirred at rt under N2 for 3 h, quenched with water (200 mL), and extracted with EtOAc (500 mL*2). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to afford 1-(3,4-dichlorophenyl)prop-2-en-1-ol (5.00 g, 86.2% yield) as a colorless oil.

[0308] Step 2: To a solution of 1-(3,4-dichlorophenyl)prop-2-en-1-ol (1.46 g, 7.19 mmol), methyl 4-hydroxy-3-iodobenzoate (1.00 g, 3.60 mmol), and N-cyclohexyl-N- methylcyclohexanamine (2.31 mL, 10.8 mmol) in toluene (25 mL) was added XPhos Pd G2 (283 mg, 360 µmol). The reaction mixture was stirred at 100oC under N2 for 16 h, diluted with water (200 mL), and extracted with EtOAc (200 mL*2). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl (E)-3-(3-(3,4-dichlorophenyl)-3-hydroxyprop-1-en-1-yl)-4-hydroxybenzoate (1.20 g, 94.5% yield) as a yellow oil.

[0309] Step 3: To a solution of methyl (E)-3-(3-(3,4-dichlorophenyl)-3-hydroxyprop-1-en-1- yl)-4-hydroxybenzoate (1.50 g, 4.25 mmol) in THF (15 mL) at 0oC was added sodium borohydride (193 mg, 5.10 mmol). The mixture was stirred at rt for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford methyl 3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)- 4-hydroxybenzoate (1.00 g, 74.6% yield) as a yellow oil.

[0310] Step 4: To a solution of methyl 3-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-4- hydroxybenzoate (800 mg, 2.14 mmol) in DMF (5 mL) was added cesium carbonate (2.09 g, 6.42 mmol). The mixture was stirred at rt for 3 h, diluted with water (40 mL), and extracted with EtOAc (80 mL*2). The combined organic extracts were washed with water (40 mL*3) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford methyl 2-(3,4-dichlorophenyl)chromane-6-carboxylate (500 mg, 69.3% yield) as a yellow oil.

[0311] Step 5: To a solution of methyl 2-(3,4-dichlorophenyl)chromane-6-carboxylate (3.20 g, 9.49 mmol) in THF (30 mL) at 0oC was added lithium aluminum hydride (432 mg, 11.4 mmol).The mixture was stirred at rt for 5 h, quenched with water (100 mL), acidified to pH = 5~6 with 3 N HCl, and extracted with EtOAc (100 mL*2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford methyl (2-(3,4-dichlorophenyl)chroman-6- yl)methanol (1.50 g, 51.1% yield) as a yellow oil.

[0312] Step 6: To a solution of methyl (2-(3,4-dichlorophenyl)chroman-6-yl)methanol (200 mg, 647 µmol) in DCM (3 mL) at 0oC was added sulfonyl chloride (56.3 µL, 776 µmol). The resulting mixture was stirred at rt for 3 h then concentrated in vacuo to afford 6-(chloromethyl)- 2-(3,4-dichlorophenyl)chromane (200 mg, 94.4% yield) as a yellow solid.

[0313] Step 7: To a solution of 6-(chloromethyl)-2-(3,4-dichlorophenyl)chroman (200 mg, 610 µmol) and methyl azetidine-3-carboxylate (141 mg, 1.22 mmol) in DMF (3 mL) was added cesium carbonate (597 mg, 1.83 mmol). The mixture was stirred at rt for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL*3). The combined organic extracts were washed with brine (20 mL*2), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford methyl 1-((2-(3,4-dichlorophenyl)chroman- 6-yl)methyl)azetidine-3-carboxylate (60.0 mg, 19.4% yield) as a yellow oil.

[0314] Step 8: To a solution of methyl 1-((2-(3,4-dichlorophenyl)chroman-6- yl)methyl)azetidine-3-carboxylate (600 mg, 1.48 mmol) in THF (20 mL) was added lithium hydroxide (310 mg, 7.38 mmol) in water (5 mL). The mixture was stirred at rt for 16 h, acidified to pH = 5~6 with 2 N HCl, diluted with water (50 mL), and extracted with EtOAc (100 mL*3). The combined organic extracts were washed with water (40 mL*3) and brine (100 mL*2), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by prep-HPLC to afford 1-((2-(3,4-dichlorophenyl)chroman-6-yl)methyl)azetidine-3-carboxylic acid (30.0 mg, 5.17% yield) as a white solid. LCMS: 392.10 [M+1]+.

[0315] Example 90 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 91: Synthesis of (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3- carboxylic acid

[0316] Step 1: To a solution of 1-(chloromethyl)-3-(trifluoromethyl) benzene (2.00 g, 10.3 mmol) and 4-hydroxybenzaldehyde (1.26 g, 10.3 mmol) in ACN (20 mL) was added potassium carbonate (4.26 g, 30.8 mmol). The mixture was stirred at 80oC for 16 h, diluted with water (100 mL), and extracted with EtOAc (100 mL*2). The combined organic extracts were washed with water (200 mL*2) and brine (200 mL), dried over Na2SO4, and concentrated in vacuo to afford 4-((3-(trifluoromethyl)benzyl)oxy) benzaldehyde (2.50 g, 86.8% yield) as a white solid.

[0317] Step 2: To a mixture of 4-{[3-(trifluoromethyl)phenyl]methoxy}benzaldehyde (500 mg, 1.78 mmol) and methyl (3R)-pyrrolidine-3-carboxylate hydrochloride (295 mg, 1.78 mmol) in DCE (10 mL) was added DIEA (231 mg, 1.78 mmol) and acetic acid (10.7 mg, 178 µmol). The mixture was stirred at 35oC for 16 h. Sodium triacetoxyborohydride (1.13 g, 5.35 mmol) was added and the mixture was stirred at 35oC for 4 h, diluted with water (50 mL) and extracted with DCM (50 mL*2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford methyl (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylate (440 mg, 62.7% yield) as a yellow oil.

[0318] Step 3: To a mixture of methyl (R)-1-(4-((3- (trifluoromethyl)benzyl)oxy)benzyl)pyrrolidine-3-carboxylate (440 mg, 1.12 mmol) in THF (3 mL) and H2O (1 mL) was added LiOH (53.6 mg, 2.24 mmol). The resulting mixture was stirred at rt for 4 h, acidified to pH 6-7 with 2 N HCl, and filtered. The isolated solid was rinsed with DCM and dried under vacuum to afford (R)-1-(4-((3-(trifluoromethyl)benzyl)oxy) benzyl)pyrrolidine-3-carboxylic acid (350 mg, 82.5% yield) as a white solid. LCMS: 380.1 [M+1]+.

[0319] Examples 92-115 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 116: Synthesis of 1-(4-((3,4-dichlorobenzyl)oxy)-3,5-dimethylbenzyl)azetidine-3- carboxylic acid

[0320] Step 1: To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (80.0 g, 533 mmol) in DMF (250 mL) was added 1,2-dichloro-4-(chloromethyl)benzene (81.2 mL, 586 mmol) and potassium carbonate (110 g, 799 mmol) and the mixture was stirred at 60 °C for 3 h. The reaction mixture was poured into ice water (300 mL) and stirred for 30 min. The resulting precipitate was filtered and washed with water then pet. ether / EtOAc (20 / 1, v / v) to afford 4- [(3,4-dichlorophenyl)methoxy]-3,5-dimethylbenzaldehyde (161 g, 97.8% yield) as a white solid.

[0321] Step 2: To a solution of 4-[(3,4-dichlorophenyl)methoxy]-3,5-dimethylbenzaldehyde (9.00 g, 29.1 mmol) in DCE (25 mL) was added azetidine-3-carboxylic acid (4.41 g, 43.7 mmol) and acetic acid (833 µL, 14.6 mmol) and the mixture was heated to 50 °C and stirred for 16 h. The mixture was cooled to rt and sodium triacetoxyborohydride (9.25 g, 43.7 mmol) was added portion-wise. The mixture was stirred for 2 h and then concentrated in vacuo. The crude residuewas purified by reverse phase chromatography and washed by DCM / n-hexane (10 / 1, v / v) to afford 1-(4-((3,4-dichlorobenzyl)oxy)-3,5-dimethylbenzyl)azetidine-3-carboxylic acid (8.20 g, 71.5% yield) as a white solid. LCMS: 394.1 [M+1]+.

[0322] Examples 117-368 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 369: Synthesis of 1-((5-((3-cyano-4-isopropoxybenzyl)oxy)-3-methylpyridin-2- yl)methyl)azetidine-3-carboxylic acid

[0323] Step 1: To a solution of methyl 5-hydroxy-3-methylpicolinate (2.18 g, 13.0 mmol) in DMF (15 mL) was added 5-(chloromethyl)-2-isopropoxybenzonitrile (4.10 g, 19.6 mmol) and potassium carbonate (3.60 g, 26.1 mmol). The mixture was stirred at 60oC for 16 h, diluted with H2O (150 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with H2O (150 mL) and brine (150 mL*2), dried over Na2SO4, concentrated in vacuo,and purified by silica gel chromatography to afford methyl 5-((3-cyano-4- isopropoxybenzyl)oxy)-3-methylpicolinate (3.20 g, 72.0% yield) as a white solid.

[0324] Step 2: To a solution of methyl 5-((3-cyano-4-isopropoxybenzyl)oxy)-3- methylpicolinate (500 mg, 1.47 mmol) in THF (3 mL) at 0oC was added lithium borohydride (1 N in THF, 2.20 mL, 2.20 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O (50 mL), and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 5-(((6-(hydroxymethyl)-5-methylpyridin-3- yl)oxy)methyl)-2-isopropoxybenzonitrile (239 mg, 52.0% yield) as a yellow solid.

[0325] Step 3: To a solution of 5-(((6-(hydroxymethyl)-5-methylpyridin-3-yl)oxy)methyl)-2- isopropoxybenzonitrile (139 mg, 445 µmol) in DCM (2 mL) at 0oC was added Dess-Martin periodinane (226 mg, 534 µmol). The reaction mixture was stirred at rt for 3 h, quenched with saturated aqueous Na2S2O3, diluted with H2O (50 mL), and extracted with DCM (30 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, and concentrated in vacuo to afford 5-(((6-formyl-5-methylpyridin-3-yl)oxy)methyl)-2- isopropoxybenzonitrile (120 mg, 86.8% yield) as a yellow solid.

[0326] Step 4: A solution of 5-(((6-formyl-5-methylpyridin-3-yl)oxy)methyl)-2- isopropoxybenzonitrile (150 mg, 429 µmol) and azetidine-3-carboxylic acid (65.1 mg, 644 µmol) in MeOH (3 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (32.4 mg, 515 µmol) was added, and the mixture was stirred at rt for 16 h. The pH was adjusted to 5-6 with 2 N HCl, and the mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (50 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-((5-((3-cyano-4- isopropoxybenzyl)oxy)-3-methylpyridin-2-yl)methyl)azetidine-3-carboxylic acid (130 mg, 54.9% yield) as a white solid. LCMS: 396.1 [M+1]+.

[0327] Examples 370-372 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 373: Synthesis of 1-((5-((3-(trifluoromethyl)benzyl)oxy)pyrazin-2- yl)methyl)azetidine-3-carboxylic acid

[0328] Step 1: To a solution of methyl 5-chloropyrazine-2-carboxylate (386 µL, 2.84 mmol) and (3-(trifluoromethyl)phenyl)methanol (490 mg, 2.84 mmol) in DMF (5 mL) was added potassium carbonate (1.85 g, 5.68 mmol). The resulting mixture was stirred at rt for 16 h, diluted with water (50 mL), and extracted with EtOAc (30 mL*3). The combined organic extracts were washed with water (50 mL*3) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 5-((3-(trifluoromethyl)benzyl)oxy)pyrazine-2-carboxylate (650 mg, 74.8% yield) as a yellow solid.

[0329] Step 2: To a solution of methyl 5-((3-(trifluoromethyl)benzyl)oxy)pyrazine-2- carboxylate (700 mg, 2.24 mmol) in MeOH (30 mL) at 0oC was added sodium borohydride (1.27 g, 33.6 mmol). The mixture was stirred at rt for 1 h, quenched with a saturated aqueous NH4Cl (20 mL), and extracted with DCM (20 mL*2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford (5-((3- (trifluoromethyl)benzyl)oxy)pyrazin-2-yl)methanol (500 mg, 80% purity, 62.8% yield) as a white solid.

[0330] Step 3: To a solution of (5-{[3-(trifluoromethyl)phenyl]methoxy}pyrazin-2- yl)methanol (500 mg, 1.41 mmol) in DCM (5 mL) at 0oC was added Dess-martin periodinane (716 mg, 1.69 mmol). The mixture was stirred at rt for 0.5 h, quenched with saturated aqueous NaHCO3(10 mL), and extracted with EtOAc (10 mL*2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 5-{[3- (trifluoromethyl)phenyl]methoxy}pyrazine-2-carbaldehyde (400 mg, 95.7% yield) as a white solid.

[0331] Step 4: To a solution of 5-{[3-(trifluoromethyl)phenyl]methoxy}pyrazine-2- carbaldehyde (200 mg, 709 µmol) in MeOH (5 mL) was added azetidine-3-carboxylic acid (243mg, 2.13 mmol) and AcOH (cat). The mixture was stirred at rt for 16 h, and sodium cyanoborohydride (26.7 mg, 425 µmol) was added. After stirring at rt for 1 h, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL*2). The combined organic extracts were washed by brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by Prep-HPLC to afford 1-((5-((3- (trifluoromethyl)benzyl)oxy)pyrazin-2-yl)methyl)azetidine-3-carboxylic acid (70.0 mg, 26.9% yield) as a white solid. LCMS: 366.1 [M+1]+.

[0332] Examples 374-377 in the table below were prepared using the procedure above, but instead employing the designated reagents:Example 378: Synthesis of 1-({4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5- methylphenyl}methyl)azetidine-3-carboxylic acid

[0333] Step 1: To a solution of sodium hydroxide (1.74 g, 43.4 mmol) in water (30 mL) was added 2-methoxy-6-methylphenol (3.00 g, 21.7 mmol) and formaldehyde (1.30 g, 43.4 mmol). The mixture was stirred at 60oC for 7 h. The reaction was neutralized to pH = 7~8 with 2 N HCl, diluted with water (100 mL) and extracted with EtOAc (200 mL*2). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, and concentrated in vacuo to afford 4-(hydroxymethyl)-2-methoxy-6-methylphenol (1.70 g, 46.6% yield) as a white solid.

[0334] Step 2: To a solution of 4-(hydroxymethyl)-2-methoxy-6-methylphenol (800 mg, 4.76 mmol) in DMF (20 mL) was added 1,2-dichloro-4-(chloromethyl)benzene (930 mg, 4.76 mmol) and cesium carbonate (3.10 g, 9.51 mmol). The reaction was stirred at rt for 16 h, filtered, and rinsed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (150 mL*3). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford (4-((3,4-dichlorobenzyl)oxy)-3-methoxy-5-methylphenyl)methanol (1.50 g, 96.3% yield) as a yellow oil.

[0335] Step 3: To a solution of (4-((3,4-dichlorobenzyl)oxy)-3-methoxy-5- methylphenyl)methanol (1.50 g, 4.58 mmol) in DCM (10 mL) at 0oC was added Dess-Martin periodinane (2.33 g, 5.5 mmol). The reaction mixture was stirred at rt for 2 h, filtered, and rinsed with DCM. The filtrate was diluted with water (100 mL) and extracted with DCM (50 mL*2). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-((3,4- dichlorobenzyl)oxy)-3-methoxy-5-methylbenzaldehyde (1.40 g, 93.9% yield) as a white solid.

[0336] Step 4: To a solution of 4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5- methylbenzaldehyde (500 mg, 1.54 mmol) and azetidine-3-carboxylic acid (155 mg, 1.54 mmol) in MeOH (5 mL) was added acetic acid (0.1 mL). The reaction mixture was stirred at rt for 16 h, and sodium cyanoborohydride (145 mg, 2.31 mmol) was added. After stirring at rt for 5 h, the pH was adjusted to 5 with 2 N HCl. The mixture was purified by reverse phase chromatography to afford 1-({4-[(3,4-dichlorophenyl)methoxy]-3-methoxy-5-methylphenyl}methyl)azetidine-3- carboxylic acid (180 mg, 28.5% yield) as a white solid. LCMS: 410.0 [M+1]+. Example 379: Synthesis of 1-(4-((3,4-dichlorobenzyl)thio)benzyl)azetidine-3-carboxylic acid

[0337] Step 1: To a solution of 1,2-dichloro-4-(chloromethyl)benzene (581 mg, 2.97 mmol) in DMF (10 mL) was added methyl 4-mercaptobenzoate (500 mg, 2.97 mmol) and cesium carbonate (822 mg, 5.94 mmol). The mixture was stirred at rt for 10 h, diluted with water (80 mL), and extracted with EtOAc (50 mL*3). The combined organic extracts were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 4-((3,4-dichlorobenzyl)thio)benzoate (800 mg, 82.3% yield) as a white solid.

[0338] Step 2: To a solution of methyl 4-((3,4-dichlorobenzyl)thio)benzoate (750 mg, 2.29 mmol) in THF (5 mL) at -75oC was added diisobutylaluminum hydride (1.5 M in THF, 4.60mL, 6.88 mmol) dropwise. The mixture was stirred at -75oC for 1 h, quenched with water (20 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-((3,4-dichlorobenzyl)thio)benzaldehyde (500 mg, 73.4% yield) as a white solid.

[0339] Step 3: To a solution of 4-((3,4-dichlorobenzyl)thio)benzaldehyde (150 mg, 505 µmol) in MeOH (2 mL) was added azetidine-3-carboxylic acid (102 mg, 1.01 mmol). The mixture was stirred at rt for 5 h. Sodium cyanoborohydride (47.6 mg, 757 µmol) was added and the resulting mixture was stirred for 2 h. The pH was adjusted to 5 with 1 N HCl. The resulting solution was purified by reverse phase chromatography to afford 1-(4-((3,4- dichlorobenzyl)thio)benzyl)azetidine-3-carboxylic acid (50.0 mg, 25.9% yield) as yellow oil. LCMS: 381.9 [M+1]+. Example 380: Synthesis of 1-[(4-{[(3,4-dichlorophenyl)methyl]sulfanyl}-3,5- dimethylphenyl)methyl]azetidine-3-carboxylic acid

[0340] Step 1: To a solution of methyl 4-amino-3,5-dimethylbenzoate (5.00 g, 27.9 mmol) and hydrogen chloride (13.9 g, 139 mmol) in water (2 mL) and acetonitrile (10 mL) at -5 ℃ was added slowly sodium nitrite (2.89 g, 41.8 mmol). The resulting mixture was stirred at -5 ℃ for 1 h. Potassium O-ethylcarbonodithioate (17.9 g, 112 mmol) was added carefully and the reaction was stirred at 75 ℃ for 2 h then quenched with water (250 mL) and extracted with EtOAc (100 mL*3). The combined organic extracts were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford methyl 4- [(ethoxymethanethioyl)sulfanyl]-3,5-dimethylbenzoate (4.00 g, 50.5% yield) as a yellow oil.

[0341] Step 2: To a solution of methyl 4-[(ethoxymethanethioyl)sulfanyl]-3,5- dimethylbenzoate (3.00 g, 10.5 mmol) in EtOH (50 mL) was added potassium hydroxide (1.48 g, 26.4 mmol). The resulting mixture was stirred at 80 ℃ for 3 h then partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was concentrated in vacuo to afford 3,5-dimethyl-4-sulfanylbenzoic acid (1.20 g, 23.6% yield) as a yellow solid and 4,4'- disulfanediylbis(3,5-dimethylbenzoic acid) (1.10 g, 10.8% yield).

[0342] Step 3: To a solution of4-[(4-carboxy-2,6-dimethylphenyl)disulfanyl]-3,5- dimethylbenzoic acid (1.00 g, 2.76 mmol) in THF at -40 ℃ was added borane-dimethyl sulfide (2.10 g, 27.6 mmol). The resulting mixture was stirred at rt for 3 h then quenched with NaHCO3(10 mL), diluted with water (500 mL), and extracted with EtOAc (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford (3,5-dimethyl-4- sulfanylphenyl)methanol (232 mg, 50.5% yield) as a yellow solid.

[0343] Step 4: To a solution of(3,5-dimethyl-4-sulfanylphenyl)methanol (842 mg, 5.00 mmol) in DMF (10 mL) was added 1,2-dichloro-4-(chloromethyl)benzene (978 mg, 5.00 mmol) and cesium carbonate (3.26 g, 10.0 mmol). The resulting mixture was stirred at rt for 16 h then diluted with water (250 mL) and extracted with EtOAc (100 mL*3). The combined organic extracts were washed with brine, concentrated in vacuo, and purified by silica gel chromatography to afford (4-{[(3,4-dichlorophenyl)methyl]sulfanyl}-3,5- dimethylphenyl)methanol (465 mg, 28.4% yield) as a white solid.

[0344] Step 5: To a solution of (4-{[(3,4-dichlorophenyl)methyl]sulfanyl}-3,5- dimethylphenyl)methanol (260 mg, 794 µmol) in DCM (5 mL, 78.1 mmol) was added sulfonyl chloride (43.6 mg, 367 µmol). The mixture was stirred at rt for 3 h then concentrated in vacuo to afford 5-(chloromethyl)-2-{[(3,4-dichlorophenyl)methyl]sulfanyl}-1,3-dimethylbenzene (260 mg, 94.7% yield) as a brown oil.

[0345] Step 6: A mixture of 5-(chloromethyl)-2-{[(3,4-dichlorophenyl)methyl]sulfanyl}-1,3- dimethylbenzene (270 mg, 781 µmol), methyl azetidine-3-carboxylate (89.9 mg, 781 µmol) and potassium carbonate (432 mg, 3.13 mmol) in DMF (10 mL) was stirred at rt for 16 h then concentrated in vacuo. The crude material was purified by prep-HPLC to afford methyl 1-[(4- {[(3,4-dichlorophenyl)methyl]sulfanyl}-3,5-dimethylphenyl)methyl]azetidine-3-carboxylate (300 mg, 90.5% yield) as a white solid.

[0346] Step 7: To a mixture of methyl 1-[(4-{[(3,4-dichlorophenyl)methyl]sulfanyl}-3,5- dimethylphenyl)methyl]azetidine-3-carboxylate (190 mg, 448 µmol) in THF (4 mL) and water (1 mL) was added lithium hydroxide hydrate (56.4 mg, 1.34 mmol). The resulting mixture was stirred at rt for 4 h then concentrated in vacuo and purified by prep-HPLC to afford 1-[(4-{[(3,4- dichlorophenyl)methyl]sulfanyl}-3,5-dimethylphenyl)methyl]azetidine-3-carboxylic acid (80.0 mg, 43.5% yield) as a white solid. LCMS: 410.2 [M+1]. Example 381: Synthesis of 1-((5-((3-(trifluoromethyl)phenoxy)methyl)pyridin-2- yl)methyl)azetidine-3-carboxylic acid

[0347] Step 1: To a solution of 5-(hydroxymethyl)pyridine-2-carboxylic acid (1.50 g, 9.8 mmol) in MeOH (15 mL) at 0oC was added thionyl chloride (2.13 mL, 29.4 mmol). The mixture was stirred at rt for 2 h then concentrated in vacuo to afford methyl 5- (hydroxymethyl)pyridine-2-carboxylate (1.50 g, 91.5% yield) as a brown oil.

[0348] Step 2: To a solution of methyl 5-(hydroxymethyl)pyridine-2-carboxylate (1.5 g, 8.97 mmol) in DCM (18 mL) at 0oC was added thionyl chloride (3.20 g, 26.9 mmol). The mixture was stirred at rt for 2 h then concentrated in vacuo to afford methyl 5-(chloromethyl)pyridine-2- carboxylate (1.20 g, 72.1% yield) as a brown solid.

[0349] Step 3: To a solution of methyl 5-(chloromethyl)pyridine-2-carboxylate (200 mg, 1.08 mmol) and 3-(trifluoromethyl)phenol (175 mg, 1.08 mmol) in DMF (3 mL) was added cesium carbonate (704 mg, 2.16 mmol). The resulting mixture was stirred at rt for 16 h, diluted with water (10 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with brine (20 mL*3), concentrated in vacuo, and purified by Prep-TLC to afford methyl 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2-carboxylate (180 mg, 53.5% yield) as a white solid.

[0350] Step 4: To a solution of methyl 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2- carboxylate (680 mg, 2.18 mmol) in MeOH (5 mL) at 0oC was added sodium borohydride (413 mg, 10.9 mmol) in portions. The mixture was stirred at rt for 16 h, diluted with water (20 mL), and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with brine (20 mL), concentrated in vacuo, and purified by Prep-TLC to afford (5-{[3- (trifluoromethyl)phenoxy]methyl}pyridin-2-yl)methanol (230 mg, 37.2% yield) as a white solid.

[0351] Step 5: To a solution of (5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2- yl)methanol (230 mg, 812 µmol) in DCM (5 mL) at 0oC was added Dess-Martin periodinane (413 mg, 974 µmol). The mixture was stirred at rt for 1 h, diluted with water (10 mL), and extracted with DCM (20 mL*3). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2-carbaldehyde (200 mg, 87.6% yield) as a white solid.

[0352] Step 6: A solution of 5-{[3-(trifluoromethyl)phenoxy]methyl}pyridine-2-carbaldehyde (200 mg, 711 µmol) and azetidine-3-carboxylic acid (71.9 mg, 711 µmol) in MeOH (3 mL) wasstirred at rt for 16 h, and sodium cyanoborohydride (89.4 mg, 1.42 mmol) was added. After stirring at rt for 1 h, the mixture was filtered and purified by reverse phase chromatography to afford 1-[(5-{[3-(trifluoromethyl)phenoxy]methyl}pyridin-2-yl)methyl]azetidine-3-carboxylic acid (100 mg, 38.4% yield) as a white solid. LCMS: 367.0 [M+1]+. Example 382: Synthesis of 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2- methylbenzyl)azetidine-3-carboxylic acid

[0353] Step 1: To a solution of 4-bromo-3-(trifluoromethyl)phenol (1.00 g, 4.15 mmol) in 1,4- dioxane (18 mL) and water (6 mL) was added cyclohex-1-en-1-ylboronic acid (575 mg, 4.56 mmol), Pd(dppf)Cl2(151 mg, 207 µmol), and potassium carbonate (1.15 g, 8.30 mmol). The mixture was stirred at 100℃ under N2 for 18 h then diluted with water (50 mL) and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (1.00 g, 99.0% yield) as a yellow oil.

[0354] Step 2: To a solution of 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (1.00 g, 4.13 mmol) in MeOH (15 mL) was added 20% Pd / C (200 mg) and HOAc (10 µL). The resulting mixture was stirred at rt under H2 for 18 h then filtered and concentrated in vacuo to afford 4-cyclohexyl-3-(trifluoromethyl)phenol (1.00 g, 99.0% yield) as a brown oil.

[0355] Step 3: To a solution of methyl 4-(hydroxymethyl)-2-methylbenzoate (1.20 g, 6.66 mmol) in DCM (20 mL) at 0oC was added thionyl chloride (1.45 mL, 20.0 mmol). The reaction mixture was stirred at rt for 20 min then concentrated in vacuo to afford methyl 4- (chloromethyl)-2-methylbenzoate (1.20 g, 90.9% yield) as a colorless oil.

[0356] Step 4: To a solution of 4-cyclohexyl-3-(trifluoromethyl)phenol (600 mg, 2.46 mmol) in DMF (10 mL) was added methyl 4-(chloromethyl)-2-methylbenzoate (488 mg, 2.46 mmol) and potassium carbonate (1.20 g, 2.91 mmol). The reaction mixture was stirred at 60oC for 18 h then diluted with water (50 mL) and extracted with EtOAc (80 mL*2). The combined organicextracts were washed with water (100 mL*2) and brine (50 mL*2), dried over Na2SO4, and concentrated in vacuo to afford methyl 4-((4-cyclohexyl-3- (trifluoromethyl)phenoxy)methyl)-2- methylbenzoate (300 mg, 30.4% yield) as a colorless oil.

[0357] Step 5: To a solution of methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)- 2-methylbenzoate (220 mg, 541 µmol)) in THF (8 mL) at 0 °C was added lithium aluminum hydride (41.0 mg, 1.08 mmol). The resulting mixture was stirred at rt for 2 h then quenched with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (30 mL*3) and brine (15 mL), dried over Na2SO4, and concentrated in vacuo to afford (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2-methylphenyl)methanol (200 mg, 97.6% yield) as a white solid.

[0358] Step 6: To a solution of (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2- methylphenyl)methanol (200 mg, 529 µmol) in THF (8 mL) was added manganese dioxide (459 mg, 5.29 mmol). The resulting mixture was stirred at rt for 18 h then filtered, concentrated in vacuo, and purified by Prep-TLC to afford 4-((4-cyclohexyl-3-(trifluoromethyl) phenoxy) methyl)-2-methylbenzaldehyde (120 mg, 60.3% yield) as a yellow solid.

[0359] Step 7: A solution of 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2- methylbenzaldehyde (120 mg, 319 µmol) and azetidine-3-carboxylic acid (32.2 mg, 319 µmol) in MeOH (8 mL) and acetic acid (0.1 mL) was stirred at rt for 18 h then sodium cyanoborohydride (22.9 mg, 383 µmol) was added. After stirring for 5 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic extracts were washed with water (15 mL*3) and brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by Prep-HPLC and then washed with EtOAc:hexane (1:2) to afford 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-2- methylbenzyl)azetidin-3-carboxylic acid (20.0 mg, 13.6% yield) as a white solid. LCMS: 462.2 [M+1]+. Example 383: Synthesis of 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3- methylbenzyl) azetidine- 3-carboxylic acid

[0360] Step 1: To a solution of 4-bromo-3-(trifluoromethyl)phenol (5.00 g, 20.7 mmol) in 1,4- dioxane (60 mL) was added (cyclohex-1-en-1-yl)boronic acid (2.87 g, 22.8 mmol), Pd(dppf)Cl2(753 mg, 1.04 mmol), potassium carbonate (5.73 g, 41.5 mmol) and H2O (20 mL). The mixture was stirred at 100oC under N2 for 16 h, diluted with water (50 mL), and extracted with EtOAc (50 mL*2). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 2- (trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (5.00 g, 99.5% yield) as a yellow oil.

[0361] Step 2: To a solution of 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-ol (5.00 g, 20.6 mmol) in MeOH (50 mL) was added 10% Pd / C (500 mg, 4.70 mmol) and HOAc (10 µL). The resulting mixture was stirred at 40oC for 16 h under H2(1 atm), filtered, and concentrated in vacuo to afford 4-cyclohexyl-3-(trifluoromethyl)phenol (4.92 g, 97.6% yield) as a brown oil.

[0362] Step 3: To a solution of methyl 4-(hydroxymethyl)-3-methylbenzoate (4.00 g, 22.2 mmol) in DCM (20 mL) at 0oC was added thionyl chloride (2.42 mL, 33.3 mmol) dropwise. The mixture was stirred at rt for 20 min and then concentrated in vacuo to afford methyl 4- (chloromethyl)-3-methylbenzoate (4.00 g, 90.7% yield) as a colorless oil.

[0363] Step 4: To a solution of 4-cyclohexyl-3-(trifluoromethyl)phenol (5.00 g, 20.5 mmol) in DMF (30 mL) was added methyl 4-(chloromethyl)-3-methylbenzoate (4.07 g, 20.5 mmol) and potassium carbonate (5.66 g, 40.9 mmol). The resulting mixture was stirred at 60oC for 16 h, diluted with water, and extracted with EtOAc (100 mL*2). The combined organic extracts were washed with water (100 mL*2) and brine (100 mL*2), dried over Na2SO4, and concentrated in vacuo to afford methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3-methylbenzoate (4.59 g, 55.2% yield) as a white solid.

[0364] Step 5: To a solution of methyl 4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)- 3-methylbenzoate (2.00 g, 4.92 mmol) in THF (20 mL) at 0oC was added lithium aluminum hydride (224 mg, 5.90 mmol). The resulting mixture was stirred at rt for 30 min and then concentrated in vacuo to afford (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3- methylphenyl) methanol (1.80 g, 96.7% yield) as a white solid.

[0365] Step 6: To a solution of (4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)-3- methylphenyl) methanol (1.80 g, 4.76 mmol) in DCM (10 mL) at 0oC was added thionyl chloride (518 µL, 7.13 mmol) dropwise. The resulting mixture was stirred at rt for 30 min and then concentrated in vacuo to afford 4-(chloromethyl)-1-((4-cyclohexyl-3- (trifluoromethyl)phenoxy)methyl)-2-methylbenzene (1.88 g, 99.6% yield) as a white solid.

[0366] Step 7: To a solution of 4-(chloromethyl)-1-((4-cyclohexyl-3- (trifluoromethyl)phenoxy)methyl)-2-methylbenzene (1.88 g, 4.74 mmol) and methyl 3- azetidinecarboxylate (1.44 g, 9.47 mmol) in DMF (20 mL) was added potassium carbonate (1.64 g, 11.8 mmol). The mixture was stirred at 60oC for 16 hours, diluted with water (10 mL), and extracted with EtOAc (10 mL*2). The combined organic extracts were washed with water (10 mL*2) and brine (10 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford methyl 1-(4-((4-cyclohexyl-3-(trifluoromethyl)phenoxy)methyl)- 3-methylbenzyl)azetidine-3-carboxylate (760 mg, 33.7% yield) as a yellow oil.

[0367] Step 8: To a solution of methyl 1-(4-((4-cyclohexyl-3- (trifluoromethyl)phenoxy)methyl)-3-methylbenzyl)azetidine-3-carboxylate (320 mg, 673 µmol) in THF (5 mL) was added LiOH·H2O (56.5 mg, 1.35 mmol) and H2O (1 mL). The mixture was stirred at rt for 3 h, diluted with water (10 mL), and extracted with EtOAc (10 mL*2). The combined organic extracts were washed with brine (10 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by reverse phase chromatography to afford 1-(4-((4-cyclohexyl-3- (trifluoromethyl)phenoxy)methyl)-3-methylbenzyl) azetidine-3-carboxylic acid (60 mg, 19.3% yield) as a white solid. LCMS: 462.22 [M+1]+. Example 384: Synthesis of 1-((2-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)azetidine-3-carboxylic acid

[0368] Step 1: To a solution of tert-butyl 6-bromo-1,2,3,4-tetrahydroisoquinoline-2- carboxylate (500 mg, 1.60 mmol) in MeOH (3 mL) and DMSO (3 mL) was added palladium acetate (8.99 mg, 40.0 µmol), triethylamine (324 mg, 3.20 mmol) and 1,3- bis(diphenylphosphino)propane (30.9 mg, 80.1 µmol). The reaction was stirred at 80oC for 16 h under CO (1 atm), diluted with water (30 mL), and extracted with EtOAc (30 mL*3). The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 2-(tert-butyl) 6-methyl 3,4-dihydroisoquinoline-2,6(1H)- dicarboxylate (200 mg, 42.9% yield) as a white solid.

[0369] Step 2: To a solution of 2-tert-butyl 6-methyl 1,2,3,4-tetrahydroisoquinoline-2,6- dicarboxylate (1.00 g, 3.43 mmol) in DCM (9 mL) was added trifluoroacetic acid (3.91 g, 34.3 mmol). The reaction was stirred at rt for 2 h then concentrated in vacuo to afford methyl 1,2,3,4- tetrahydroisoquinoline-6-carboxylate (600 mg, 91.4% yield) as a brown oil.

[0370] Step 3: To a solution of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate (850 mg, 4.44 mmol) in 1,4-dioxane (10 mL) was added 1,2-dichloro-4-iodobenzene (1.21 g, 4.44 mmol), Pd2(dba)3 (407 mg, 444 µmol), xantphos (514 mg, 889 µmol), and cesium carbonate (4.34 g, 13.3 mmol). The reaction was stirred at 110oC under N2for 16 h, filtered, and concentrated. The crude material was purified by silica gel chromatography to afford methyl 2-(3,4- dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (800 mg, 53.5% yield) as a yellow solid.

[0371] Step 4: To a solution of methyl 2-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline- 6-carboxylate (800 mg, 2.38 mmol) in THF (10 mL) at 0oC was added lithium aluminum hydride (181 mg, 4.76 mmol). The reaction was stirred at 0oC for 2 h, quenched with water (30 mL), filtered, and the filtrate was extracted with EtOAc (30 mL*3). The combined organic extracts were washed with brine (30 mL) and concentrated in vacuo to afford (2-(3,4- dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methanol (580 mg, 79.1% yield) as a white solid.

[0372] Step 5: To a solution of (2-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)methanol (400 mg, 1.3 mmol) in DCM (10 mL) at 0oC was added Dess-Martin periodinane (1.20 g, 2.82 mmol). The reaction was stirred at rt for 16 h, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 2-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (350 mg, 60.7% yield) as a white solid.

[0373] Step 6: To a solution of 2-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline-6- carbaldehyde (120 mg, 392 µmol) in MeOH (3 mL) was added azetidine-3-carboxylic acid (47.5 mg, 470 µmol) and acetic acid (5 mg). The reaction was stirred at rt for 16 h, and then sodium cyanoborohydride (49.3 mg, 784 µmol) was added. The reaction was stirred at rt for 4 h,concentrated in vacuo, and purified by reverse phase chromatography followed by prep-HPLC to afford 1-((2-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)azetidine-3- carboxylic acid (20.0 mg, 11.7% yield) as a white solid. LCMS: 391.1 [M+1]+.

[0374] Examples 385 and 386 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 387: Synthesis of 1-(3-methyl-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)benzyl)azetidine-3-carboxylic acid

[0375] Step 1: To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (500 mg, 2.10 mmol) and methyl 4-iodo-3-methylbenzoate (697 mg, 2.52 mmol) in 1,4-dioxane (25 mL) was added cesium carbonate (2.06 g, 6.31 mmol), xantphos (98.2 mg, 210 µmol), and Pd2(dba)3(193 mg, 210 µmol). The resulting mixture was stirred at 110oC for 16 h under N2, diluted with water (50 mL), and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (20 mL*2), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford methyl 3-methyl-4-[7-(trifluoromethyl)- 1,2,3,4-tetrahydroisoquinolin-2-yl]benzoate (450 mg, 61.4% yield) as a yellow oil.

[0376] Step 2: To a solution of methyl 3-methyl-4-[7-(trifluoromethyl)-1,2,3,4- tetrahydroisoquinolin-2-yl]benzoate (800 mg, 2.29 mmol) in THF (20 mL, 246 mmol) at 0oC was added lithium aluminum hydride (104 mg, 2.75 mmol). The mixture was stirred at rt for 16 h, quenched with water ( 20 mL) and saturated aqueous potassium sodium tartrate (20 mL), filtered, and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford {3-methyl-4-[7-(trifluoromethyl)-1,2,3,4- tetrahydroisoquinolin-2-yl]phenyl}methanol (500 mg, 68.1% yield) as a yellow oil.

[0377] Step 3: To a solution of {3-methyl-4-[7-(trifluoromethyl)-1,2,3,4- tetrahydroisoquinolin-2-yl]phenyl}methanol (400 mg, 1.24 mmol) in THF (5 mL, 61.4 mmol) at 0oC was added Dess-Martin periodinane (634 mg, 1.49 mmol). The mixture was stirred at 40oC for 4 h, diluted with water (20 mL), and extracted with EtOAc (20 mL*2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by Prep-TLC to afford 3-methyl-4-[7-(trifluoromethyl)- 1,2,3,4-tetrahydroisoquinolin-2-yl]benzaldehyde (240 mg, 60.6% yield) as a yellow oil.

[0378] Step 4: To a solution of 3-methyl-4-[7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin- 2-yl]benzaldehyde (140 mg, 438 µmol) in MeOH (2 mL) was added azetidine-3-carboxylic acid (88.7 mg, 877 µmol) and acetic acid (0.1 mL). The resulting mixture was stirred at rt for 16 h. Sodium cyanoborohydride (33.0 mg, 526 µmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with water (50 mL), adjusted to pH= 5 with 2 N HCl, and extracted with EtOAc (40 mL*2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by reverse phase chromatography to afford 1-({2-methyl-4-[7-(trifluoromethyl)-1,2,3,4- tetrahydroisoquinolin-2-yl]phenyl}methyl)azetidine-3-carboxylic acid (30.0 mg, 73.8 µmol) as a yellow solid. LCMS: 405.1 [M+1]+.

[0379] Example 388 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 389: Synthesis of 1-(4-((3,4-dichlorobenzyl)oxy)-3-fluoro-5- methylbenzyl)azetidine-3-carboxylic acid

[0380] Step 1: To a solution of 2-fluoro-6-methylphenol (1.00 g, 7.9 mmol) in acetic acid (10 mL) was added N-bromosuccinimide (1.41 g, 7.90 mmol). The mixture was stirred at rt for 18 h then diluted with water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic extracts were washed with water (100 mL) and brine (50 mL*2), dried over Na2SO4, and concentrated in vacuo to afford 4-bromo-2-fluoro-6-methylphenol (1.60 g, 99.3% yield) as a white solid.

[0381] Step 2: To a solution of 4-bromo-2-fluoro-6-methylphenol (500 mg, 2.44 mmol) in MeOH (3 mL) and DMSO (3 mL) was added Pd(OAc)2 (54.8 mg, 244 µmol), triethylamine (1.02 mL, 7.32 mmol) and DPPP (50.3 mg, 122 µmol). The reaction mixture was stirred at 80°C for 18 h under CO atmosphere then diluted with water (30 mL) and extracted with EtOAc (30 mL*2). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by Prep-TLC to afford methyl 3-fluoro-4- hydroxy-5-methylbenzoate (300 mg, 66.8% yield) as a white solid.

[0382] Step 3: To a solution of methyl 3-fluoro-4-hydroxy-5-methylbenzoate (330 mg, 1.79 mmol) and 1,2-dichloro-4-(chloromethyl)benzene (350 mg, 1.79 mmol) in DMF (5 mL) was added potassium carbonate (495 mg, 3.58 mmol). The reaction mixture was stirred at rt for 18 h then diluted with water (40 mL) and extracted with EtOAc (40 mL*2). The combined organic extracts were washed with water (40 mL*2) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 4-((3,4-dichlorobenzyl)oxy)-3-fluoro-5-methylbenzoate (600 mg, 97.5% yield) as a white solid.

[0383] Step 4: To a solution of methyl 4-((3,4-dichlorobenzyl)oxy)-3-fluoro-5-methylbenzoate (600 mg, 1.75 mmol) in THF (5 mL) was added lithium borohydride (79.6 mg, 2.10 mmol) and the mixture was stirred at rt for 18 h. Water (20 mL) and 2N HCl were added and the mixture was extracted with EtOAc (80 mL*2). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford (4-((3,4-dichlorobenzyl)oxy)- 3-fluoro-5-methylphenyl)methanol (510 mg, 92.5% yield) as a colorless oil.

[0384] Step 5: To a solution of (4-((3,4-dichlorobenzyl)oxy)-3-fluoro-5- methylphenyl)methanol (500 mg, 1.59 mmol) in DCM (3 mL) was added DMF (cat.) and sulfonyl chloride (230 µL, 3.17 mmol). The resulting mixture was stirred at rt for 4h then concentrated in vacuo to afford 5-(chloromethyl)-2-((3,4-dichlorobenzyl)oxy)-1-fluoro-3- methylbenzene (500 mg, 94.4% yield) as a yellow oil.

[0385] Step 6: To a solution of 5-(chloromethyl)-2-((3,4-dichlorobenzyl)oxy)-1-fluoro-3- methylbenzene (550 mg, 1.65 mmol) and methyl azetidine-3-carboxylate (380 mg, 3.30 mmol) in DMF (5 mL) was added potassium carbonate (570 mg, 4.12 mmol). The resulting mixture was stirred at rt for 18 h then diluted with water (50 mL) and extracted with EtOAc (50 mL*2).The combined organic extracts were washed with water (40 mL*2) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 1-(4-((3,4-dichlorobenzyl)oxy)-3- fluoro-5-methylbenzyl)azetidine-3-carboxylate (500 mg, 73.5% yield) as a white solid.

[0386] Step 7: To a solution of methyl 1-(4-((3,4-dichlorobenzyl)oxy)-3-fluoro-5- methylbenzyl)azetidine-3-carboxylate (300 mg, 728 µmol) in THF (2 mL) was added LiOH.H2O (58.2 mg, 1.46 mmol) in water (0.5 mL). The resulting mixture was stirred at rt for 18 h and then adjusted to pH=4-5 with 2 N HCl and concentrated in vacuo. The crude material was purified by reverse phase chromatography followed by Prep-HPLC to afford 1-(4-((3,4- dichlorobenzyl)oxy)-3-fluoro-5-methylbenzyl)azetidine-3-carboxylic acid (70.0 mg, 24.1% yield) as a yellow solid. LCMS: 398.05 [M+1]+. Example 390: Synthesis of 1-(4-((3,4-dichlorobenzyl)(methyl)amino)benzyl)azetidine-3- carboxylic

[0387] Step 1: To a solution of 4-aminobenzaldehyde (1.00 g, 8.25 mmol) in DMF (5 mL) was added potassium carbonate (2.28 g, 16.5 mmol) and 1,2-dichloro-4-(chloromethyl)benzene (3.23 g, 16.5 mmol). After stirring at 25oC for 16 h, water (50 mL) was added, and the resulting mixture was extracted with EtOAc (30 mL*3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography afforded 4-{[(3,4-dichlorophenyl)methyl]amino}benzaldehyde (650 mg, 28.1% yield) as a white solid.

[0388] Step 2: To a solution of 4-{[(3,4-dichlorophenyl)methyl]amino}benzaldehyde (650 mg, 2.32 mmol) in THF (6 mL) at 0oC was added sodium hydride (60% dispersion in mineral oil, 185 mg, 4.64 mmol). The reaction was stirred at 0oC for 2 h, then iodomethane (362 mg, 2.55 mmol) was added. After stirring at 25oC for 3 h, water (50 mL) was added, and the resulting mixture was extracted with EtOAc (30 mL*3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford 4-{[(3,4- dichlorophenyl)methyl](methyl)amino}benzaldehyde (525 mg, 76.9% yield) as a yellow solid.

[0389] Step 3: To a solution of methyl azetidine-3-carboxylate hydrochloride (325 mg, 2.14 mmol) in DCE (5 mL) was added ethylbis(propan-2-yl)amine (346 mg, 2.68 mmol) and the mixture was stirred for 5 min.4-{[(3,4-Dichlorophenyl)methyl](methyl)amino}benzaldehyde (525 mg, 1.78 mmol) and a drop of acetic acid were added and the reaction was stirred at rt for16 h. Sodium triacetoxyborohydride (757 mg, 3.57 mmol) was added and stirring was continued at rt for 2 h. Water (30 mL) was added and the resulting mixture was extracted with EtOAc (30 mL*2). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to afford methyl 1-[(4-{[(3,4- dichlorophenyl)methyl](methyl)amino}phenyl)methyl]azetidine-3-carboxylate (680 mg, 96.8%) as a white solid.

[0390] Step 4: To a solution of methyl 1-[(4-{[(3,4- dichlorophenyl)methyl](methyl)amino}phenyl)methyl]azetidine-3-carboxylate (680 mg, 1.73 mmol) in THF (4 mL) and water (1 mL) was added LiOH (133 mg, 3.16 mmol) and the mixture was stirred for 2 h at rt. The reaction mixture was purified by reverse phase chromatography to afford 1-[(4-{[(3,4-dichlorophenyl)methyl](methyl)amino}phenyl)methyl]azetidine-3- carboxylic acid (300 mg, 75.0%) as a yellow solid. LCMS: 377.1 [M-1].

[0391] Example 391 in the table below was prepared using the procedure above, but instead employing the designated reagents:Example 392 and Example 393: Synthesis of 1-({4-[(1E)-2-[3-cyano-4-(propan-2- yloxy)phenyl]ethenyl]-2-methylphenyl}methyl)azetidine-3-carboxylic acid and 1-[(4-{2-[3- cyano-4-(propan-2-yloxy)phenyl]ethyl}-2-methylphenyl)methyl]azetidine-3-carboxylic acid

[0392] Step 1: To a solution of 5-bromo-2-(propan-2-yloxy)benzonitrile (1.20 g, 5.00 mmol) and 4-ethenyl-2-methylbenzaldehyde (804 mg, 5.50 mmol) in DMF (20 mL) was added cesium carbonate (3.26 g, 10.0 mmol) and palladium bis(triphenylphosphane) dichloride (351 mg, 0.500 mmol). The resulting mixture was stirred under nitrogen at 120 ℃ for 16 h then diluted with water (50 mL) and extracted with EtOAc (300 mL). The organic phase was washed with brine,dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 5-[(1E)-2-(4-formyl-3-methylphenyl)ethenyl]-2-(propan-2- yloxy)benzonitrile (0.800 g, 2.62 mmol) as a white solid.

[0393] Step 2: To a solution of 5-[(1E)-2-(4-formyl-3-methylphenyl)ethenyl]-2-(propan-2- yloxy)benzonitrile (250 mg, 819 µmol) and azetidine-3-carboxylic acid (124 mg, 1.23 mmol) in ACN (3 mL) was added acetic acid (4.92 mg, 81.9 µmol). The mixture was stirred at rt for 6 h then sodium cyanoborohydride (30.9 mg, 491 µmol) was added. After stirring at rt for 16 h, the reaction mixture was diluted with water was purified using reverse phase chromatography to afford 1-({4-[(1E)-2-[3-cyano-4-(propan-2-yloxy)phenyl]ethenyl]-2- methylphenyl}methyl)azetidine-3-carboxylic acid (150 mg, 46.9% yield) as a white solid. LCMS: 391.2 [M+1].

[0394] Step 3: To a solution of 1-({4-[(1E)-2-[3-cyano-4-(propan-2-yloxy)phenyl]ethenyl]-2- methylphenyl}methyl)azetidine-3-carboxylic acid (Example 392, 150 mg, 384 µmol) in MeOH (10 mL) was added Pd / C (30 mg). The resulting mixture was stirred under H2 atmosphere at 50 ℃ for 16 h, then filtered, rinsed with MeOH, and concentrated in vacuo. The crude material was purified by reverse phase chromatography and prep-HPLC to afford 1-[(4-{2-[3-cyano-4- (propan-2-yloxy)phenyl]ethyl}-2-methylphenyl)methyl]azetidine-3-carboxylic acid (10.0 mg, 6.2% yield) as a yellow oil. LCMS: 393.2 [M+1].

[0395] Examples 394-407 below were synthesized in a similar manner as described for Examples 392 and 393, but instead employing the designated reagents.Example 408: Synthesis of 1-[(4-{2-[4-cyclohexyl-3- (trifluoromethyl)phenyl]ethyl}phenyl)methyl]azetidine-3-carboxylic acid

[0396] Step 1: To a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (3.19 g, 9.08 mmol), 4-ethenylbenzaldehyde (1.00 g, 7.57 mmol) in DMF (20 mL) was added palladium diacetate (849 mg, 3.78 mmol), triphenylphosphine (397 mg, 1.51 mmol) and potassiumcarbonate (2.61 g, 18.9 mmol). The resulting mixture was stirred under nitrogen at 60 °C for 16 h then filtered, diluted with water (50 mL), and extracted with EtOAc (300 mL*3). The combined organic extracts were washed with brine (100 mL*2), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford 4- [(1E)-2-[4-bromo-3-(trifluoromethyl)phenyl]ethenyl]benzaldehyde (2.00 g, 74.4% yield) as a yellow solid.

[0397] Step 2: To a solution of 4-[(1E)-2-[4-bromo-3- (trifluoromethyl)phenyl]ethenyl]benzaldehyde (1.60 g, 4.51 mmol) and (cyclohex-1-en-1- yl)boronic acid (851 mg, 6.76 mmol) in 1,4-dioxane (48 mL) and water (8 mL) was added 1,1'- bis(di...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein: X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R3is phenyl substituted with R3a, R3b, R3c, R3d, and R3e; R3ais selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; or R3aand R3bare combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 from 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 p is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from -OR10, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - C(O)OR10.

3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais selected from halogen, C1-6alkyl, and C1-6haloalkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R3ais halogen.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R3b, R3c, R3d, and R3eare independently selected from hydrogen, halogen, -CN, C1-6alkyl, and C1-6haloalkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis selected from hydrogen, halogen, -CN, and C1-6haloalkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R3bis halogen.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein R3c, R3d, and R3eare hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

14. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ib):

16. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):

17. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Id):

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

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

23. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

24. A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein:ring A and ring B are each independently selected from 6-membered heteroaryl and phenyl, wherein at least one of ring A and ring B is 6-membered heteroaryl; X is selected from -C(R7)(R8)C(R7)(R8)-, -C(R7)(R8)C(O)-, -C(O)C(R7)(R8)-, - C(R7)(R8)S-, -SC(R7)(R8)-, -C(R7)(R8)O-, -OC(R7)(R8)-, -C(R7)(R8)N(R9)-, - N(R9)C(R7)(R8)-, -C(R7)(R8)-, -C(O)-, -N(R9)-, -O-, -S-, -S(O)-, and -S(O)2-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13;each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is phenyl.

26. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl and ring B is pyridyl.

27. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridyl and ring B is pyridyl.

28. The compound of any one of claims 24-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-6cycloalkyl and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

29. The compound of any one of claims 24-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, -CN, -OR10, C1- 6alkyl, C1-6haloalkyl, and unsubstituted C3-6cycloalkyl and each R10is independently selected from C1-6alkyl and C1-6haloalkyl.

30. The compound of any one of claims 24-29, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

31. The compound of any one of claims 24-29, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

32. The compound of any one of claims 24-31, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

33. The compound of any one of claims 24-32, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl.

34. The compound of any one of claims 24-33, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

35. The compound of any one of claims 24-31, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

36. The compound of any one of claims 24-35, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from -C(R7)(R8)C(R7)(R8)- and -C(R7)(R8)O-.

37. The compound of any one of claims 24-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)O-.

38. The compound of any one of claims 24-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(R7)(R8)C(R7)(R8)-.

39. The compound of any one of claims 24-38, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7and each R8are hydrogen.

40. The compound of any one of claims 24-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

41. A compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein:ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl;each R7and each R8are independently selected from hydrogen and C1-C6alkyl; 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; n is 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):

43. A compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof: wherein:ring A is a C2-C6heterocycloalkyl ring; Z is -N(R1)(R2) or -OH;R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13; each R3and each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IVa):

45. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl.

46. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from halogen.

47. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from C1-6haloalkyl.

48. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is selected from -OR10and each R3is C1-6alkyl.

49. The compound of any one of claims 41-48, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

50. The compound of any one of claims 41-48, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

51. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

52. The compound of any one of claims 41-51, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

53. The compound of any one of claims 41-52, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from C1-6alkyl.

54. The compound of any one of claims 41-53, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

55. The compound of any one of claims 41-51, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

56. The compound of any one of claims 41-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

57. The compound of any one of claims 41-56, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R1)(R2).

58. A compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: wherein:Y is selected from -O-, -N(R9)-, -S-, -S(O)-, -S(O)2-, -C(R7)(R8)-, and -C(O)-; R1is selected from hydrogen, -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl- phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; R2is selected from -OR7, -N(R7)(R8), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, C2-C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2- C9heterocycloalkyl, C1-9heteroaryl, phenyl, and -C1-C6alkyl-phenyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, C3-C6cycloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13; or R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and - S(O)2R13;R3is selected from C3-C8alkyl, C3-C8alkenyl, and C3-C8alkynyl, wherein C3-C8alkyl, C3- C8alkenyl, and C3-C8alkynyl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)R13, and -S(O)2R13; each R4is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, 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), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), 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, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; R5and R6are independently selected from hydrogen and C1-C6alkyl; each R7and each R8are independently selected from hydrogen and C1-C6alkyl; R9is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, 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 m is 0, 1, 2, 3, or 4.

59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from -O-, -N(R9)-, -S-, and -C(R7)(R8)-.

60. The compound of claim 58 or claim 59, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-.

61. The compound of any one of claims 58-60, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)R13, and -S(O)2R13.

62. The compound of any one of claims 58-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C3-C8alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11).

63. The compound of any one of claims 58-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted C3-C8alkyl.

64. The compound of any one of claims 58-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

65. The compound of any one of claims 58-64, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen.

67. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl.

68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 groups selected from halogen, C1-6haloalkyl, -OR10, and -N(R10)(R11).

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 -OH.

71. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-C6alkyl substituted with 1, 2, or 3 of halogen.

72. The compound of any one of claims 1-68 or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-C6alkyl.

73. The compound of claim 72, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3.

74. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11).

75. The compound of claim 74, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C3-C6cycloalkyl.

76. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and - S(O)2R13.

77. The compound of claim 76, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1-6haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13, wherein C1-9heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

78. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl.

79. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form a C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -S(O)2R13.

80. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2are combined to form an unsubstituted C2-C9heterocycloalkyl.

81. The compound of any one of claims 41-56, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OH.

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

83. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:, ,84. A pharmaceutical composition comprising a compound of any one of claims 1-83, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

85. The pharmaceutical composition of claim 84, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

86. The pharmaceutical composition of claim 85, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

87. A method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-83, or a pharmaceutically acceptable salt or solvate thereof.

88. The method of claim 87, further comprising administering a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

89. The method of claim 88, wherein the peripherally restricted FAAH inhibitor is ASP- 3652.

90. A method of treating a CNS disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of claims 84-86, or a pharmaceutically acceptable salt or solvate thereof.

91. The method of any one of claims 87-90, wherein the CNS disease or disorder is selected from a neurodegenerative disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, epilepsy, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, schizoaffective disorder, smoking cessation, multiple sclerosis, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, neurodegeneration, and neuropathic pain.

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