Bicyclic heteroaryl compounds as TREM2 activators

Abstract

This disclosure is drawn to bicyclic heteroaryl compounds, compositions thereof, and associated methods, useful for activation of TREM2 activity and / or for treating neurological disorders.

Description

BICYCLIC HETEROARYL COMPOUNDS AS TREM2 ACTIVATORSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 604,802 filed on November 30, 2023, which is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] Described herein are compounds and compositions, and associated methods, useful for activation of TREM2 activity and / or for treating or preventing a neurological disorder.BACKGROUND OF THE INVENTION

[0003] Age is the main risk factor for the development of neurodegenerative diseases. Dysregulated immune response is an important pathological event in many neurodegenerative and neurological disorders, including Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, dysregulated microglial response is now being recognized as an early event that contributes to the underlying pathophysiology across these chronic diseases. Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on the surface of cells of myeloid lineage including microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 rare variant was identified as a significant risk factor for late-onset AD and is associated with loss-of-function of the protein. Recently, it has been shown that loss-of-function of TREM2 results in an exacerbation of symptoms in preclinical models of AD. TREM2 over-expression or treatment with TREM2 activating antibodies restores microglial function in preclinical models of AD. In order to effectively activate TREM2 residing on microglial cell surfaces, modalities that can more easily cross the blood-brain barrier like CNS-penetrant small molecules are highly desirable.SUMMARY OF THE INVENTION

[0004] In one aspect described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein:ring A is a 5- or 6-membered heteroaryl ring or phenyl;X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

[0005] In some embodiments is a compound of Formula (I), wherein X is N. In some embodiments is a compound of Formula (I), wherein X is C(R7). In some embodiments is a compound of Formula (I), wherein X is C(R7) and R7is hydrogen. In some embodiments is a compound of Formula (I), wherein X is C(R7) and R7is C1-6alkyl.

[0006] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula (la):Formula (la); wherein m is 0, 1, 2, or 3.

[0007] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula (lb):Formula (lb); wherein m is 0, 1, or 2.

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

[0009] In some embodiments is a compound of Formula (I), (la), (lb), or (Ic), wherein R8is hydrogen. In some embodiments is a compound of Formula (I), (la), (lb), or (Ic), wherein R8is halogen. In some embodiments is a compound of Formula (I), (la), (lb), or (Ic), wherein R8is C1-6alkyl. In some embodiments is a compound of Formula (I), (la), (lb), or (Ic), wherein R9is hydrogen.

[0010] In another aspect described herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II); wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl,C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)( R11); or two R5are combined to form a C3-6cycloalkyl ring;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, 2, or 3.

[0011] In some embodiments is a compound of Formula (II), wherein X is N. In some embodiments is a compound of Formula (II), wherein X is C(R7). In some embodiments is acompound of Formula (II), wherein R7is hydrogen. In some embodiments is a compound of Formula (II), wherein R7is C1-6alkyl.

[0012] In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is pyridyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is pyridyl substituted with 1 R5group. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is phenyl substituted with 1 R5group. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R4is selected from:some embodiments is a compound of Formula (I), (la), (lb), (Ic), or(II) wherein R4is selected from:

[0013] In another aspect described herein is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:Formula (III); wherein: ring A is a 5- or 6-membered heteroaryl ring or phenyl;ring B is a 5- or 6-membered heteroaryl ring or phenyl;X is N or C(R7);Y is O, S, or N(R7a);Z is N or C(R7b); each R1and each R1ais independently selected from halogen, -CN, -OR10, -SR10, - N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups;each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R7, R7a, and R7bare independently selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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; andp is 0, 1, 2, 3, or 4; wherein the compound of Formula (III) is not

[0014] In some embodiments is a compound of Formula (III), wherein X is C(R7) and R7is hydrogen. In some embodiments is a compound of Formula (III), wherein X is N.

[0015] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, having Formula (Illa):Formula (Illa).

[0016] In some embodiments is a compound of Formula (III) or (Illa), wherein Y is O. In some embodiments is a compound of Formula (III) or (Illa), wherein Y is S. In some embodiments is a compound of Formula (III) or (Illa), wherein Z is N. In some embodiments is a compound of Formula (III) or (Illa), wherein Z is C(H). In some embodiments is a compound of Formula (III) or (Illa), wherein ring B is a 6-membered heteroaryl ring. In some embodiments is a compound of Formula (III) or (Illa), wherein ring B is a pyridyl ring. In some embodiments is a compound of Formula (III) or (Illa), wherein each R1ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III) or (Illa), wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected fromC1-6alkyl. In some embodiments is a compound of Formula (III) or (Illa), wherein p is 1. In some embodiments is a compound of Formula (III) or (Illa), wherein R4ais selected from

[0017] In another aspect described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:Formula (IV); wherein:X is N or C(R7);J is N, C(H), or C(R1); each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C 1-6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatomsselected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, or 2.

[0018] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, having Formula (IVa):Formula (IVa).

[0019] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, having Formula (IVb):Formula (IVb).

[0020] In some embodiments is a compound of Formula (IV), (IVa), or (IVb), wherein X is N. In some embodiments is a compound of Formula (IV), (IVa), or (IVb), wherein X is C(R7) and R7is hydrogen.

[0021] In another aspect described herein is a compound of Formula (V), or a pharmaceutically acceptable salt thereof:Formula (V); wherein: each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

[0022] In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V), wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V), wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V),wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and - OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IV), (IVa), (IVb), or (V), wherein R4bis selected from

[0023] In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (I), (la),(lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein R2is selected from:compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R1is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R1is -CH3. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein m is 2.

[0024] In another aspect is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound described herein, or a pharmaceutically acceptable salt thereof.

[0025] In another aspect is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is a neurodegenerative disease. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is selected from Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is Alzheimer’s disease.

[0026] In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a further pharmaceutically active agent.

[0027] In some embodiments is a use of a compound described herein, or a pharmaceutically acceptable salt thereof, in treating a neurological disorder in a patient in need thereof.

[0028] In some embodiments is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating a neurological disorder in a patient in need thereof. In some embodiments is a compound described herein, or apharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating Alzheimer’s disease, frontotemporal dementia, or amyotrophic lateral sclerosis. In some embodiments is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating Alzheimer’s disease in a patient in need thereof.DETAILED DESCRIPTION

[0029] Alzheimer’s disease (AD) is the most common form of age-associated dementia and is characterized by neurofibrillary tangles and amyloid plaques. Changes in inflammatory response accompanies AD pathology, observed by the increase in activated astrocytes and microglia in the brain. Microglia, known as the resident immune cells of the brain, play an active role in immune surveillance and signaling, including the release of pro-inflammatory cytokines that influence surrounding neurons and astrocytes. Genome-wide association studies for AD risk have identified several microglial genes that indicate a causative role for immune cell response in disease. Rare loss-of-function variants in TREM2 (triggering receptor expressed on myeloid cells 2) have been reported to increase the risk of AD and other neurodegenerative diseases including Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson’s disease (PD). The most common AD- risk variant within TREM2, rs75932628, encodes an arginine to histidine change at position 47 (R47H) which has been shown to result in a partial loss-of-function and increases risk of developing late-onset AD (LOAD) 4-fold.

[0030] TREM2 is a V-type immunoglobulin (Ig) domain-containing transmembrane protein that is highly expressed in microglia, macrophages and osteoclasts. TREM2 is 230 amino acid protein containing a single-pass transmembrane region with a large extracellular domain and short cytoplasmic tail. Putative ligands of TREM2 include phospholipids and lipoproteins, and when activated, TREM2 signals through the transmembrane receptor protein TYROBP / DAP12, an adaptor protein that contains an immunoreceptor tyrosine-bases activation motif (IT AM) which then leads to SYK phosphorylation and activation. Activation of TREM2 signaling promotes microglial activation and survival. Microglial functions regulated by TREM2 include migration, phagocytosis and cytokine release. In mouse models of AD, TREM2 deficiency and haploinsufficiency results in decreased microglial clustering around amyloidβ (aβ ) plaques indicating the requirement of TREM2 for microglial activation and response to amyloid plaques.Compounds

[0031] Described herein are TREM2 activator compounds that specifically bind to TREM2 and activate signaling in a cellular context. TREM2 activation by small molecules has implications for the treatment of age-associated neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and rare microgliopathies.

[0032] In some embodiments is a compound of Formula (I):Formula (I); or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5- or 6-membered heteroaryl ring or phenyl;X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one,two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

[0033] In some embodiments is a compound of Formula (I), wherein X is N. In some embodiments is a compound of Formula (I), wherein X is C(R7). In some embodiments is a compound of Formula (I), wherein R7is hydrogen. In some embodiments is a compound of Formula (I), wherein R7is C1-6alkyl.

[0034] In some embodiments is a compound of Formula (I), wherein ring A is a 6-membered heteroaryl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyridyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyrazinyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyrimidinyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyridazinyl ring.

[0035] In some embodiments is a compound of Formula (I), wherein ring A is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (I), wherein ring A is a furanyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a thienyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyrrolyl ring.

[0036] In some embodiments is a compound of Formula (I), wherein ring A is phenyl.

[0037] In some embodiments is a compound of Formula (I), wherein R8is hydrogen. In some embodiments is a compound of Formula (I), wherein R8is halogen. In some embodiments is a compound of Formula (I), wherein R8is C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R8is -CH3.

[0038] In some embodiments is a compound of Formula (I), wherein R9is hydrogen. In some embodiments is a compound of Formula (I), wherein R9is halogen. In some embodiments is a compound of Formula (I), wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R9is -CH3.

[0039] In some embodiments is a compound of Formula (I), wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl optionally substituted with 1-4 R5groups andeach R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl.

[0040] In some embodiments is a compound of Formula (I), wherein R4is selected from:

[0041] In some embodiments is a compound of Formula (I), wherein R4is selected from:

[0042] In some embodiments is a compound of Formula (I), wherein R4is selected from:

[0043] In some embodiments is a compound of Formula (I), wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (I), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compoundof Formula (I), wherein R4is phenyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6haloalkyl. In some embodiments is a compound of Formula (I),

[0044] In some embodiments is a compound of Formula (I), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (I), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (I), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (I), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), -S(O)2R13, and - S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C 1-6haloalky 1, - OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound ofFormula (I), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (I), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein each R3is independently selected from unsubstituted C1-6haloalkyl.

[0045] In some embodiments is a compound of Formula (I), wherein R2is selected from

[0046] In some embodiments is a compound of Formula (I), wherein R2is

[0047] In some embodiments is a compound of Formula (I), wherein R2is

[0048] In some embodiments is a compound of Formula (I), wherein R2is

[0049] In some embodiments is a compound of Formula (I), wherein R2is

[0050] In some embodiments is a compound of Formula (I), wherein R2is

[0051] In some embodiments is a compound of Formula (I), wherein R2is

[0052] In some embodiments is a compound of Formula (I), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (I), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein each R1is -CH3.

[0053] In some embodiments is a compound of Formula (I), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (I), wherein m is 2. In some embodiments is acompound of Formula (I), wherein m is 1. In some embodiments is a compound of Formula (I), wherein m is 0.

[0054] In some embodiments is a compound of Formula (la):Formula (la); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups;each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, 2, or 3.

[0055] In some embodiments is a compound of Formula (la), wherein R8is hydrogen. In some embodiments is a compound of Formula (la), wherein R8is halogen. In some embodiments is a compound of Formula (la), wherein R8is C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R8is -CH3.

[0056] In some embodiments is a compound of Formula (la), wherein R9is hydrogen. In some embodiments is a compound of Formula (la), wherein R9is halogen. In some embodiments is a compound of Formula (la), wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R9is -CH3.

[0057] In some embodiments is a compound of Formula (la), wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is acompound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl.

[0058] In some embodiments is a compound of Formula (la), wherein R4is selected from:

[0059] In some embodiments is a compound of Formula (la), wherein R4is selected from:

[0060] In some embodiments is a compound of Formula (la), wherein R4is selected from:

[0061] In some embodiments is a compound of Formula (la), wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (la), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6haloalkyl. Insome embodiments is a compound of Formula (la), wherein R4is. In some embodiments is a compound of Formula (la), wherein R4is

[0062] In some embodiments is a compound of Formula (la), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (la), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (la), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (la), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (la), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0063] In some embodiments is a compound of Formula (la), wherein R2is selected from

[0065] In some embodiments is a compound of Formula (la), wherein R2is

[0066] In some embodiments is a compound of Formula (la), wherein R2is

[0067] In some embodiments is a compound of Formula (la), wherein R2isF

[0068] In some embodiments is a compound of Formula (la), wherein R2is

[0069] In some embodiments is a compound of Formula (la), wherein R2is

[0070] In some embodiments is a compound of Formula (la), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (la), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein each R1is -CH3.

[0071] In some embodiments is a compound of Formula (la), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (la), wherein m is 2. In some embodiments is a compound of Formula (la), wherein m is 1. In some embodiments is a compound of Formula(la), wherein m is 0.

[0072] In some embodiments is a compound of Formula (lb):Formula (lb); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl,C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci -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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 Ci -9heteroaryl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci -9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci -9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci -9heteroaryl; and m is 0, 1, or 2.

[0073] In some embodiments is a compound of Formula (lb), wherein R8is hydrogen. In some embodiments is a compound of Formula (lb), wherein R8is halogen. In some embodiments is a compound of Formula (lb), wherein R8is C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R8is -CH3.

[0074] In some embodiments is a compound of Formula (lb), wherein R9is hydrogen. In some embodiments is a compound of Formula (lb), wherein R9is halogen. In some embodiments is a compound of Formula (lb), wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R9is -CH3.

[0075] In some embodiments is a compound of Formula (lb), wherein R4is Ci -9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl.

[0076] In some embodiments is a compound of Formula (lb), wherein R4is selected from:

[0077] In some embodiments is a compound of Formula (lb), wherein R4is selected from:

[0078] In some embodiments is a compound of Formula (lb), wherein R4is selected from:

[0079] In some embodiments is a compound of Formula (lb), wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (lb), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In someembodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R4is. In some embodiments is a compound of Formula (lb), wherein R4is

[0080] In some embodiments is a compound of Formula (lb), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (lb), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (lb), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is acompound of Formula (lb), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein each R3is independently selected from unsubstituted C 1-6haloalky 1.

[0081] In some embodiments is a compound of Formula (lb), wherein R2is selected from

[0082] In some embodiments is a compound of Formula (lb), wherein R2is

[0083] . In some embodiments is a compound of Formula (lb), wherein R2isci

[0084] In some embodiments is a compound of Formula (lb), wherein R2is

[0085] In some embodiments is a compound of Formula (lb), wherein R2

[0086] In some embodiments is a compound of Formula (lb), wherein R2

[0087] In some embodiments is a compound of Formula (lb), wherein R2is

[0088] In some embodiments is a compound of Formula (lb), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein each R1is -CH3.

[0089] In some embodiments is a compound of Formula (lb), wherein m is 2. In some embodiments is a compound of Formula (lb), wherein m is 1. In some embodiments is a compound of Formula (lb), wherein m is 0.

[0090] In some embodiments is a compound of Formula (Ic):Formula (Ic); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl;each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

[0091] In some embodiments is a compound of Formula (Ic), wherein R8is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R8is halogen. In some embodiments is a compound of Formula (Ic), wherein R8is C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R8is -CH3.

[0092] In some embodiments is a compound of Formula (Ic), wherein R9is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R9is halogen. In some embodiments is a compound of Formula (Ic), wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R9is -CH3.

[0093] In some embodiments is a compound of Formula (Ic), wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments isa compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl.

[0094] In some embodiments is a compound of Formula (Ic), wherein R4is selected from:

[0095] In some embodiments is a compound of Formula (Ic), wherein R4is selected from:

[0097] In some embodiments is a compound of Formula (Ic), wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In someembodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R4is. In some embodiments is a compound of Formula (Ic), wherein R4is

[0098] In some embodiments is a compound of Formula (Ic), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (Ic), whereinR2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0099] In some embodiments is a compound of Formula (Ic), wherein R2is selected from

[0100] In some embodiments is a compound of Formula (Ic), wherein R2is

[0101] In some embodiments is a compound of Formula (Ic), wherein R2is

[0102] In some embodiments is a compound of Formula (Ic), wherein R2is

[0103] In some embodiments is a compound of Formula (Ic), wherein R2is

[0104] In some embodiments is a compound of Formula (Ic), wherein R2is

[0105] In some embodiments is a compound of Formula (Ic), wherein R2is

[0106] In some embodiments is a compound of Formula (Ic), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein each R1is -CH3.

[0107] In some embodiments is a compound of Formula (Ic), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (Ic), wherein m is 2. In some embodiments is a compound of Formula (Ic), wherein m is 1. In some embodiments is a compound of Formula (Ic), wherein m is 0.

[0108] In some embodiments is a compound of Formula (II):Formula (II); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7);each R1is independently selected from halogen, -CN, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromhalogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, 2, or 3.

[0109] In some embodiments is a compound of Formula (II), wherein X is N. In some embodiments is a compound of Formula (II), wherein X is C(R7). In some embodiments is a compound of Formula (II), wherein R7is hydrogen. In some embodiments is a compound of Formula (II), wherein R7is C1-6alkyl.

[0110] In some embodiments is a compound of Formula (II), wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (II),wherein R4is pyridinyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (II), wherein R4is pyridinyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl.

[0111] In some embodiments is a compound of Formula (II), wherein R4is selected from:

[0112] In some embodiments is a compound of Formula (II), wherein R4is selected from:

[0113] In some embodiments is a compound of Formula (II), wherein R4is selected from:

[0114] In some embodiments is a compound of Formula (II), wherein R4is phenyl optionally substituted with 1-4 R5groups. In some embodiments is a compound of Formula (II), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl optionally substituted with 1-4 R5groups and each R5is independently selected from halogen,unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 or 2 R5groups and each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group and R5is halogen. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group and R5is C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group and R5is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group, R5is -OR10, and R10is C3-6cycloalkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6alkyl. In some embodiments is a compound of Formula (II), wherein R4is phenyl substituted with 1 R5group, R5is -S(O)2R13, and R13is C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein R4is In some embodiments is a compound of Formula (II), wherein R4is

[0115] In some embodiments is a compound of Formula (II), wherein R6is hydrogen. In some embodiments is a compound of Formula (II), R6is C1-6alkyl. In some embodiments is a compound of Formula (II), R6is -CH3. In some embodiments is a compound of Formula (II), R6is C1-6haloalkyl.

[0116] In some embodiments is a compound of Formula (II), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (II), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (II), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (II), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (II), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (II), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), wherein each R3is independently selected from unsubstituted C1-6haloalkyl.

[0117] In some embodiments is a compound of Formula (II), wherein R2is selected from

[0118] In some embodiments is a compound of Formula (II), wherein R2is

[0119] In some embodiments is a compound of Formula (II), wherein R2is

[0120] In some embodiments is a compound of Formula (II), wherein R2is

[0121] In some embodiments is a compound of Formula (II), wherein R2is

[0122] In some embodiments is a compound of Formula (II), wherein R2is

[0123] In some embodiments is a compound of Formula (II), wherein R2is

[0124] In some embodiments is a compound of Formula (II), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (II), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), wherein each R1is -CH3.

[0125] In some embodiments is a compound of Formula (II), wherein m is 2. In some embodiments is a compound of Formula (II), wherein m is 1. In some embodiments is a compound of Formula (II), wherein m is 0.

[0126] In some embodiments is a compound of Formula (III):Formula (III); or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5- or 6-membered heteroaryl ring or phenyl;ring B is a 5- or 6-membered heteroaryl ring or phenyl;X is N or C(R7);Y is O, S, or N(R7a);Z is N or C(R7b); each R1and each R1ais independently selected from halogen, -CN, -OR10, -SR10, - N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromhalogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C 1-6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R7, R7a, and R7bare independently selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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; and p is 0, 1, 2, 3, or 4; wherein the compound of Formula (III) is not

[0127] In some embodiments is a compound of Formula (III), wherein ring A is a 6-membered heteroaryl ring. In some embodiments is a compound of Formula (III), wherein ring A is a pyridyl ring. In some embodiments is a compound of Formula (III), wherein ring A is a pyrazinyl ring. In some embodiments is a compound of Formula (III), wherein ring A is a pyrimidinyl ring. In some embodiments is a compound of Formula (III), wherein ring A is a pyridazinyl ring.

[0128] In some embodiments is a compound of Formula (III), wherein ring A is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (III), wherein ring A is a furanyl ring. In some embodiments is a compound of Formula (III), wherein ring A is a thienyl ring. In some embodiments is a compound of Formula (III), wherein ring A is a pyrrolyl ring.

[0129] In some embodiments is a compound of Formula (III), wherein ring A is phenyl.

[0130] In some embodiments is a compound of Formula (III), wherein ring B is a 6-membered heteroaryl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyridyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyrazinyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyrimidinyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyridazinyl ring.

[0131] In some embodiments is a compound of Formula (III), wherein ring B is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (III), wherein ring B is afuranyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a thienyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyrrolyl ring.

[0132] In some embodiments is a compound of Formula (III), wherein ring B is phenyl.

[0133] In some embodiments is a compound of Formula (III), wherein X is N. In some embodiments is a compound of Formula (III), wherein X is C(R7). In some embodiments is a compound of Formula (III), wherein R7is hydrogen. In some embodiments is a compound of Formula (II), wherein R7is C1-6alkyl.

[0134] In some embodiments is a compound of Formula (III), wherein Y is O. In some embodiments is a compound of Formula (III), wherein Y is S. In some embodiments is a compound of Formula (III), wherein Y is N(R7a). In some embodiments is a compound of Formula (III), wherein R7ais hydrogen. In some embodiments is a compound of Formula (III), wherein R7ais C1-6alkyl.

[0135] In some embodiments is a compound of Formula (III), wherein Z is N. In some embodiments is a compound of Formula (III), wherein Z is C(R7b). In some embodiments is a compound of Formula (III), wherein Z is C(H).

[0136] In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from halogen. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), wherein each R1ais -CH3. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (III), wherein each R1ais -CF3. In some embodiments is a compound of Formula (III), wherein each R1ais independently selected from -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (III), wherein each R1ais -OR10, and R10is -CH3.

[0137] In some embodiments is a compound of Formula (III), wherein p is 1. In some embodiments is a compound of Formula (III), wherein p is 2. In some embodiments is a compound of Formula (III), wherein p is 3. In some embodiments is a compound of Formula (III), wherein p is 4. In some embodiments is a compound of Formula (III), wherein p is 0.

[0138] In some embodiments is a compound of Formula (III), wherein R4ais selected from:

[0139] In some embodiments is a compound of Formula (III), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (III), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (III), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (III), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (III), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (III), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (III), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0140] In some embodiments is a compound of Formula (III), wherein R2is selected fromsome embodiments is a compound of Formula (III), wherein In some embodiments is a compound ofFormula (III), wherein

[0141] In some embodiments is a compound of Formula (III), wherein R2is

[0142] In some embodiments is a compound of Formula (III), wherein R2is

[0143] In some embodiments is a compound of Formula (III), wherein R2is

[0144] In some embodiments is a compound of Formula (III), wherein R2is

[0145] In some embodiments is a compound of Formula (III), wherein R2is

[0146] In some embodiments is a compound of Formula (III), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (III), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), wherein each R1is -CH3.

[0147] In some embodiments is a compound of Formula (III), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (III), wherein m is 2. In some embodiments is a compound of Formula (III), wherein m is 1. In some embodiments is a compound of Formula (III), wherein m is 0.

[0148] In some embodiments is a compound of Formula (Illa):Formula (Illa); or a pharmaceutically acceptable salt thereof, wherein:ring B is a 5- or 6-membered heteroaryl ring or phenyl;Y is O, S, or N(R7a);Z is N or C(R7b); each R1and each R1ais independently selected from halogen, -CN, -OR10, -SR10, - N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R7aand R7bare independently selected from hydrogen and C1-6alkyl;each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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; and p is 0, 1, 2, 3, or 4; wherein the compound of Formula (Illa) is not

[0149] In some embodiments is a compound of Formula (Illa), wherein ring B is a 6-membered heteroaryl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a pyridyl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a pyrazinyl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a pyrimidinyl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a pyridazinyl ring.

[0150] In some embodiments is a compound of Formula (Illa), wherein ring B is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a furanyl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a thienyl ring. In some embodiments is a compound of Formula (Illa), wherein ring B is a pyrrolyl ring.

[0151] In some embodiments is a compound of Formula (Illa), wherein ring B is phenyl.

[0152] In some embodiments is a compound of Formula (Illa), wherein Y is O. In some embodiments is a compound of Formula (Illa), wherein Y is S. In some embodiments is a compound of Formula (Illa), wherein Y is N(R7a). In some embodiments is a compound of Formula (Illa), wherein R7ais hydrogen. In some embodiments is a compound of Formula (II), wherein R7ais C1-6alkyl.

[0153] In some embodiments is a compound of Formula (Illa), wherein Z is N. In some embodiments is a compound of Formula (Illa), wherein Z is C(R7b). In some embodiments is a compound of Formula (Illa), wherein Z is C(H).

[0154] In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from halogen. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais -CH3. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from C1-6haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais -CF3. In some embodiments is a compound of Formula (Illa), wherein each R1ais independently selected from -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (Illa), wherein each R1ais -OR10, and R10is - CH3.

[0155] In some embodiments is a compound of Formula (Illa), wherein p is 1. In some embodiments is a compound of Formula (Illa), wherein p is 2. In some embodiments is acompound of Formula (Illa), wherein p is 3. In some embodiments is a compound of Formula (Illa), wherein p is 4. In some embodiments is a compound of Formula (Illa), wherein p is 0.

[0156] In some embodiments is a compound of Formula (Illa), wherein R4ais selected from:

[0157] In some embodiments is a compound of Formula (Illa), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (Illa), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (Illa), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Illa), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0158] In some embodiments is a compound of Formula (Illa), wherein R2is selected fromsome embodiments is a compound of Formula (Illa), wherein In some embodiments is a compound of

[0159] In some embodiments is a compound of Formula (Illa), wherein R2is

[0160] In some embodiments is a compound of Formula (Illa), wherein R2is

[0161] In some embodiments is a compound of Formula (Illa), wherein R2is

[0162] In some embodiments is a compound of Formula (Illa), wherein R2is

[0163] In some embodiments is a compound of Formula (Illa), wherein R2is

[0164] In some embodiments is a compound of Formula (Illa), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Illa), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Illa), wherein each R1is -CH3.

[0165] In some embodiments is a compound of Formula (Illa), wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (Illa), wherein m is 2. In some embodiments is a compound of Formula (Illa), wherein m is 1. In some embodiments is a compound of Formula (Illa), wherein m is 0.

[0166] In some embodiments is a compound of Formula (IV):Formula (IV); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7);J is N, C(H), or C(R1); each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2- C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, or 2.

[0167] In some embodiments is a compound of Formula (IV), wherein J is C(H). In some embodiments is a compound of Formula (IV), wherein J is C(R1). In some embodiments is a compound of Formula (IV), wherein J is N.

[0168] In some embodiments is a compound of Formula (IV), wherein X is N. In some embodiments is a compound of Formula (IV), wherein X is C(R7). In some embodiments is a compound of Formula (IV), wherein R7is hydrogen. In some embodiments is a compound of Formula (IV), wherein R7is C1-6alkyl.

[0169] In some embodiments is a compound of Formula (IV), wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis C1-9heteroaryl substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis C1-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis C5-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis C5-9heteroaryl substituted with 1 R5agroup, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IV), wherein R4bis a C1-9heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IV), wherein R4bis an oxazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R4bis an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R4bis a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R4bis a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R4bis an imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IV), wherein R4bis a benzoxazole. In some embodiments is a compound of Formula (IV), wherein R4bis a benzothiazole. In some embodiments is a compound of Formula (IV), wherein R4bis a benzimidazole.

[0170] In some embodiments is a compound of Formula (IV), wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV), wherein each R5aisindependently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3.6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IV), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais halogen. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais -CH3. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais C1-6haloalkyl. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais -CF3. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (IV), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C3-6cycloalkyl.

[0171] In some embodiments is a compound of Formula (IV), wherein R4bis selected from:

[0172] In some embodiments is a compound of Formula (IV), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IV), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IV), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3.6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl areoptionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0173] In some embodiments is a compound of Formula (IV), wherein R2is selected fromembodiments is a compound of Formula (IV), wherein R2is

[0174] In some embodiments is a compound of Formula (IV), wherein R2isci

[0175] In some embodiments is a compound of Formula (IV), wherein R2is

[0176] In some embodiments is a compound of Formula (IV), wherein R2is

[0177] In some embodiments is a compound of Formula (IV), wherein R2is

[0178] In some embodiments is a compound of Formula (IV), wherein R2is

[0179] In some embodiments is a compound of Formula (IV), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IV), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IV), wherein each R1is -CH3.

[0180] In some embodiments is a compound of Formula (IV), wherein m is 2. In some embodiments is a compound of Formula (IV), wherein m is 1. In some embodiments is a compound of Formula (IV), wherein m is 0.

[0181] In some embodiments is a compound of Formula (IVa):Formula (IVa); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one,two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, or 2.

[0182] In some embodiments is a compound of Formula (IVa), wherein X is N. In some embodiments is a compound of Formula (IVa), wherein X is C(R7). In some embodiments is a compound of Formula (IVa), wherein R7is hydrogen. In some embodiments is a compound of Formula (IVa), wherein R7is C1-6alkyl.

[0183] In some embodiments is a compound of Formula (IVa), wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis C1-9heteroaryl substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis C1-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis C5-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis C5-9heteroaryl substituted with 1 R5agroup, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVa), wherein R4bis a C1-9heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IVa), wherein R4bis an oxazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IVa), wherein R4bis an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVa), wherein R4bis a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IVa), wherein R4bis a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVa), wherein R4bis an imidazo[4,5- c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IVa), wherein R4bis a benzoxazole. In some embodiments is a compound of Formula (IVa), wherein R4bis a benzothiazole. In some embodiments is a compound of Formula (IVa), wherein R4bis a benzimidazole.

[0184] In some embodiments is a compound of Formula (IVa), wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, andC2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais halogen. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais -CH3. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais -CF3. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (IVa), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C3-6cycloalkyl.

[0185] In some embodiments is a compound of Formula (IVa), wherein R4bis selected from:

[0186] In some embodiments is a compound of Formula (IVa), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IVa), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IVa), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVa), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0187] In some embodiments is a compound of Formula (IVa), wherein R2is selected fromembodiments is a compound of Formula (IVa), wherein R2is

[0188] In some embodiments is a compound of Formula (IVa), wherein R2isci

[0189] In some embodiments is a compound of Formula (IVa), wherein R2is

[0190] In some embodiments is a compound of Formula (IVa), wherein R2is

[0191] In some embodiments is a compound of Formula (IVa), wherein R2is

[0192] In some embodiments is a compound of Formula (IVa), wherein R2is

[0193] In some embodiments is a compound of Formula (IVa), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVa), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVa), wherein each R1is -CH3.

[0194] In some embodiments is a compound of Formula (IVa), wherein m is 2. In some embodiments is a compound of Formula (IVa), wherein m is 1. In some embodiments is a compound of Formula (IVa), wherein m is 0.

[0195] In some embodiments is a compound of Formula (IVb):Formula (IVb); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl;each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, or 2.

[0196] In some embodiments is a compound of Formula (IVb), wherein X is N. In some embodiments is a compound of Formula (IVb), wherein X is C(R7). In some embodiments is a compound of Formula (IVb), wherein R7is hydrogen. In some embodiments is a compound of Formula (IVb), wherein R7is C1-6alkyl.

[0197] In some embodiments is a compound of Formula (IVb), wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis C1-9heteroaryl substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis C1-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis C5-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis C5-9heteroaryl substituted with 1 R5agroup, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (IVb), wherein R4bis a C1-9heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IVb), wherein R4bis an oxazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R4bis an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R4bis a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R4bis a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R4bis an imidazo[4,5- c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IVb), wherein R4bis a benzoxazole. In some embodiments is a compound of Formula (IVb), wherein R4bis a benzothiazole. In some embodiments is a compound of Formula (IVb), wherein R4bis a benzimidazole.

[0198] In some embodiments is a compound of Formula (IVb), wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IVb), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (IVb), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais halogen. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais -CH3. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais C1-6haloalkyl. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais -CF3. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (IVb), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C3-6cycloalkyl.

[0199] In some embodiments is a compound of Formula (IVb), wherein R4bis selected from:

[0200] In some embodiments is a compound of Formula (IVb), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IVb), whereinR2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (IVb), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVb), wherein each R3is independently selected from unsubstituted C1 -6haloalky 1.

[0201] In some embodiments is a compound of Formula (IVb), wherein R2is selected fromembodiments is a compound of Formula (IVb), wherein R2is

[0202] In some embodiments is a compound of Formula (IVb), wherein R2is

[0203] In some embodiments is a compound of Formula (IVb), wherein R2is

[0204] In some embodiments is a compound of Formula (IVb), wherein R2is

[0205] In some embodiments is a compound of Formula (IVb), wherein R2is

[0206] In some embodiments is a compound of Formula (IVb), wherein R2is

[0207] In some embodiments is a compound of Formula (IVb), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IVb), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IVb), wherein each R1is -CH3.

[0208] In some embodiments is a compound of Formula (IVb), wherein m is 2. In some embodiments is a compound of Formula (IVb), wherein m is 1. In some embodiments is a compound of Formula (IVb), wherein m is 0.

[0209] In some embodiments is a compound of Formula (V):Formula (V); or a pharmaceutically acceptable salt thereof, wherein: each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C 1-6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl;each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

[0210] In some embodiments is a compound of Formula (V), wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis C1-9heteroaryl substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis C1-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis C5-9heteroaryl substituted with 1 or 2 R5agroups, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis C5-9heteroaryl substituted with 1 R5agroup, wherein the C5-9heteroaryl is a bicyclic heteroaryl. In some embodiments is a compound of Formula (V), wherein R4bis a C1-9heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (V), wherein R4bis an oxazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (V), wherein R4bis an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (V), wherein R4bis a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (V), wherein R4bis a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (V), wherein R4bis an imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (V), wherein R4bis a benzoxazole. In some embodiments is a compound of Formula (V), wherein R4bis a benzothiazole. In some embodiments is a compound of Formula (V), wherein R4bis a benzimidazole.

[0211] In some embodiments is a compound of Formula (V), wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (V), wherein each R5aisindependently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3.6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and -S(O)2R13, each R10is independently selected from C1-6alkyl and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments is a compound of Formula (V), wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais halogen. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais -CH3. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais C1-6haloalkyl. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais -CF3. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup and R5ais unsubstituted C3-6cycloalkyl. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C1-6alkyl. In some embodiments is a compound of Formula (V), wherein R4bis substituted with 1 R5agroup, R5ais -OR10, and R10is C3-6cycloalkyl.

[0212] In some embodiments is a compound of Formula (V), wherein R4bis selected from:

[0213] In some embodiments is a compound of Formula (V), wherein R2is phenyl optionally substituted with 1-4 R3groups. In some embodiments is a compound of Formula (V), wherein R2is phenyl substituted with 1-4 R3groups. In some embodiments is a compound of Formula (V), wherein R2is phenyl substituted with 1 or 2 R3groups. In some embodiments is a compound of Formula (V), wherein each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3.6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)N(R10)(R11), - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl areoptionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (V), wherein each R3is independently selected from halogen, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments is a compound of Formula (V), wherein each R3is independently selected from halogen. In some embodiments is a compound of Formula (V), wherein each R3is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (V), wherein each R3is independently selected from unsubstituted C1-6haloalkyl.

[0214] In some embodiments is a compound of Formula (V), wherein R2is selected fromembodiments is a compound of Formula (V), wherein R2is

[0215] In some embodiments is a compound of Formula (V), wherein R2isci

[0216] In some embodiments is a compound of Formula (V), wherein R2is

[0217] In some embodiments is a compound of Formula (V), wherein R2is

[0218] In some embodiments is a compound of Formula (V), wherein R2is

[0219] In some embodiments is a compound of Formula (V), wherein R2is

[0220] In some embodiments is a compound of Formula (V), wherein each R1is independently selected from C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (V), wherein each R1is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (V), wherein each R1is -CH3.

[0221] In some embodiments is a compound of Formula (V), wherein m is 2. In some embodiments is a compound of Formula (V), wherein m is 1. In some embodiments is a compound of Formula (V), wherein m is 3. In some embodiments is a compound of Formula (V), wherein m is 4. In some embodiments is a compound of Formula (V), wherein m is 0.

[0222] In some embodiments is a compound selected from:

[0224] In some embodiments is a compound selected from:pharmaceutically acceptable salt thereof.

[0225] In some embodiments is a compound selected from:

[0226] In some embodiments is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0227] It is further appreciated that certain features of the disclosure described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure described herein which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0228] At various places in the present specification, substituents of compounds described herein are disclosed in groups or in ranges. It is specifically intended that the groups or rangesinclude each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0229] At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “pyridinyl,” “pyridyl,” or “a pyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0230] At various places in the present specification a di-valent or linking group may be present. Each linking group is understood as linking in either direction. That is, if a linking group is described as -A-B-, then it is understood, unless otherwise specified, that the linking group is not directionally limited and can also be -B-A-. For example, when a linking group is written as -C(=O)-O-, it also means -O-C(=O)-.

[0231] The term “n-membered,” where “n” is an integer, typically describes the number of ringforming atoms in a moiety where the number of ring-forming atoms is “n”. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0232] For compounds described herein in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0233] As used herein, the phrase “optionally substituted” means unsubstituted or substituted.

[0234] As used herein, the term “substituted” means that a hydrogen atom is replaced by a nonhydrogen group. It is to be understood that substitution at a given atom is limited by valency. In some embodiments, an atom substituted by oxo (=0) has two hydrogen atoms replaced by the oxo substituent.

[0235] As used herein, the term “Ci-j” where i and j are integers, employed in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range. For example, C1-6alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0236] As used herein, the term “alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplesof alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ec-butyl, tert-butyl, / / -pentyl, 2-methyl-l -butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, / / -heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl. In some embodiments, the alkyl group is methyl.

[0237] As used herein, “halo” or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0238] As used herein, the term “haloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCl2, C2CI5, and the like.

[0239] As used herein, the term “alkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0240] As used herein, “haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3.

[0241] As used herein, “amino,” employed alone or in combination with other terms, refers to NH2.

[0242] As used herein, the term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-l-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl groupis a C3-7 monocyclic cycloalkyl group. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0243] As used herein, the term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-l-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [l,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ringforming atoms, or about 3 to 8 ring forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl portion is a C2-7 monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahydropyridine, azetidine ring, or tetrahydrofuran ring.

[0244] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1 -naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0245] As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen.

[0246] In some embodiments, the heteroaryl group is a 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[l,2-b]thiazolyl or the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N- oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quatemized, provided the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0247] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds described herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds described herein may be isolated as a mixture of isomers or as separated isomeric forms.

[0248] Compounds described herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropictautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.

[0249] Compounds described herein also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds described herein include at least one deuterium atom.

[0250] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. The term “compound” is also not limited by the way in which it was made. Thus, a compound described herein includes molecules that were made by a synthetic process or by a biological process (such as through enzyme conversion or metabolism), or combinations thereof.

[0251] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.

[0252] In some embodiments, the compounds described herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds described herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0253] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0254] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the compounds described herein include the non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.Methods of Use

[0255] Compounds described herein are TREM2 activators. For example, the compounds described herein can be used to activate TREM2 in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound described herein to the cell, individual, or patient. As used herein, the term “in a cell” includes both inside the cell membrane and on the surface of the cell membrane.

[0256] The compounds described herein are useful in the treatment and prevention of various diseases which would benefit from TREM2 activation. For example, the compounds described herein are useful in the treatment and prevention of neurodegenerative and neurological disorders. In some embodiments, the compounds described herein are useful in the treatment of neurological disorders. In some embodiments, the compounds described herein are useful in the prevention of neurological disorders. In some embodiments, the compounds described herein are useful in the treatment of neurodegenerative disorders. In some embodiments, the compounds described herein are useful in the prevention of neurodegenerative disorders.

[0257] In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is a neurodegenerative disease. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is selected from Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient atherapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is Alzheimer’s disease. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is frontotemporal dementia. In some embodiments is a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is amyotrophic lateral sclerosis.

[0258] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0259] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” TREM2 or “contacting” a cell with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having TREM2, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing TREM2.

[0260] As used herein, the term “individual” or “patient,” used interchangeably, refers to mammals, and particularly humans. The individual or patient can be in need of treatment.

[0261] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0262] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (z.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (z.e., reversing the pathology and / or symptomatology).

[0263] As used herein the term “preventing” or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments is a method of preventing a disease in a patient, by administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.Combination Therapy

[0264] One or more additional pharmaceutically active agents or treatment methods can be used in combination with the compounds described herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. Examples of additional agents include acamprosate, agomelatine, almotriptan, amantadine, amisulpride, amitriptyline, apomorphine, aripiprazole, asenapine, atomoxetine, baclofen, botulinum toxin type A, bromocriptine, buccal midazolam, buprenorphine, buspirone, cabergoline, carbamazepine, chlordiazepoxide, chlorpromazine, citalopram, clobazam, clomethiazole, clomipramine, clonazepam, clozapine, denzapine, co- beneldopa, co-careldopa, dantrolene, dexamfetamine, diazepam, divalproex sodium, donepezil, doxepin, duloxetine, eletriptan, entacapone, epinephrine, escitalopram, eslicarbazepine, ethosuximide, fmgolimod, fluoxetine, flupentixol, flupentixol, fluphenazine long-acting injection (modecate), fluvoxamine (Faverin), frovatriptan, gabapentin, galantamine, haloperidol, imipramine, lacosamide, lamotrigine, levetiracetam, levomepromazine, lisdexamfetamine, lithium, lofepramine, loprazolam, lorazepam, lormetazepam, lurasidone, melatonin, memantine, methylphenidate, mianserin, mirtazapine, moclobemide, modafinil, naratriptan, neostigmine, nitrazepam, nortriptyline, olanzapine, orlistat, orphenadrine, oxazepam, oxcarbazepine, paliperidone, paliperidone, paroxetine, perampanel, pergolide, pericyazine, phenobarbital, phenytoin, piracetam, pizotifen, pramipexole, pregabalin, primidone, prochlorperazine, procyclidine, pyridostigmine, quetiapine, rasagiline, reboxetine, risperidone, rivastigmine, rizatriptan, ropinirole, rotigotine, rufmamide, selegiline, sertraline, sodium oxybate, sodium valproate, sulpiride, sumatriptan, temazepam, tetrabenazine, tiagabine, tizanidine, tolcapone, topiramate, trazodone, trihexyphenidyl, trimipramine, valproate semisodium, venlafaxine, vigabatrin, vortioxetine, zolmitriptan, zolpidem, zonisamide, zopiclone, and zuclopenthixol.

[0265] In some embodiments, the one or more additional pharmaceutically active agent can include a neuroprotective agent. In some embodiments, the neuroprotective agent is a dual leucine-zipper kinase (DLK) inhibitor. In some embodiments, the neuroprotective agent is a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.

[0266] In some embodiments, the one or more additional pharmaceutically active agent can be NAD+ or an NAD+ precursor. NAD+ precursors include, for example, nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan, vitamin B3, and nicotinic acid adenine dinucleotide (NAAD).Pharmaceutical Formulations and Dosage Forms

[0267] When employed as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of a compound described herein, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

[0268] In some embodiments, pharmaceutical compositions described herein are formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be 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 & Wilkinsl999), herein incorporated by reference for such disclosure.

[0269] Administration may be oral, topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular (e.g., eye drops or intravitreal, subconjunctival, subtenon, or retrobulbar injection), or parenteral.

[0270] Also described herein are pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers. In making the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0271] The compositions can be formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0272] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0273] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound described herein. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.

[0274] The tablets or pills described herein can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0275] The liquid forms in which the compounds and compositions described herein can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0276] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0277] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0278] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0279] The therapeutic dosage of the compounds described herein can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.EXAMPLESGeneral Experimental:

[0280] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be activators of TREM2 according to one or more of the assays provided herein.

[0281] All reactions sensitive to air or moisture were carried out in flame-dried glassware under an atmosphere of nitrogen. All commercially available reagents were purchased from suppliers such as Sigma-Aldrich (MilliporeSigma), Combi-Blocks, Enamine, Sinopharm Chemical Reagent Co. (SCRC), and Alfa Aesar and were used without purification unless otherwise noted.6roton nuclear magnetic resonance (1H NMR) spectra were recorded on Bruker AVIII 400 or Bruker AVIII 500 spectrometers. Samples were dissolved in deuterated chloroform (CDCI3), dimethyl sulfoxide (DMSO-6), acetonitrile (CD3CN) or methanol (CD3OD). Chemical shifts are recorded in parts per million (ppm) and are referenced to the centerline of deuterochloroform (δ 7.26 ppm), of DMSO-d6(δ 2.50 ppm), of CD3CN (δ 1.94 ppm) or of CD3OD (δ 3.31 ppm). Data were recorded as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quintet, m = multiplet, br = broad). Coupling constants (J values) are given in Hertz (Hz). Chemical shift, multiplicity and coupling constants were assigned using Mnova, version 14.3. Low resolution ESI mass spectra were recorded on a either an Agilent 1200 HPLC / 6100 SQ system or an Agilent 1260 Infinity II HPLC / 6125 SQ system. LCMS measurements were recorded on Agilent 1200 HPLC / 6100 SQ System.List of Abbreviations: aq aqueousBoc tert-butyl oxy carbonylBOC2O Boc-anhydride or di- tert-butyl dicarbonateCDI 1,1-carbonyl-diimidazole d day(s)D2H (deuterium)DABCO l,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetoneDCM di chloromethaneDMP Dess-Martin periodinane or 3-Oxo-lλ5,2-benziodoxole-l,l,l(3H)-triyl triacetateDEA diethylamineDHP 3,4-dihydropyranDIAD diisopropyl azodicarboxylateDIPEA N, N-diisopropylethylamineDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethylsulfoxideDPPA diphenyl phosphoryl azideEDC HC1 V-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochlorideESI-MS electrospray ionization - mass spectrometryEt ethylEtOAc ethyl acetateEtOH ethanol equiv equivalent(s)FA formic acid(g) gaseous h hour(s)HATU l-[bis(dimethylamino)methylene]-lA-l,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphateHOBt 1 -hydroxybenzotriazoleLAH lithium aluminum hydrideLCMS liquid chromatography mass spectrometryLiHMDS lithium bis(trimethylsilyl)amideMS mass spectrometryMeCN acetonitrileMeOH methanolMHz megahertz min minute(s) mg milligram(s) mL milliliter(s) mmol millimole(s)M molarMeCN acetonitrile mol mole(s)Ms methanesulfonylMW micro waveN normalNBS A-bromosuccinimideNCS A-chlorosuccinimideNTF A-phenyl-bis(trifluoromethanesulfomimideOTf trifluoromethanesulfonatePBM-SH (4-methoxyphenyl)-m ethanethiolPd / C palladium on carbonPE petroleum etherPh phenylPTSA / ?-toluenesulfonic acid1H NMR proton nuclear magnetic resonanceRP-HPLC reverse-phase high performance liquid chromatographyRT retention time rt room temperature sat saturatedSEM 2-(trimethylsilyl)ethoxymethylSFC supercritical fluid chromatography T3P propylphosphonic anhydrideTBAF tetrabutyl ammonium fluorideTBPH tert-butyl hydroperoxide solution (Luperox®, TBH70X)Z-BuOK potassium tert-butoxideTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTHP tetrahydropyranTLC thin layer chromatographyTol tolueneTosMIC -toluenesulfony Im ethyl isocyanide wt % weight percent v / v % volume by volume percent w / v % weight by volume percentXPhos 2-dicy cl ohexylphosphino-2’, 4’, 6’ -triisopropylbiphenylSynthesis of intermediates (Int-1 to Int-17)Synthesis of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2- c]pyridazine-3-carboxylic acid (Int-1):lnt-1

[0282] To a stirred solution of 3-bromo-5,6-dimethylpyridine-2-carboxylic acid (6.7 g, 29.1 mmol, 1 eq.) in THF (13 mL) was added to CDI (5.2 g, 32.0 mmol, 1.1 eq.) in THF (54 mL) dropwise at rt in flask 1 and stirred for 2 h at rt. To a stirred solution of 1 -ethyl 3 -potassium propanedioate (5.45 g, 32.1 mmol, 1.1 eq.) in ACN (54 mL) was added TEA (5.89 g, 58.2 mmol, 2 eq.) and MgCl2(3.33 g, 34.9 mmol, 1.2 eq.) in portions at 10 °C in flask 2 and stirred for 2.5 h at rt. Added flask 2 into flask 1 over 10 min at rt and stirred for additional 45.5 h at rt. The resulting mixture was dissolved in water (400 mL) and extracted with EA (5 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as a yellow oil (12.50 g, crude).

[0283] To a stirred solution of ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (12 g, 40 mmol, 1 eq.) and K2CO3 (16.6 g, 120 mmol, 3 eq.) in MeOH:dioxane (2 / 1, 180 mL) was added (Z)-chloro(4-chloro-2-fluorophenyl) diazene (9.3 g, 48 mmol, 1.2 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 12 h at rt. The resulting mixture was dissolved in water (600 mL). The resulting mixture was extracted with EA (5 x 300 mL). The extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford the title compound as a brown solid (8.8 g, 55% yield (2 steps)).

[0284] To a stirred solution of ethyl (2E)-3-(3-bromo-5,6-dimethylpyridin-2-yl)-2-(2-(4-chloro- 2-fluorophenyl)hydrazin-l-ylidene)-3-oxopropanoate (Int-lb) (5 g, 11 mmol, 1 eq.) in dioxane (50 mL) was added NaH (481.7 mg, 12 mmol, 1.1 eq) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 100 °C. The resulting mixture was poured into ice water (150 mL). The resulting mixture was extracted with EA (3 x 200 mL). The extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to the title compound as a brown solid (3.2 g, 78% yield).

[0285] To a stirred solution of ethyl l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2- c]pyridazine-3 -carboxylate (Int-lc) (3.2 g, 8.52 mmol, 1 eq.) and LiOH (0.31 g, 12.8 mmol, 1.5 eq.) in THF (24 mL) and H2O (8 mL) was stirred at room temperature for 12 h under nitrogen atmosphere. The mixture was acidified to pH 2 with HC1 (6 M in water). The resulting mixture was poured into water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The extracts were dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow solid (2.2 g, 74% yield).Synthesis of 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrido [3,2-c] pyridazin- 4(lH)-one (Int-2):Int-1 lnt-2a lnt-2

[0286] To a stirred solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2- c]pyridazine-3-carboxylic acid (Int-1) (600 mg, 1.73 mmol, 1 eq.) and TEA (437 mg, 2.59 mmol, 1.5 eq.) in toluene (4.2 mL) was added DPPA (712 mg, 2.59 mmol, 1.5 eq.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 60 °C. The resulting mixture was added to NaOH (8M in water, 3 mL) and stirred for 0.5 h at 60 °C. The resulting mixture was extracted with EA (3 x 5 mL). The extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reversed phase flash chromatography to afford the title compound as a yellow solid (220 mg, 40% yield).

[0287] To a stirred solution of 3-amino-l-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrido[3,2- c]pyridazin-4-one (Int-2a) (220 mg, 0.69 mmol, 1 eq.) and CuBr2 (185 mg, 0.83 mmol, 1.2 eq.) in DMF (3 mL) were added 3-methylbutyl nitrite (207 mg, 1.77 mmol, 2.5 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 60 °C. The residue was purified by reversed phase flash chromatography to afford the title compound as off-white solid (190 mg, 72% yield).Synthesis of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydro-l,5- naphthyridine-3-carboxylic acid (Int-3):

[0288] A solution of ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (7 g, 23.3 mmol, 1 eq.) and DMF-DMA (8.34 g, 70 mmol, 3 eq.) in toluene (35 mL) was stirred for 1 h at 110°C. The mixture was allowed to cool down to rt and was quenched by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous MgSO4After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a brown oil (3 g, 36% yield).

[0289] A solution of ethyl 2-(3-bromo-5,6-dimethylpyridine-2-carbonyl)-3- (dimethylamino)prop-2-enoate (Int-3a) (3 g, 8.4 mmol, 1 eq.) and 4-chloro-2-fluoroaniline (1.8 g, 12.7 mmol, 1.5 eq.) in toluene (60 mL) was stirred for 2 h at 110 °C. The resulting mixture was allowed to cool down to rt and quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a brown solid (2.2 g, 57% yield).

[0290] A mixture of ethyl 2-(3-bromo-5,6-dimethylpyridine-2-carbonyl)-3-((4-chloro-2- fluorophenyl)amino)prop-2-enoate (Int-3b) (2.2 g, 4.8 mmol, 1 eq.) and CS2CO3 (1.57 g, 4.8 mmol, 1 eq.) in toluene (44 mL) was stirred for 2 h at 110 °C. The mixture was allowed to cool down to rt and quenched with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a brown solid (2.2 g, crude). The crude product was used in the next step directly without further purification.

[0291] Compound Int-3 was synthesized using ethyl l-(4-chloro-2-fluorophenyl)-6,7-dimethyl- 4-oxo-l,5-naphthyridine-3-carboxylate (Int-3c) (2.2 g, 5.9 mmol) by following the procedure from Compound Int-1 to afford the title compound as a brown solid (1.2 g, 72% yield (2 steps)).Synthesis of l-(3,4-dichlorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2- c]pyridazine-3-carboxylic acid (Int-4):I l l

[0292] To a stirred solution of 3, 4-di chloroaniline (7.07 g, 43.6 mmol, 1 eq.) in HC1 (99 mL, 6 N) was added NaNCL (3.01 g, 43.6 mmol, 1 eq.) in H2O (49.5 mL) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The resulting solution (around 150 mL) was used in the next step directly without further purification.

[0293] To a stirred solution of ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (4.13 g, 13.8 mmol, 1 eq.) and KOAc (4.05 g, 41.3 mmol, 3 eq.) in MeOH (52.8 mL) and 1,4-dioxane (26.4 mL) was added a solution of 3,4-dichlorobenzenediazonium chloride (Int-4a) (150 mL, from step 1) at 0 °C. The reaction was quenched with water (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid (4.6 g, 22% yield (2 steps)).

[0294] Compound Int-4c was synthesized using ethyl-3-(3-bromo-5,6-dimethylpyridin-2-yl)-2- (2-(3,4-dichlorophenyl)hydrazineylidene)-3-oxopropanoate (Int-4b) (4.6 g, 9.72 mmol) by following the procedure from Compound Int-lc to afford the title compound as a yellow solid (3 g, 78% yield).

[0295] Compound Int-4 was synthesized using ethyl l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxo- l,4-dihydropyrido[3,2-c]pyridazine-3 -carboxylate (Int-4c) (3 g, 7.65 mmol) by following the procedure from Compound Int-1 to afford the title compound as a white solid (1.8 g, 64% yield).Synthesis of 3-bromo-l-(3,4-dichlorophenyl)-6,7-dimethylpyrido [3,2-c] pyridazin-4(lH)-one (Int-5):

[0296] Compound Int-5a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (1.6 g, 4.39 mmol) by following the procedure from Compound Int-2a to afford the title compound (950 mg, 64% yield).

[0297] Compound Int-5 was synthesized using 3-amino-l-(3,4-dichlorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Int-5a) (950 mg, 2.83 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (350 mg, 29% yield).Synthesis of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydropyrazino[2,3- c]pyridazine-3-carboxylic acid (Int-6):Int-6c lnt-6

[0298] Compound Int-6a was synthesized using 3-chloro-5,6-dimethylpyrazine-2-carboxylic acid (15 g, 80 mmol, 1 eq.) and 1-ethyl 3-potassium propanedioate (16.4 g, 96 mmol, 1.2 eq.) by following the procedure from Compound Int-la to afford the title compound as a light yellow oil (15 g, 72% yield).

[0299] A solution of 4-chloro-2-fluoroaniline (7 g, 48.1 mmol, 2 eq.) in HC1 (100 mL, 6M) was stirred for 10 min at 0 °C in flask 1. A solution of NaNO2(3.32 g, 48.1 mmol, 2 eq.) in H2O (50 mL) was added to the mixture in flask 1 dropwise at 0 °C. The resulting mixture was stirred for additional 10 min in flask 1. A solution of ethyl 3 -(3 -chi oro-5, 6-dimethylpyrazin-2-yl)-3- oxopropanoate (Int-6a) (5 g, 19.5 mmol, 1 eq.) and KAc (5.74 g, 58.4 mmol, 3 eq.) in MeOH (50 mL) and 1,4-di oxane (25 mL) was stirred for 0.5 h at 0 °C in flask 2. The mixture in flask 1 was added to flask 2 dropwise at 0 °C. The resulting mixture was warmed to rt and stirred for 12 h and was dissolved in water (200 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as an orange red solid (5.4 g, 53% yield).

[0300] Compound Int-6c was synthesized using ethyl 2-(2-(4-chloro-2- fluorophenyl)hydrazineylidene)-3-(3-chloro-5,6-dimethylpyrazin-2-yl)-3-oxopropanoate (Int- 6b) (5.4 g, 13.1 mmol) by following the procedure from Compound Int-lc to afford the title compound as a black solid (4.5 g, 64% yield).

[0301] Compound Int-6 was synthesized using ethyl l-(4-chloro-2-fluorophenyl)-6,7-dimethyl- 4-oxo- l,4-dihydropyrazino[2, 3 -c]pyridazine-3 -carboxylate (Int-6c) (4.5 g, 11.9 mmol) by following the procedure from Compound Int-1 to afford the title compound as a brown solid (1.7 g, 41% yield).Synthesis of 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrazino [2,3-c] pyridazin- 4(lH)-one (Int-7):

[0302] To a stirred solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrazino[2, 3- c]pyridazine-3-carboxylic acid (Int-6) (550 mg, 1.58 mmol, 1 eq.) and TEA (399 mg, 3.9 mmol, 2.5 eq.) in t-BuOH (4 mL) was added DPPA (812 mg, 2.95 mmol, 1.9 eq.) dropwise at rt under a nitrogen atmosphere. The resulting mixture was heated to 85 °C and stirred for 4 h. The reaction was cooled to rt and poured in ice water (20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was dissolved in DCM (12 mL) and to the resulting mixture was added HCl / dioxane (6 mL) dropwise at rt. The resulting mixture was stirred for 2 h and was concentrated under reduced pressure. The residue was dissolved in ice water (10 mL) and basified to pH 9 with saturated NaHCCL (aq.). The resulting mixture was extracted with EA (5 x 10 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by trituration with PE / EA(10 / l, 5 mL) to afford the title compound as a brown solid (500 mg, 89% yield).

[0303] Compound Int-7 was synthesized using 3-amino-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrazino[2, 3-c]pyridazin-4-one (Int-7a) (500 mg, 1.56 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (200 mg, 33% yield).Synthesis of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3- carboxylic acid (Int-8):lnt-8a Int-8b lnt-8

[0304] A solution of 4-chloro-2-fhioroaniline (3.78 g, 26 mmol, 1.3 eq.) in HC1 (6 M, 37.8 mL) was stirred at rt under nitrogen atmosphere in flask 1. To a stirred solution of NaNCh (1.79 g, 26 mmol, 1.3 eq.) in H2O (18.9 mL) was added the mixture flask 1 dropwise at 0°C in flask 2. A solution of ethyl 3-(2-methoxy-4,5-dimethylphenyl)-3-oxopropanoate (5 g, 20 mmol, 1 eq.) andKOAc (5.88 g, 59.9 mmol, 3 eq.) in MeOH (50 mL) and 1,4-dioxane (25 mL) were stirred at 0°C for 0.5 h in flask 3. Added the mixture in flask 2 to flask 3 dropwise at 0°C. The resulting mixture was stirred for an additional 2 h at rt. The resulting mixture was extracted with water (200 mL) and EA (3 x 200 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography afford the title compound as a yellow solid (5.26 g, 65% yield).

[0305] A solution of ethyl (2E)-2-[2-(4-chloro-2-fluorophenyl)hydrazin-l-ylidene]-3-(2- methoxy-4,5-dimethylphenyl)-3-oxopropanoate (Int-8a) (5.26 g, 12.9 mmol, 1 eq.) and BSA (60.5 g, 297 mmol, 23 eq.) in ultra-dried DMF (78.9 mL) was stirred at 80 °C for 12 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and dissolved in water (400 mL). The resulting mixture was extracted with EA (5 x 300 mL). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid (1.1 g, 21% yield).

[0306] Compound Int-8 was synthesized using ethyl l-(4-chloro-2-fluorophenyl)-6,7-dimethyl- 4-oxo- l,4-dihydrocinnoline-3 -carboxylate (Int-8b) (1.1 g, 2.94 mmol) by following the procedure from Compound Int-1 to afford the title compound as a yellow solid (1 g, 98% yield).Synthesis of 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7-dimethylcinnolin-4(lH)-one (Int-9):

[0307] Compound Int-9a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (Int-8) (750 mg, 2.16 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (740 mg, crude).

[0308] Compound Int-9 was synthesized using 3-amino-l-(4-chloro-2-fluorophenyl)-6,7- dimethylcinnolin-4(lH)-one (Int-9a) (740 mg, 2.3 mmol) by following the procedure from Compound Int-2 to afford the title compound as a brown solid (500 mg, 60% yield (2 steps)).Synthesis of 3-bromo-l-(4,4-difluorocyclohexyl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)- one (Int-10):

[0309] Into a 3 L 4-necked round-bottom flask were added ethyl 3-(3-bromo-5,6- dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (140 g, 446 mmol, 1 eq.), ACN (1.4 L), K2CO3 (92.6 g, 670 mmol, 1.5 eq.) and 4-acetamidobenzenesulfonyl azide (161.0 g, 670 mmol, 1.5 eq.) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (2x500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6: 1) to afford the title compound as a yellow oil (107 g, 72% yield). LCMS ESI-MS m / z: = 326 / 328 [M+H]+.

[0310] Into a 2.0 L 4-necked round-bottom flask were added ethyl 3-(3-bromo-5,6- dimethylpyridin-2-yl)-2-diazo-3-oxopropanoate (Int-lOa) (100 g, 306 mmol, 1 eq.) and THF (1.0 L) at room temperature. Then trimethylphosphine (337 mL, 337 mmol, 1.1 eq.) was added to the mixture at room temperature. The resulting mixture was stirred for 30 min at room temperature. Followed by the addition of H2O (55.24 g, 3066 mmol, 10 eq.) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford the title compound as a light yellow solid (90 g, 89% yield). LCMS ESI-MS m / z: = 328 [M+H]+.

[0311] Into a 3.0 L 4-necked round-bottom flask were added ethyl (2Z)-3-(3-bromo-5,6- dimethylpyridin-2-yl)-2-hydrazinylidene-3-oxopropanoate (Int-lOb) (90 g, 274 mmol, 1 eq.), Pd2(dba)3 (25.1 g, 27 mmol, 0.10 eq.), Na2CO3(58.1 g, 548 mmol, 2 eq.), and X-Phos (26.1 g, 54 mmol, 0.2 eq.) at room temperature. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (900 mL) at room temperature. The resulting mixture was concentrated under vacuum. The residue mixture was extracted with EtOAc (3x900 mL). The aqueous phase were purified by reversed-phase flash chromatography to afford the title compound as a yellow solid (43.0 g, 60% yield).1HNMR (300 MHz, DMSO-d6) δ 8.00 (d, J= 1.1 Hz, 1H), 4.25 (q, J= 7.1 Hz, 2H), 2.56 (s, 3H), 2.43 - 2.37 (m, 3H), 1.61 (s, 1H), 1.31 (t, J= 7.1 Hz, 3H).

[0312] To a stirred solution of l,l-difluoro-4-iodocyclohexane (40 g, 161 mmol, 8 eq.) and ethyl 6,7-dimethyl-4-oxo-lH-pyrido [3,2-c]pyridazine-3-carboxylate (Int-lOc) (5 g, 20 mmol, 1 eq.) in DMF (200 mL) was added K2CO3 (14 g, 101 mmol, 5 eq.) at rt. The resulting mixture was heated to 100 °C and stirred overnight. The resulting mixture was cooled down to rt and quenched by the addition of water (50 mL) at rt. Then the resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were dried over anhydrous MgSO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid (2.6 g, 35% yield).

[0313] Compound Int-lOe was synthesized using ethyl l-(4,4-difluorocyclohexyl)-6,7- dimethyl-4-oxopyrido[3,2-c]pyridazine-3 -carboxylate (Int-lOd) (2.6 g, 7.1 mmol) by following the procedure from Compound Int-1 to afford the title compound as a grey solid (1.6 g, 67% yield).

[0314] Compound Int-lOf was synthesized using l-(4,4-difluorocyclohexyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-lOe) (1.6 g, 4.7 mmol) by following the procedure from Compound Int-2a to afford the title compound as a grey solid (1.45 g, crude).

[0315] Compound Int-10 was synthesized using 3-amino-l-(4,4-difluorocyclohexyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-lOf) (1.45 g, 4.7 mmol) by following the procedure from Compound Int-2 to afford the title compound as a grey solid (1.3 g, 74% yield).Synthesis of 3-bromo-l-(4-chlorophenyl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Int-11):

[0316] Compound Int-lla was synthesized using ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)- 3-oxopropanoate (Int-la) (5.15 g, 17.1 mmol, 1 eq.) and chloro (4-chlorophenyl)diazene (7.5 g, 42.9 mmol, 2.5 eq.) by following the procedure from Compound Int-4b to afford the title compound as a yellow solid (4.5 g, 22% yield (2 steps)).

[0317] Compound Int-llb was synthesized using ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)- 2-(2-(4-chlorophenyl)hydrazineylidene)-3-oxopropanoate (Int-lla) (4.5 g, 10.3 mmol) by following the procedure from Compound Int-lc to afford the title compound without further purification.

[0318] Compound Int-llc was synthesized using ethyl l-(4-chlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylate (Int-llb) (3 g, 8.39 mmol) by following the procedure from Compound Int-1 to afford the title compound without further purification.

[0319] Compound Int-lld was synthesized using l-(4-chlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-llc) (2 g, 6.07 mmol) by following the procedure from Compound Int-2a to afford the title compound without further purification.

[0320] Compound Int-11 was synthesized using 3-amino-l-(4-chlorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-lld) (1 g, 3.33 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (410 mg, 11% yield (4 steps)).Synthesis of 3-bromo-l-(2,4-dichlorophenyl)-6,7-dimethylpyrido [3,2-c] pyridazin-4(lH)-one (Int-12):

[0321] Compound Int-12a was synthesized using 2,4-dichloroaniline (7 g, 43 mmol) and ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5.16 g, 17 mmol) by following the procedure from Compound Int-8a to afford the title compound as a yellow solid (5.1 g, 25% yield).

[0322] Compound Int-12b was synthesized using ethyl (2E)-3-(3-bromo-5,6-dimethylpyridin- 2-yl)-2-(2-(2,4-dichlorophenyl)hydrazin-l-ylidene)-3-oxopropanoate (Int-12a) (5 g, 10.5 mmol) by following the procedure from Compound Int-lc to afford the title compound without further purification.

[0323] Compound Int-12c was synthesized using ethyl l-(2,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylate (Int-12b) (4 g, 10.1 mmol) by following the procedure from Compound Int-1 to afford the title compound as a yellow solid (3.15 g, 81% yield (2 steps)).

[0324] Compound Int-12d was synthesized using l-(2,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-12c) (2 g, 5.49 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (1.45 g, 78% yield).

[0325] Compound Int-12 was synthesized using 3-amino-l-(2,4-dichlorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-12d) (1.45 g, 4.3 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (840 mg, 46% yield).Synthesis of 3-bromo-l-(4-chloro-2-methylphenyl)-6,7-dimethylpyrido [3,2-c] pyridazin- 4(lH)-one (Int-13):

[0326] Compound Int-13a was synthesized using 4-chloro-o-toluidine (5.9 g, 41.6 mmol, 2.5 eq.) and ethyl 3-(3-bromo-5, 6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5 g, 16.7 mmol, 1 eq.) by following the procedure from Compound Int-6b to afford the title compound as a yellow oil (2.68 g, 36% yield).

[0327] Compound Int-13b was synthesized using ethyl (E)-3-(3-bromo-5,6-dimethylpyridin-2- yl)-2-(2-(4-chloro-2-methylphenyl)hydrazineylidene)-3-oxopropanoate (Int-13a) (2.68 g, 5.92 mmol) by following the procedure from Compound Int-lc to afford the title compound as a yellow oil (3.2 g, crude).

[0328] Compound Int-13c was synthesized using ethyl l-(4-chloro-2-methylphenyl)-6,7- dimethyl-4-oxopyrido[3,2-c]pyridazine-3 -carboxylate (Int-13b) (3.2 g, 8.6 mmol) by following the procedure from Compound Int-1 to afford the title compound as a yellow solid (1.9 g, 64% yield (2 steps)).

[0329] Compound Int-13d was synthesized using l-(4-chloro-2-methylphenyl)-6,7-dimethyl-4- oxo- l,4-dihydropyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-13c) (1.7 g, 4.95 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (1 g, 64% yield).

[0330] Compound Int-13 was synthesized using 3-amino-l-(4-chloro-2-methylphenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Int-13d) (1 g, 3.18 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (600 mg, 50% yield).Synthesis of 3-bromo-l-(2,4-difluorophenyl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (lnt-14):

[0331] Compound Int-14a was synthesized using ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)- 3-oxopropanoate (Int-la) (5.5 g, 18.3 mmol, 1 eq.) and (Z)-chloro(2,4-difluorophenyl)diazene (82.5 mL, 25 mmol, 1.4 eq.) by following the procedure from Compound Int-4b to afford the title compound as a yellow solid (5.8 g, 71% yield).

[0332] Compound Int-14b was synthesized using ethyl (E)-3-(3-bromo-5,6-dimethylpyridin-2- yl)-2-(2-(2,4-difluorophenyl)hydrazineylidene)-3-oxopropanoate (Int-14a) (5.8 g, 13.1 mmol) by following the procedure from Compound Int-lc to afford the title compound as a yellow solid (3.7 g, crude). The crude product was used in the next step directly without further purification.

[0333] Compound Int-14c was synthesized using ethyl l-(2,4-difluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylate (Int-14b) (3.7 g, 10.2 mmol) by following the procedure from Compound Int-1 to afford the title compound as a yellow solid (3.7 g, 84% yield (2 steps)).

[0334] Compound Int-14d was synthesized using l-(2,4-difhiorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-14c) (3.2 g, 9.6 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (2 g, 69% yield).

[0335] Compound lnt-14 was synthesized using 3-amino-l-(2,4-difluorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-14d) (2 g, 6.6 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (1.3 g, 60% yield).Synthesis of 3-bromo-6,7-dimethyl-l-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,2- c]pyridazin-4(lH)-one (Int-15):

[0336] Compound Int-15a was synthesized using 6-(trifluoromethyl) pyridin-3 -amine (8.1 g, 49 mmol, 3 eq.) and ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5.0 g, 16 mmol, 1 eq.) by following the procedure from Compound Int-8a to afford the title compound as an orange oil (5.32 g, 67% yield).

[0337] Compound Int-15b was synthesized using ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)- 3-oxo-2-(2-(6-(trifluoromethyl)pyridin-3-yl)hydrazineylidene)propanoate (Int-15a) (5.3 g, 11.1 mmol) by following the procedure from Compound Int-lc to afford the title compound as a brown solid (4.8 g, crude). The crude product was used in the next step directly without further purification.

[0338] Compound Int-15c was synthesized using ethyl 6,7-dimethyl-4-oxo-l-(6- (trifluoromethyl)pyri din-3 -yl)-l,4-dihydropyrido[3,2-c]pyridazine-3 -carboxylate (Int-15b) (4.8 g, 12.2 mmol) by following the procedure from Compound Int-1 to afford the title compound as a grey white solid (2.8 g, 62% yield (2 steps)).

[0339] Compound Int-15d was synthesized using of 6,7-dimethyl-4-oxo-l-(6- (trifluoromethyl)pyri din-3 -yl)-l,4-dihydropyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-15c) (2.5 g, 6.8 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (1.5 g, 66% yield).

[0340] Compound Int-15 was synthesized using 3-amino-6,7-dimethyl-l-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Int-15d) (1.5 g, 4.4 mmol) by following the procedure from Compound Int-2 to afford the title compound as a light yellow solid (900 mg, 50% yield).Synthesis of 3-bromo-l-(4-chlorophenyl)-6-cyclopropylpyridazin-4(lH)-one (Int-16):

[0341] To a stirred solution of 6-cyclopropyl-4-hydroxypyran-2-one (1.38 g, 8.8 mmol, 1 eq.) and Na2CC>3 (5.2 g, 48.9 mmol, 5.5 eq.) in H2O (50 mL) was added (4-chlorophenyl) diazene hydrochloride (1.7 g, 9.8 mmol, 1.1 eq.) dropwise at 0 °C under. The resulting mixture was warmed to rt and stirred for 0.5 h. The mixture was used in the next step directly without further purification.

[0342] To the above mixture was added HC1 (38 ml, 6 M in H2O) dropwise at 0-5 °C. The resulting mixture was heated to 100 °C and stirred for an additional 12 h. The mixture was cooled to rt and diluted with water (50 mL), then extracted with EA (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the title compound as a yellow solid (1.75 g, 61% yield (2 steps)).

[0343] Compound Int-16c was synthesized using l-(4-chlorophenyl)-6-cyclopropyl-4- oxopyridazine-3 -carboxylic acid (Int-16b) (1.75 g, 6 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (750 mg, 48% yield).

[0344] Compound Int-16 was synthesized using 3-amino-l-(4-chlorophenyl)-6- cyclopropylpyridazin-4-one (Int-16c) (750 mg, 2.9 mmol) by following the procedure from Compound Int-2 to afford the title compound as a brown solid (1 g, 92% yield).Synthesis of 3-bromo-l-(4-chlorophenyl)-6-methylpyridazin-4(lH)-one (Int-17):

[0345] To a 3-necked flask 1 were added 4-chloroaniline (10 g, 78.4 mmol, 1.05 eq.) and HC1(200 mL, 6 M) at rt. To the above mixture was added NaNCh (6.5 g, 94.8 mmol, 1.3 eq.) in H2O(10 mL) dropwise at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C in the flask 1. To flask 2 were added H2O (400 mL), triacetic acid lactone (9.38 g, 74.3 mmol, 1 eq.) and Na2CO3(41.9 g, 391 mmol, 5.2 eq.) and the solution was stirred for 0.5 h at 0 °C. The mixture from flask 1 was added dropwise into flask 2 at 0 °C. The resulting mixture was heated to 100 °C and stirred for 3 h, cooled down to rt. The precipitated solids were collected by filtration and washed H2O water (3 x 10 mL) to afford the title compound as a light brown solid (13 g, 62% yield).

[0346] Compound Int-17b was synthesized using l-(4-chlorophenyl)-6-methyl-4- oxopyridazine-3 -carboxylic acid (Int-17a) (5 g, 18.8 mmol) by following the procedure from Compound Int-2a to afford the title compound as a light brown solid (2.05 g, 46% yield).

[0347] Compound Int-17 was synthesized using 3-amino-l-(4-chlorophenyl)-6- methylpyridazin-4-one (1.65 g, 7 mmol) by following the procedure from Compound Int-2 to afford the title compound as a light brown solid (1.15 g, 54% yield).Example 1: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[4,5-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 1)

[0348] A solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) (50 mg, 0.144 mmol, 1 eq.), 5-amino-2-(trifluoromethyl) pyridin-4-ol(30.7 mg, 0.173 mmol, 1.2 eq.), T3P (137 mg, 0.216 mmol, 50% purity, 1.5 eq.), DIEA (55.8 mg, 0.432 mmol, 3 eq.), and DMAP (3.51 mg, 0.029 mmol, 0.2 eq.) in THF (1 mL) was stirred for 30 min at rt. The precipitated solids were collected by filtration and washed with H2O (3 mL). The solid was collected and dried under reduced pressure to afford Compound la as an orange solid (50 mg, 68% yield).

[0349] A solution of C2CI6 (46.6 mg, 0.198 mmol, 2.5 eq.), TEA (63.8 mg, 0.632 mmol, 8 eq.), PPI13 (62 mg, 0.237 mmol, 3 eq.) in DCM (3 mL) was stirred for 10 min at rt. To the resulting mixture was added l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6-(trifluoromethyl)pyri din-3 -yl)- 6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxamide (la) (40 mg, 0.079 mmol, 1 eq.) at rt. The reaction was stirred for 30 min at rt and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography to afford the title compound as an off-white solid (27.5 mg, 70%).1HNMR (300 MHz, Chloroform-d6) δ 9.29 (s, 1H), 8.02 (d, J= 1.0 Hz,1H), 7.68 - 7.57 (m, 1H), 7.54 - 7.41 (m, 2H), 7.20 - 7.13 (m, 1H), 2.77 (s, 3H), 2.45 (s, 3H).LCMS ESI-MS m / z: = 490 [M+H]+.Example 2: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[5,4-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound

[0350] A solution of 4-amino-6-(trifluoromethyl)pyridin-3-ol (120 mg, 0.283 mmol, 1.6 eq.), 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxylic acid (Int-1) (61 mg, 0.175 mmol, 1 eq.), PyBOP (221 mg, 0.424 mmol, 2.4 eq.) and DMAP (51.9 mg, 0.424 mmol, 2.4 eq) in THF (2.4 mL) was treated with DIEA (110 mg, 0.849 mmol, 4.8 eq.). The resulting mixture was heated to 60 °C and stirred for 1 h. The reaction was allowed to cool down to rt and purified by reversed-phase flash chromatography to afford Compound 2a as a red solid (50 mg, 35% yield).

[0351] Compound 2 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (2a) (50 mg, 0.098 mmol) by following the procedure from Compound 1 to afford Compound 2 as a white solid (6.0 mg, 12% yield).1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.59 (s, 1H), 8.01 - 7.91 (m, 2H), 7.72 - 7.66 (m, 1H), 7.61 (s, 1H), 2.66 (s, 3H), 2.42 (s, 3H).19F NMR (376 MHz, DMSO-d6) 6 -64.9, -119.1. LCMS ESI-MS m / z: = 490 [M+H]+.Example 3: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- methyloxazolo [4,5-c] pyridin-2-yl)pyrido [3,2-c] pyridazin-4(lH)-one (Compound 3)

[0352] Compound 3a was synthesized using 5-amino-2-methylpyridin-4-ol (50 mg, 0.4 mmol, 2.8 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido [3, 2-c] pyridazine-3- carboxylic acid (Int-1) (50 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound la heating the reaction to 60 °C to afford Compound 3a as a yellow solid (20 mg).

[0353] Compound 3 was synthesized using l-(4-chl oro-2 -fluorophenyl)-N-(4-hydroxy-6- methylpyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide(3a) (20 mg, 0.044 mmol) by following the procedure from Compound 1 to afford Compound 3 as an off-white solid (2.6 mg, 13% yield).1H NMR (300 MHz, Chloroform-d) 5 9.13 (s, 1H), 7.69 - 7.43 (m, 4H), 7.17 (s, 1H), 2.81 (d, J= 12.6 Hz, 6H), 2.46 (s, 3H). LCMS ESI-MS m / z: = 436 [M+H]+.Example 4: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- methyloxazolo [5,4-c] pyridin-2-yl)pyrido [3,2-c] pyridazin-4(lH)-one (Compound 4)

[0354] To a stirred solution of 4-amino-6-methylpyri din-3 -ol (50 mg, 0.121 mmol, 1.5 eq.), HOBT (16 mg, 0.121 mmol, 1.5 eq.) and DIEA (44.2 mg, 0.288 mmol, 3.5 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxylic acid (Int-1) (28 mg, 0.081 mmol, 1 eq.) in DMA (1 mL) were added EDCI (23.2 mg, 0.121 mmol, 1.5 eq.) at rt. The reaction mixture was heated to 60 °C and stirred for 1 h. The resulting mixture was allowed to cool down to rt and then was purified by reversed-phase flash chromatography to afford Compound 4a as an off-white solid (35 mg, 90% yield).

[0355] A mixture of C2CI6 (46 mg, 0.193 mmol), PPI13 (61 mg, 0.231 mmol) and DIEA (62 mg, 0.616 mmol) in DCM (3.5 mL) was stirred for 10 min at rt under a nitrogen atmosphere. To the above mixture was added l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2-methylpyridin-4-yl)-6,7- dimethyl-4-oxopyrido[3,2-c]pyridazine-3 -carboxamide (4a) (35 mg, 0.077 mmol) at rt. The resulting mixture was stirred for an additional 1 h at rt and then was purified directly by reversed-phase flash chromatography to afford Compound 4 as an off-white solid (4.6 mg, 13% yield).1H NMR (400 MHz, Chloroform-d) 5 8.98 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.49 (t, J= 9.4 Hz, 2H), 7.19 (s, 1H), 2.80 (d, J= 6.9 Hz, 6H), 2.47 (s, 3H). LCMS ESI-MS m / z: = 436 [M+H]+.Example 5: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-methoxyoxazolo[4,5-c]pyridin-2-yl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Compound 5)

[0356] Compound 5a was synthesized using 5-amino-2-methoxypyridin-4-ol (50 mg, 0.36 mmol, 1 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) (124 mg, 0.36 mmol, 1 eq.) by following the procedure from Compound 2a to afford Compound 5a as a dark green solid (20 mg, 9% yield).

[0357] Compound 5 was synthesized using l-(4-chl oro-2 -fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (5a) (20 mg, 0.04 mmol) by following the procedure from Compound 4 to afford Compound 5 as a white solid (1.0 mg, 5% yield).1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.00 - 7.88 (m, 2H), 7.74 - 7.63 (m, 1H), 7.55 (s, 1H), 7.27 (s, 1H), 3.94 (s, 3H), 2.63 (s, 3H), 2.40 (s, 3H). LCMS ESI-MS m / z: = 452 [M+H]+.Example 6: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-methoxyoxazolo[5,4-c]pyridin- 2-yl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Compound 6)

[0358] Compound 6a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-1) (70 mg, 0.201 mmol, 1 eq.) and 4-amino- 6-methoxypyri din-3 -ol (28.2 mg, 0.201 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 6a as an orange solid (35 mg, 37% yield).

[0359] To a stirred solution of C2CI6 (44.1 mg, 0.185 mmol, 2.5 eq.) and PPI13 (58.6 mg, 0.22 mmol, 3 eq.) in toluene (5 mL) was added TEA (60.3 mg, 0.59 mmol, 8 eq.) at rt under a nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred for 5 min under a nitrogen atmosphere. To the above mixture was added l-(4-chloro-2-fluorophenyl)-N-(5- hydroxy-2-methoxypyridin-4-yl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxamide (6a) (35 mg, 0.074 mmol, 1 eq.) at rt. The reaction mixture was heated to 80 °C and stirred for 1 h. The mixture was cooled to rt and purified by reversed-phase flash chromatography and Prep- HPLC to afford Compound 6 as a yellow solid (4.2 mg, 12% yield).1H NMR (400 MHz, Chloroform-d) 5 8.56 (d, J= 0.9 Hz, 1H), 7.68 (t, J= 8.1 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.19 - 7.11 (m, 2H), 3.99 (s, 3H), 2.74 (s, 3H), 2.41 (s, 3H). LCMS ESI-MS m / z: = 452 [M+H]+.Example 7: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-fluorooxazolo[4,5-c]pyridin-2- yl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Compound 7)

[0360] Compound 7a was synthesized using 5-amino-2-fluoropyridin-4-ol (150 mg, 1.17 mmol, 1.6 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) (252 mg, 0.726 mmol, 1 eq.) by following the procedure from Compound la to afford Compound 7a as a red solid (80 mg, 15% yield).

[0361] Compound 7 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(6-fluoro-4- hydroxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (7a) (80 mg, 0.175 mmol) by following the procedure from Compound 1 to afford Compound 7 as a white solid (9.7 mg, 12% yield).1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.00 - 7.91 (m, 2H), 7.80 (d, J= 2.4 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.58 (s, 1H), 2.64 (s, 3H), 2.41 (s, 3H).19F NMR: (376 MHz, DMSO-d6): 6 -70.2, -119.1. LCMS ESI-MS m / z: = 440 [M+H]+.Example 8: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound

[0362] To a stirred solution of 4-chloro-5-nitro-2-(trifluoromethyl)pyridine (500 mg, 2.2 mmol, 1 eq.) and (4-methoxyphenyl)methanethiol (340 mg, 2.2 mmol, 1 eq.) in THF (10 mL) was added NaH (63.6 mg, 2.64 mmol, 1.2 eq.) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was warmed to rt and stirred for 1 h. The reaction was quenched with ice water (10 mL) at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers were driedover anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford Compound 8a as a yellow solid (700 mg, 86% yield).

[0363] To a stirred solution of 4-((4-methoxybenzyl)thio)-5-nitro-2-(trifluoromethyl)pyridine (8a) (350 mg, 1.01 mmol, 1 eq.) and SnCl22H2O (2.31 g, 10.1 mmol, 1 eq.) in ether (3.5 mL) was added cone. HC1 (3.5 mL) dropwise at 0 °C. The resulting mixture was warmed to rt and stirred for 1 h. The reaction was quenched with ice water (10 mL) at 0 °C. The residue was basified to pH 8-9 with NaOH (solid). The resulting mixture was filtered, and the filter cake was washed with EA (2 x 7 mL). The filtrate was extracted with EA (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford Compound 8b as an off-white solid (310 mg, 91% yield).

[0364] To a stirred solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2- c]pyridazine-3-carboxylic acid (Int-1) (60 mg, 0.17 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (65.1 mg, 0.20 mmol, 1.2 eq.) in Py (2.5 mL) was added POCI3 (52.9 mg, 0.34 mmol, 2 eq.) dropwise at 0 °C. The resulting mixture was stirred for 1 h at 0 °C and then was quenched with ice water (3 mL) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 x 4 mL) to afford Compound 8c as a light-yellow solid (98 mg, 83% yield).

[0365] A solution of l-(4-chloro-2-fluorophenyl)-N-(4-((4-methoxybenzyl)thio)-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (8c) (50 mg, 0.07 mmol) in TFA (5 mL) was stirred for 3 h at 80 °C. The resulting mixture was cooled to rt, concentrated under reduced pressure and the residue was diluted with water (2 mL). The resulting mixture was basified pH 8-9 with saturated NaHCCf and then diluted with MeOH (2 mL). The mixture was purified by reversed-phase flash chromatography to afford Compound 8 as an off-white solid (35.5 mg, 88% yield).1H NMR (300 MHz, DMSO- d6) δ 9.48 (s, 1H), 8.92 (d, J= 1.0 Hz, 1H), 8.07 - 7.93 (m, 2H), 7.74 - 7.61 (m, 2H), 2.64 (s, 3H), 2.42 (s, 3H). LCMS ESI-MS m / z: = 506 [M+H]+.Example 9: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 9)

[0366] To a stirred solution of DMF (2.1 g, 29.6 mmol, 10 eq.) in DCE (14 mL) was added oxalyl chloride (1.4 g, 11.5 mmol, 4 eq.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 5 min at 0 °C. To the stirred mixture was added 6- (trifluoromethyl)-lH-[l,3]thiazolo[5,4-c]pyridine-2-thione (700 mg, 2.9 mmol, 1 eq.) in portions at 0 °C and the resulting mixture was stirred at 70 °C for 2 h. The reaction was quenched with water (15 mL) at rt. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 9a as an off-white solid (600 mg, 85% yield).

[0367] A solution of 2-chloro-6-(trifluoromethyl)-[l,3]thiazolo[5,4-c]pyridine (9a) (600 mg, 2.5 mmol, 1 eq.), H2PO3 (1.2 mL) and KI (835 mg, 5.0 mmol, 2 eq.) in AcOH (12 mL) was stirred for 30 min at 80 °C under a nitrogen atmosphere. The mixture was basified to pH 9 with saturated Na2CO3(aq.). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 9b as an off-white solid (400 mg, 78% yield).

[0368] To a stirred solution of 6-(trifluoromethyl)-[l,3]thiazolo[5,4-c]pyridine (9b) (200 mg, 0.98 mmol, 1 eq.) in tetrahydrofuran (4 mL) was added n-BuLi (0.5 mL, 1.2 mmol, 2.5 M in hexane) dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C. To the above mixture was added ZnCl2(5.4 mL, 3.8 mmol, 0.7 M in THF, 3.9 eq.) dropwise at -78 °C. The resulting mixture was stirred for an additional 1 h at -78 °C. Then the resulting mixture was allowed to warm to -10 °C. The resulting mixture containing Compound 9c (around 10 mL) was used in the next step directly without further purification.

[0369] To a stirred solution of 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrido[3,2- c]pyridazin-4-one (Int-2) (100 mg, 0.26 mmol, 1 eq.) and Pd(PPh3)4(30.2 mg, 0.026 mmol, 0.1 eq.) in THF (10 mL) was added chloro[6-(trifluoromethyl)-[l,3]thiazolo [5,4-c]pyridin-2-yl]zinc (9c) (10 mL, from previous step) dropwise at rt under a nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred for 1 h. Then the resulting mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, reverse phase and Prep-HPLC to afford Compound 9 as a white solid (3.2 mg, 2.3% yield).1HNMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.50 (s, 1H), 7.94 - 7.82 (m, 2H), 7.67 - 7.60 (m, 1H), 7.54 (s, 1H), 2.65 (s, 3H), 2.42 (s, 3H). LCMS ESI-MS m / z: = 506 [M+H]+.Example 10: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-methoxythiazolo[4,5- c]pyridin-2-yl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Compound 10)

[0370] Compound 10a was synthesized using 4-chloro-2-methoxy-5-nitropyridine (800 mg, 4.2 mmol, 1 eq.) and PMB-SH (654 mg, 4.2 mmol, 1 eq.) by following the procedure from Compound 8a to afford Compound 10a as a light-yellow solid (1.2 g, 92% yield).

[0371] Compound 10b was synthesized using 2 -methoxy -4-((4-methoxybenzyl)thio)-5- nitropyridine (10a) (1.2 g, 3.92 mmol) by following the procedure from Compound 8b to afford Compound 10b as a grey solid (1.1 g, crude).

[0372] Compound 10c was synthesized using 6-methoxy-4-((4-methoxybenzyl)thio)pyridin-3- amine (10b) (47.7 mg, 0.17 mmol, 1.2 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido [3, 2-c] pyridazine-3 -carboxylic acid (Int-1) (50 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 10c as a brown solid (90 mg, 98% yield).

[0373] Compound 10 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(6-methoxy-4-((4- methoxybenzyl)thio)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (10c) (50 mg, 0.08 mmol) by following the procedure from Compound 8 to afford Compound 10 as a light-yellow solid (7 mg, 18% yield).1H NMR (300 MHz, Chloroform-d) 5 9.13 (d, J= 0.9 Hz, 1H), 7.69 (t, J= 8.1 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.33 (d, J= 0.9 Hz, 1H), 7.18 (s, 1H), 4.07 (s, 3H), 2.79 (s, 3H), 2.49 - 2.43 (m, 3H). LCMS ESI-MS m / z: = 468 [M+H]+.Example 11: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)-l,5-naphthyridin-4(lH)-one (Compound 11)

[0374] To a stirred solution of 5-bromo-2-(trifluoromethyl)pyridin-4-amine (2 g, 8.3 mmol, 1 eq.) and CS2CO3 (5.42 g, 16.6 mmol, 2 eq.) in DMSO (80 mL) was added PMB-SH (2.56 g, 16.6 mmol, 2 eq.) dropwise at rt. The resulting mixture was stirred at 25 °C under light conditions for 16 h and then was concentrated under reduced pressure. The residue was diluted with water (100 mL) and the resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA to afford Compound Ila as a yellow solid (520 mg, 19% yield).

[0375] Compound 11b was synthesized using l-(4-chloro-2-fhiorophenyl)-6,7-dimethyl-4-oxo- l,5-naphthyridine-3-carboxylic acid (Int-3) (55 mg, 0.16 mmol, 1 eq.) and 5-(((4- methoxyphenyl)methyl)sulfanyl)-2-(trifluoromethyl)pyridin-4-amine (Ila) (50 mg, 0.16 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 11b as a yellow solid (45 mg, 44% yield).

[0376] A solution of l-(4-chloro-2-fluorophenyl)-A-(4-([(4-methoxyphenyl)methyl]sulfanyl)-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxocinnoline-3-carboxamide (11b) (45 mg, 0.07 mmol) in TFA (5 mL) was irradiated with microwave radiation for 10 min at 140 °C. The resulting mixture was cooled down to rt and concentrated under reduced pressure. The residue was basified pH 8-9 with saturated NaHCCL. The resulting mixture was extracted with CH2CI2 (3 x 15mL) and dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford Compound 11 as an off-white solid (8 mg, 23% yield).1H NMR (400 MHz, Chloroform-d) 5 9.36 (s, 1H), 9.06 (s, 1H), 8.14 (d, J= 0.9 Hz, 1H), 7.74 (t, J= 8.1 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.09 (s, 1H), 2.75 (s, 3H), 2.36 (s, 3H). LCMS ESI-MS m / z: = 505 [M+H]+.Example 12: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)-l,5-naphthyridin-4(lH)-one (Compound 12)

[0377] Compound 12a was synthesized by l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxoquinoline-3-carboxylic acid (Int-3) (50 mg, 0.14 mmol, 1 eq.) and 4-([(4- methoxyphenyl)methyl]sulfanyl)-6-(trifluoromethyl)pyridin-3-amine (8b) (45.3 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 12a as a brown solid (25.2 mg), which was used in the next step directly without further purification.

[0378] Compound 12 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-(((4- methoxyphenyl)methyl)sulfanyl)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,5- naphthyridine-3 -carboxamide (12a) (25.2 mg, 0.039 mmol) by following the procedure from Compound 11 to afford Compound 12 as an off-white solid (17 mg, 23% yield (2 steps)).1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.22 (s, 1H), 8.83 (s, 1H), 8.06 (t, J= 8.4 Hz, 1H), 7.93 (dd, J= 9.9, 2.3 Hz, 1H), 7.75 - 7.65 (m, 1H), 7.44 (s, 1H), 2.61 (s, 3H), 2.37 (s, 3H). LCMS ESI-MS m / z: = 505 [M+H]+.Example 13: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thieno[3,2-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 13)Compound 13

[0379] To a stirred mixture of 4-chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde (2 g, 9.54 mmol, 1 eq.) and methyl thioglycolate (1.01 g, 9.54 mmol, 1 eq.) in DCM (50 mL) was added TEA (1.93 g, 19.1 mmol, 2 eq.) dropwise at rt. The mixture was stirred for 5 h at rt and wasdiluted with water (30 mL). The resulting mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford Compound 13a as a light yellow solid (2.6 g, 99% yield).

[0380] To a stirred mixture of methyl 6-(trifluoromethyl)thieno[3,2-c]pyridine-2-carboxylate (13a) (2.6 g, 9.95 mmol, 1 eq.) in THF (19.5 mL) and H2O (6.5 mL) was added LiOH (0.36 g, 14.9 mmol, 1.5 eq.) at rt. The reaction mixture was stirred for 30 min at rt. The resulting mixture was diluted with water (80 mL) and was allowed to cool down to 0 °C. The mixture was acidified to pH=3 with HC1 (4 M). The precipitated solids were collected by filtration and washed with water (3 x 5 mL) to afford Compound 13b as a light grey solid (2.18 g, 88% yield).

[0381] To a stirred mixture of 6-(trifluoromethyl)thieno[3,2-c]pyridine-2-carboxylic acid (13b) (1.5 g, 6.07 mmol, 1 eq.) and Ag2CO3(167 mg, 0.607 mmol, 0.1 eq.) in DMSO (7.5 mL) were added AcOH (18.2 mg, 0.303 mmol, 0.05 eq.) at rt under nitrogen atmosphere. The reaction mixture was heated to 120 °C and stirred for 2 h. The mixture was allowed to cool down to rt and then was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 13c as an oyster white solid (1.06 g, 85% yield).1HNMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.74 (s, 1H), 8.18 (d, J= 5.4 Hz, 1H), 7.78 (dd, J= 5.4, 0.8 Hz, 1H).

[0382] To a stirred solution of 6-(trifluoromethyl)thieno[3,2-c]pyridine (13c) (500 mg, 2.46 mmol, 1 eq.) in THF (10 mL) was added LDA (1.8 mL, 0.017 mmol, 2M in THF) dropwise at - 78 °C under nitrogen atmosphere. The mixture was stirred for 30 min at -78 °C. Then Bu3SnCl (1.2 g, 3.69 mmol, 1.5 eq.) was added into above mixture at -78 °C. The mixture was allowed to warm to rt and was stirred for 2 h. The reaction was quenched with sat. NH4CI (aq.) at rt and was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 13d as a light yellow oil (1.03 g, 85% yield).

[0383] To a stirred mixture of 2-(tributylstannyl)-6-(trifluoromethyl)thieno[3,2-c]pyridine (13d) (203 mg, 0.412 mmol, 1.43 eq.) and 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-2) (110 mg, 0.288 mmol, 1 eq.) in toluene (2 mL) was added Pd(PPh3)4(47.7 mg, 0.041 mmol, 0.1 eq.) at rt under nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred for 1 h. The mixture was allowed to cooldown to rt and was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography, silica gel column chromatography and slurry with n-hexane to afford Compound 13 as a light yellow solid (6.2 mg, 2% yield).1H NMR (300 MHz, Chloroform-de) 8 9.22 (s, 1H), 8.87 (s, 1H), 8.17 (s, 1H), 7.65 (d, J= 92 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.15 (s, 1H), 2.76 (s, 3H), 2.43 (s, 3H). LCMS ESI-MS m / z: = 505 [M+H]+.Example 14: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(5- (trifluoromethyl)thieno[2,3-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 14)Compound 14

[0384] To a stirred solution of 5-chloro-2-(trifluoromethyl)pyridine-4-carbaldehyde (1.5 g, 7.16 mmol, 1 eq.) and methyl thioglycolate (0.76 g, 7.16 mmol, 1 eq.) in DCM (37.5 mL) was added TEA (1.45 g, 14.3 mmol, 2 eq.) at rt. The reaction mixture was stirred for 1 h at rt. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (37.5 mL) and to the mixture was added K2CO3 (1.48 g, 10.7 mmol, 1.5 eq.) at rt. The resulting mixture was stirred for an additional 2 h at rt. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford Compound 14a as a yellow solid (2.2 g, 94% yield).

[0385] Compound 14b was synthesized using methyl 5-(trifluoromethyl)thieno[2,3-c]pyridine- 2-carboxylate (14a) (2.2 g, 8.42 mmol) by following the procedure from Compound 13b to afford Compound 14b as an off-white solid (1.24 g, 59% yield).

[0386] Compound 14c was synthesized using 5-(trifluoromethyl)thieno[2,3-c]pyridine-2- carboxylic acid (14b) (1 g, 4.04 mmol) by following the procedure from Compound 13c to afford Compound 14c as an off-white solid (680 mg, 82% yield).

[0387] Compound 14d was synthesized using 5-(trifluoromethyl)thieno[2,3-c]pyridine (14c) (630 mg, 3.1 mmol) by following the procedure from Compound 13d to afford Compound 14d as a light yellow oil (1.2 g, 78% yield).

[0388] Compound 14 was synthesized using 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-2) (50 mg, 0.131 mmol, 1 eq.) and 2- (tributylstannyl)-5-(trifluoromethyl)thieno[2,3-c]pyridine (14d) (90.1 mg, 0.183 mmol, 1.4 eq) by following the procedure from Compound 13 to afford Compound 14 as a light yellow solid (14 mg, 21% yield).1HNMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.69 (d, J= 0.8 Hz, 1H), 8.50 (d, J= 1.0 Hz, 1H), 8.03 - 7.91 (m, 2H), 7.70 (ddd, J= 8.6, 2.3, 1.1 Hz, 1H), 7.56 (t, J= 1.6 Hz, 1H), 2.63 (s, 3H), 2.40 (d, J= 1.0 Hz, 3H). LCMS ESI-MS m / z: = 505 [M+H]+.Example 15: Preparation of l-(3,4-dichlorophenyl)-3-(6-methoxyoxazolo[4,5-c]pyridin-2- yl)-6,7-dimethylpyrido[3,2-c]pyridazin-4(lH)-one (Compound 15)

[0389] Compound 15a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (45 mg, 0.124 mmol, 1 eq.) and 5-amino- 2-methoxypyridin-4-ol (20.8 mg, 0.149 mmol, 1.2 eq.) by following the procedure from Compound 4a. The precipitated solids of Compound 15a were collected by filtration and washed with water (3 x 3 mL) to afford Compound 15a as a light-yellow solid (49 mg, 76% yield).

[0390] Compound 15 was synthesized using l-(3,4-dichlorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxamide (15a) (45 mg, 0.093 mmol) by following the procedure from Compound 1. The residue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 5 mL) to afford Compound 15 as a yellow solid (25.3 mg, 58% yield).1H NMR (300 MHz, Chloroform-d) 5 8.76 (s, 1H), 7.75 (dd, J= 5.5, 3.0 Hz, 2H), 7.59 (dd, J= 8.6, 2.5 Hz, 1H), 7.31 (s, 1H), 6.94 (s, 1H), 4.03 (s, 3H), 2.73 (s, 3H), 2.41 (s, 3H). LCMS ESI-MS m / z: = 468 [M+H]+.Example 16: Preparation of l-(3,4-dichlorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[5,4-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 16)

[0391] Compound 16a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (127 mg, 0.348 mmol, 1 eq.) and 4-amino- 6-(trifluorom ethyl)pyri din-3 -ol (100 mg, 0.561 mmol, 1.6 eq.) by following the procedure from Compound 4a to afford Compound 16a as a red solid (60 mg, 20% yield).

[0392] Compound 16 was synthesized using l-(3,4-dichlorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (16a) (60 mg, 0.114 mmol) by following the procedure from Compound 6 to afford Compound 16 as a white solid (0.9 mg, 2% yield).1H NMR (300 MHz, DMSO-d6) 5 9.37 (s, 1H), 8.55 (d, J= 1.0 Hz, 1H), 8.19 (d, J= 2.4 Hz, 1H), 8.02 (d, J= 8.5 Hz, 1H), 7.82 (dd, J= 8.6, 2.4 Hz, 1H), 7.64 (s, 1H), 2.64 (s, 3H), 2.40 (s, 3H).19F NMR (376 MHz, DMSO- d6) δ -64.9. LCMS ESI-MS m / z: = 506 [M+H]+.Example 17: Preparation of l-(3,4-dichlorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[4,5-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 17)

[0393] Compound 17a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (80 mg, 0.22 mmol, 1 eq.) and 5-amino-2- (trifluoromethyl)pyridin-4-ol (39.1 mg, 0.22 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 17a as a white solid (60 mg, 47% yield).

[0394] Compound 17 was synthesized using l-(3,4-dichlorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (17a) (55 mg, 0.105 mmol) by following the procedure from Compound 1. Theresidue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 2 mL) to afford Compound 17 as a white solid (24.1 mg, 43% yield).1HNMR (300 MHz, Chloroform-d) 5 9.31 (s, 1H), 8.04 (s, 1H), 7.82 - 7.75 (m, 2H), 7.52 (dd, J= 8.5, 2.4 Hz, 1H), 7.38 (s, 1H), 2.77 (s, 3H), 2.46 (s, 3H). LCMS ESI-MS m / z: = 506 [M+H]+.Example 18: Preparation of l-(3,4-dichlorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 18)

[0395] Compound 18a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (100 mg, 0.32 mmol, 1 eq.) and l-(3,4-dichlorophenyl)- 6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxylic acid (Int-4) (116 mg, 0.32 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 18a as a brown solid (70 mg, 28% yield).

[0396] To a stirred solution of l-(3,4-dichlorophenyl)-N-(5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (18a) (70 mg, 0.106 mmol) in TFA (7 mL) was irradiated with microwave radiation for 10 min at 100 °C, concentrated under reduced pressure and diluted with water (2 mL). The mixture was basified to pH 8-9 with saturated NaHCCL and extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography afford Compound 18 as a grey solid (14.1 mg, 25% yield).1HNMR (300 MHz, Chloroform-d) 5 9.46 (s, 1H), 8.43 (s, 1H), 7.90 - 7.74 (m, 2H), 7.53 (dd, J= 8.5, 2.5 Hz, 1H), 7.40 (s, 1H), 2.79 (s, 3H), 2.47 (s, 3H). LCMS ESI-MS m / z: = 522 [M+H]+.Example 19: Preparation of l-(3,4-dichlorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 19)

[0397] Compound 19a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (50 mg, 0.137 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (43.2 mg, 0.137 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 19a as a yellow solid (55 mg, 88% yield).

[0398] Compound 19 was synthesized using l-(3,4-dichlorophenyl)-N-(4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4- dihydropyrido[3,2-c]pyridazine-3 -carboxamide (19a) (50 mg, 0.17 mmol) by following the procedure from Compound 8 to afford Compound 19 as an off-white solid (5.0 mg, 12% yield).1HNMR (400 MHz, DMSO ) 8 9.43 (s, 1H), 8.79 (s, 1H), 8.11 - 8.06 (m, 1H), 7.94 (d, J= 8.5 Hz, 1H), 7.76 (dd, J= 8.6, 2.5 Hz, 1H), 7.59 (s, 1H), 2.64 (s, 3H), 2.40 (s, 3H). LCMS ESI-MS m / z: = 522 [M+H]+.Example 20: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6-(trifluoromethyl)oxazolo[4,5-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one(Compound 20)

[0399] Compound 20a was synthesized was using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxo-1, 4-dihydropyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (97.9 mg, 0.281 mmol, 1 eq.) and 5-amino-2-(trifluoromethyl)pyridin-4-ol (50 mg, 0.281 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 20a as a dark green solid (22 mg, 15% yield).

[0400] Compound 20 was synthesized by using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyri din-3 -yl)-6,7-dimethyl-4-oxo- 1 ,4-dihydropyrazino[2,3 -c]pyridazine-3 -carboxamide (20a) (20 mg, 0.039 mmol) by following the procedure from Compound 6 to afford Compound 20 as a white solid (1.3 mg, 6% yield).1H NMR (300 MHz, Chloroform-d) 5 9.41 (s, 1H), 8.63 (s, 1H), 7.91 - 7.80 (m, 2H), 7.64 (dd, J= 8.9, 2.3 Hz, 1H), 2.73 (s, 3H), 2.61 (s, 3H). LCMS ESI-MS m / z: = 491 [M+H]+.Example 21: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[5,4-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one(Compound 21)

[0401] Compound 21a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (150 mg, 0.431 mmol, 1 eq.) and 4- amino-6-(trifluoromethyl) pyridin-3-ol (120 mg, 0.674 mmol, 1.5 eq.) by following the procedure from Compound 4a to afford Compound 21a as a brown solid (60 mg, 17% yield).

[0402] Compound 21 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo- 1 ,4-dihydropyrazino[2,3 -c]pyridazine-3 - carboxamide (21a) (50 mg, 0.098 mmol) by following the procedure from Compound 6 to afford Compound 21 as a light-yellow solid (1.1 mg, 4% yield).1HNMR (400 MHz, DMSO- d6) δ 9.41 (s, 1H), 8.61 (d, J= 1.0 Hz, 1H), 7.92 - 7.82 (m, 2H), 7.64 (dd, J= 8.7, 2.3 Hz, 1H), 2.74 (s, 3H), 2.61 (s, 3H).19F NMR (376 MHz, DMSO-d6) 6 -64.9, -116.8. LCMS ESI-MS m / z: = 491 [M+H]+.Example 22: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-methoxyoxazolo[4,5- c]pyridin-2-yl)-6,7-dimethylpyrazino[2,3-c]pyridazin-4(lH)-one (Compound 22)

[0403] Compound 22a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (80 mg, 0.23 mmol, 1 eq.) and 5-amino- 2-methoxypyridin-4-ol (48.2 mg, 0.34 mmol, 1.5 eq.) by following the procedure from Compound 4a to afford Compound 22a as a yellow solid (50 mg, 46% yield).

[0404] Compound 22 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrazino[2,3-c]pyridazine-3-carboxamide (22a) by following the procedure from Compound 6 to afford Compound 22 as a yellow solid (10.8 mg, 33% yield).1HNMR (300 MHz, DMSO-d6) δ 8.81 (d, J= 0.9 Hz, 1H), 7.92 - 7.78 (m, 2H), 7.67 - 7.57 (m, 1H), 7.29 (d, J= 0.8 Hz, 1H), 3.95 (s, 3H), 2.72 (s, 3H), 2.59 (s, 3H). LCMS ESI-MS m / z: = 453 [M+H]+.Example 23: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one(Compound 23)

[0405] Compound 23a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (50 mg, 0.143 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (45.1 mg, 0.143 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 23a as an off-white solid (85 mg, 88% yield).

[0406] Compound 23 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4- dihydropyrazino[2,3-c]pyridazine-3 -carboxamide (23a) (80 mg, 0.07 mmol) by following the procedure from Compound 8 to afford Compound 23 as an off-white solid (38 mg, 56% yield).1H NMR (400 MHz, DMSO-d6) 6 9.48 (s, 1H), 8.81 (s, 1H), 7.86 - 7.78 (m, 1H), 7.74 (dd, J = 9.8, 2.3 Hz, 1H), 7.57 (dd, J = 8.6, 2.4, 1.2 Hz, 1H), 2.73 (s, 3H), 2.60 (s, 3H). LCMS ESI-MS m / z: = 507 [M+H]+.Example 24: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one (Compound 24)

[0407] Compound 24a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (100 mg, 0.32 mmol, 1 eq.) and l-(4-chloro-2- fluorophenyl)-6,7-dimethyl-4-oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (111 mg, 0.32 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 24a as a brown solid (70 mg, 34% yield).

[0408] Compound 24 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-((4- methoxybenzyl)thio)-2-(trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4- dihydropyrazino[2,3-c]pyridazine-3 -carboxamide (24a) (70 mg, 0.11 mmol) by following the procedure from Compound 18 and reacting at 120 °C for 10 min to afford Compound 24 as a light-yellow solid (12.3 mg, 22% yield).1HNMR (300 MHz, Chloroform-d) 5 9.47 (s, 1H), 8.49 (d, J= 1.0 Hz, 1H), 7.65 (dd, J= 8.5, 7.6 Hz, 1H), 7.51 - 7.34 (m, 2H), 2.87 (s, 3H), 2.71 (s, 3H). LCMS ESI-MS m / z: = 507 [M+H]+.Example 25: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-on (Compound 25)

[0409] Compound 25a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (100 mg, 0.29 mmol, 1 eq.) and 6- (trifluoromethyl)pyridine-3,4-diamine (61 mg, 0.34 mmol, 1.2 eq.) by following the procedure from Compound la to afford Compound 25a as a solid (90 mg, crude).

[0410] A solution of N-[5-amino-2-(trifluoromethyl)pyridin-4-yl]-l-(4-chloro-2-fluorophenyl)- 6,7-dimethyl-4-oxopyrazino[2,3-c]pyridazine-3-carboxamide (25a) (90 mg, 0.177 mmol) in AcOH (1.8 mL) was irradiated with microwave radiation for 10 min at 140 °C. The reaction mixture was cooled down to rt and then was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford Compound 25 as an off-white solid (34.7 mg, 24% yield (2 steps)). ‘HNMR (400 MHz, DMSO-d6) 5 13.59 (s, 1H), 9.15 (s, 1H), 8.17 (s, 1H), 7.96 - 7.77 (m, 2H), 7.69 - 7.54 (m, 1H), 2.74 (s, 3H), 2.61 (s, 3H). LCMS ESI-MS m / z: = 490 [M+H]+.Example 26: Preparation of l-(4-chloro-2-fluorophenyl)-3-(6-methoxyoxazolo[4,5- c]pyridin-2-yl)-6,7-dimethylcinnolin-4(lH)-one (Compound 26)

[0411] Compound 26a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (lnt-8) (45 mg, 0.13 mmol, 1 eq.) and 5-amino-2- methoxypyridin-4-ol (21.8 mg, 0.16 mmol, 1.2 eq.) by following the procedure from Compound 4a. The precipitated solids were collected by filtration and washed with water (3 x 3 mL) to afford Compound 26a as a yellow solid (47 mg, 73% yield).

[0412] Compound 26 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (26a) (45 mg, 0.096 mmol) by following the procedure from Compound 1. The residue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 5 mL) to afford Compound 26 as an off-white solid (22.1 mg, 50% yield).1H NMR (300 MHz, Chloroform-d) 5 8.75 (d, J= 0.9 Hz, 1H), 8.27 (s, 1H), 7.58 (dd, J= 8.8, 7.7 Hz, 1H), 7.49 - 7.38 (m, 2H), 6.93 (d, J= 0.9 Hz, 1H), 6.81 (t, J= 1.5 Hz, 1H), 4.02 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H). LCMS ESI-MS m / z: = 451 [M+H]+.Example 27: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[5,4-c]pyridin-2-yl)cinnolin-4(lH)-one (Compound 27)

[0413] Compound 27a was synthesized using l-(4-chloro-2-fhiorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (lnt-8) (84.5 mg, 0.244 mmol, 1 eq.) and 4-amino-6- (trifluorom ethyl)pyri din-3 -ol (70 mg, 0.393 mmol, 1.6 eq.) by following the procedure from Compound 4a to afford Compound 27a as a brown solid (30 mg, 15% yield).

[0414] Compound 27 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (27a) (30 mg, 0.059 mmol) by following the procedure from Compound 1 to afford Compound 27 asa white solid (4.1 mg, 14% yield).1H NMR (400 MHz, DMSO-d6) 8 9.35 (s, 1H), 8.54 (d, J= 1.0 Hz, 1H), 8.13 (s, 1H), 8.01 - 7.93 (m, 2H), 7.73 - 7.66 (m, 1H), 7.13 (s, 1H), 2.43 (s, 3H), 2.37 (s, 3H).19F NMR: (376 MHz, DMSO-d6): δ -64.9, -119.4. LCMS ESI-MS m / z: = 489 [M+H]+.Example 28: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[4,5-c]pyridin-2-yl)cinnolin-4(lH)-one (Compound 28)lnt-8 28a Compound 28

[0415] Compound 28a was synthesized using 5-amino-2-(trifluoromethyl)pyridin-4-ol (30 mg, 0.168 mmol, 1 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxocinnoline-3-carboxylic acid (lnt-8) (58.4 mg, 0.168 mmol, 1 eq.) by following the procedure from Compound 4a. The precipitated solids were collected by filtration and washed with water (3 x 1 mL) to afford Compound 28a as a yellow solid (40 mg, 43% yield).

[0416] Compound 28 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (28a) (16 mg, 0.032 mmol) by following the procedure from Compound 1 to afford Compound 28 as a white solid (3.4 mg, 21% yield).1H NMR (300 MHz, Chloroform-d) δ 9.35 (s, 1H), 8.58 (s, 1H), 8.11 (s, 1H), 8.01 - 7.93 (m, 2H), 7.69 (dd, J = 8.9, 2.3 Hz, 1H), 7.11 (s, 1H), 2.42 (s, 3H), 2.36 (s, 3H). LCMS ESI-MS m / z: = 489 [M+H]+.Example 29: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6-(trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)cinnolin-4(lH)-one (Compound 29)

[0417] Compound 29a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (50 mg, 0.159 mmol, 1 eq.) and l-(4-chloro-2- fluorophenyl)-6,7-dimethyl-4-oxocinnoline-3-carboxylic acid (lnt-8) (55.2 mg, 0.159 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 29a as an off-white solid (65 mg, 55% yield).

[0418] Compound 29 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-((4- methoxybenzyl)thio)-2-(trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline- 3-carboxamide (29a) (60 mg, 0.093 mmol) by following the procedure from Compound 18 and reacting at 140 °C for 15 min to afford Compound 29 as an off-white solid (22.7 mg, 47% yield).1HNMR (400 MHz, Chloroform-d) 5 9.43 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.66 (t, J= 8.2 Hz, 1H), 7.53 - 7.43 (m, 2H), 6.95 - 6.90 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H). LCMS ESIMS m / z: = 505 [M+H]+.Example 30: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)cinnolin-4(lH)-one (Compound 30)Compound 30

[0419] Compound 30a was synthesized using l-(4-chloro-2-fhrorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (Int-8) (40 mg, 0.12 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (36.3 mg, 0.12 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 30a as a yellow solid (98 mg, 67% yield).

[0420] Compound 30 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline- 3-carboxamide (30a) (45 mg, 0.07 mmol) by following the procedure from Compound 8 to afford Compound 30 as an off-white solid (7.1 mg, 20% yield).1H NMR (400 MHz, DMSO-d6) 5 9.43 (s, 1H), 8.78 (s, 1H), 8.16 (s, 1H), 7.90 (t, J= 8.3 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 2.43 (s, 3H), 2.37 (s, 3H). LCMS ESI-MS m / z: = 505 [M+H]+.Example 31: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)-3H-imidazo[4,5-c]pyridin-2-yl)cinnolin-4(lH)-one (Compound 31)

[0421] Compound 31a was synthesized using l-(4-chloro-2-fhrorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (Int-8) (100 mg, 0.29 mmol) and 6-(trifluoromethyl)pyridine-3,4-diamine (61 mg, 0.35 mmol) by following the procedure from Compound 4a and reacting at RT to afford Compound 31a as a yellow solid (90 mg, 59% yield).

[0422] Compound 31 was synthesized using N-(5-amino-2-(trifluoromethyl)pyridin-4-yl)-l-(4- chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (31a) (90 mg, 0.18 mmol) by following the procedure from Compound 25 to afford Compound 31 as a yellow solid (11.0 mg, 12% yield). ‘HNMR (300 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.11 (s, 1H), 8.19 - 8.09 (m, 2H), 8.03 - 7.87 (m, 2H), 7.68 (ddd, J= 8.6, 2.3, 1.1 Hz, 1H), 7.13 (s, 1H), 2.43 (s, 3H), 2.37 (s, 3H). LCMS ESI-MS m / z: = 488 [M+H]+.Example 32: Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-N-(2-methylpyridin- 4-yl)-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (Compound 32)Int-1 Compound 32

[0423] To a stirred solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2- c]pyridazine-3- carboxylic acid (Int-1) (50 mg, 0.15 mmol, 1 eq.), 2-methylpyridin-4-amine (21.6 mg, 0.22 mmol, 1.5 eq.), DMAP (26.4 mg, 0.22 mmol, 1.5 eq.), DIEA (55.8 mg, 0.43 mmol, 2.8 eq.) in THF (2.5 mL) was added T3P (146.4 mg, 0.24 mmol, 50 wt.%, 1.6 eq.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was heated to 60 °C and stirred for 2 h. The resulting mixture was cooled to rt. Desired product could be detected by LCMS. The resulting mixture was purified by reversed-phase flash chromatography to afford Compound 32 (50.1 mg, 99% yield).1HNMR (300 MHz, Chloroform-d) 5 12.42 (s, 1H), 8.47 (d, J= 5.7 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.56 (dd, J= 5.7, 2.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.24 (dd, J= 2.5, 1.2 Hz, 1H), 2.80 (s, 3H), 2.61 (s, 3H), 2.49 (d, J= 1.0 Hz, 3H).19F NMR (282 MHz, Chloroform-d): 5 -116.8. LCMS ESI-MS m / z: 438 [M+H]+.

[0424] Compounds 33-82 were synthesized using the coupling procedure as described in the Example 32 using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) and the appropriate amine.Example 33: Preparation of l-(4-chloro-2-fluorophenyl)-N-(2-fluoropyridin-4-yl)-6,7- dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (Compound 83)

[0425] To a stirred solution of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2- c]pyridazine-3-carboxylic acid (Int-1) (500 mg, 1.44 mmol, 1 eq.) and 2-fluoropyridin-4-amine (242 mg, 2.16 mmol, 1.5 eq.) in pyridine (25 mL) was added POCI3(441 mg, 2.88 mmol, 2 eq.) dropwise at -15 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional 30 min at -15 °C. The reaction was quenched with water (50 mL) at 0 °C and then concentrated under reduced pressure. The resulting mixture was diluted with MeCN (15 mL) and purified by reversed-phase chromatography to afford Compound 83 as a white solid (385.1 mg, 61% yield).1HNMR (400 MHz, Chloroform-d) δ 12.65 (s, 1H), 8.16 (d, J= 5.7 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.50 - 7.41 (m, 2H), 7.38 (dt, J= 5.8, 1.5 Hz, 1H), 7.25 - 7.20 (m, 1H), 2.78 (s, 3H), 2.48 (s, 3H), 2.03 - 1.98 (m, 2H). LCMS ESI-MS m / z: = 442 [M+H]+.

[0426] Compounds 84-104 were synthesized using the coupling procedure as described in the Example 33 using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1), l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,5-naphthyridine-3- carboxylic acid (Int-3), or l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4- dihydrocinnoline-3 -carboxylic acid (Int-8) and the appropriate amine.Example 34: Preparation of l-(4-chloro-2-fluorophenyl)-N-(2-fluoro-6-isopropylpyridin-4- yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (Compound105)

[0427] To a stirred solution of benzyl N-(2-chloro-6-fluoropyridin-4-yl)carbamate (900 mg, 3.21 mmol, 1 eq.), K2CO3 (1.33 g, 9.62 mmol, 3 eq.) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)- 1,3,2-dioxaborolane (593 mg, 3.53 mmol, 1.1 eq.) in dioxane (18 mL) was added Pd(PPh3)4(370 mg, 0.32 mmol, 0.1 eq.) at rt under nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight. The resulting mixture was cooled to rt, diluted with water (15 mL) and the organics were extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography to afford Compound 105a as a yellow solid (450 mg, 49% yield).

[0428] To a stirred solution of benzyl (2-fluoro-6-(prop-l-en-2-yl)pyridin-4-yl)carbamate (105a) (450 mg, 1.57 mmol) in MeOH (9 mL) were added Pd / C (45 mg, 10%wt.). The mixture was hydrogenated at rt under 30 psi of hydrogen pressure overnight, filtered through a celite pad and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to a brown solid. The residue was purified by reversed-phase chromatography to afford Compound 105b as a brown solid (200 mg, 82% yield).

[0429] Compound 56 was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-1) (94.7 mg, 0.23 mmol, 1 eq.) and 2-fluoro- 6-isopropylpyridin-4-amine (105b) (200 mg, 0.30 mmol, 1.3 eq.) by following the procedure from Compound 32 to afford Compound 105 as a yellow solid (30.3 mg, 15% yield).1H NMR (300 MHz, Chloroform-d) 5 12.53 (s, 1H), 7.63 (t, J= 8.3 Hz, 1H), 7.44 (ddd, J= 9.7, 7.7, 2.1 Hz, 2H), 7.35 (s, 1H), 7.28 - 7.19 (m, 2H), 2.98 (p, J= 6.9 Hz, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.30 (d, J= 6.9 Hz, 6H).19F NMR (282 MHz, Chloroform-d) 5 -67.0, -116.9. LCMS ESI-MS m / z: = 484 [M+H]+.Example 35: Preparation of l-(4-chloro-2-fluorophenyl)-N-(l,2-dimethyl-6-(2- methylpyridin-4-yl)piperidin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine- 3-carboxamide (Compound 106)

[0430] To a stirred solution of tert-butyl 2-iodo-6-methyl-4-oxo-5,6-dihydropyridine-l- carboxylate (920 mg, 2.7 mmol, 1 eq.), NaHCCL (573 mg, 6.8 mmol, 2.5 eq.), 2-methylpyridin- 4-ylboronic acid (448 mg, 3.3 mmol, 1.2 eq.) and Pd(PPh3)4(157 mg, 0.13 mmol, 0.05 eq.) in DME / H2O = 18.4 mL / 9.2 mL at rt under nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred overnight. The resulting mixture was cooled to rt, poured into water (100 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to brown oil. The residue was purified by reversed phase chromatography to Compound 106a as an off-white solid (500 mg, 57% yield). LCMS ESI-MS m / z: = 303 [M+H]+.

[0431] To a stirred solution of tert-butyl 2',6-dimethyl-4-oxo-5,6-dihydro-[2,4'-bipyridine]-l- carboxylate (106a) (500 mg, 1.65 mmol) in DCM (2.5 mL) was added HCl / dioxane (4 M, 2.5 mL) at 0 °C under nitrogen atmosphere, warmed to rt and stirred for 2 h. The resulting mixture was concentrated under reduced pressure to afford Compound 106b as an off-white solid (250 mg), which was used in the next step directly without further purification. LCMS ESI-MS m / z: = 203 [M+H]+.

[0432] To a solution of 2',6-dimethyl-5,6-dihydro-lH-[2,4'-bipyridin]-4-one hydrochloride (106b) (205 mg, 0.85 mmol, 1 eq.) and HCHO (51.5 mg, 1.71 mmol, 2 eq.) in MeOH (4.1 mL) was added Pd / C (20.5 mg, 10% wt.). The mixture was placed under 20 atm of H2 for 16 h at rt. The resulting mixture was filtered through a celite pad and concentrated under reduced pressure to afford a brown oil. The residue was purified by reversed-phase chromatography to afford Compound 106c as a brown solid (40 mg, 11% yield (2 steps)). LCMS ESI-MS m / z: = 221 [M+H]+.

[0433] To a stirred solution of l,2-dimethyl-6-(2-methylpyridin-4-yl)piperidin-4-ol (106c) (25 mg, 0.11 mmol, 1 eq.), phthalimide (20.03 mg, 0.13 mmol, 1.2 eq.), PPI13 (35.7 mg, 0.13 mmol, 1.2 eq.) and DIAD (27.5 mg, 0.136 mmol, 1.2 eq.) in T...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of F ormula (I) :Formula (I); or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5- or 6-membered heteroaryl ring or phenyl;X is N or C(R7); each R1is independently selected from halogen, -CN, -OR10, -SR10, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl;R8and R9are independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl;each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C(R7).

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R7is C1-6alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (la):Formula (la); wherein m is 0, 1, 2, or 3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb):Formula (lb) ; wherein m is 0, 1, or 2.

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

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R8is halogen.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R8is C1-6alkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

13. A compound of Formula (II):Formula (II); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); each R1is independently selected from halogen, -CN, -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)-, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11);R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R5groups; each R5is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-6cycloalkyl ring;R6is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, 2, or 3.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein X is N.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein X is C(R7).

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R7is C1-6alkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R4is C1-9heteroaryl optionally substituted with 1-4 R5groups.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is pyridyl optionally substituted with 1-4 R5groups.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R4is pyridyl substituted with 1 R5group.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl optionally substituted with 1-4 R5groups.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl substituted with 1 R5group.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, and each R13is independently selected from C1-6alkyl and C1-6haloalkyl.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:

27. A compound of Formula (III):221Formula (III); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7); ring A is a 5- or 6-membered heteroaryl ring or phenyl;ring B is a 5- or 6-membered heteroaryl ring or phenyl;Y is O, S, or N(R7a);Z is N or C(R7b); each R1and each R1ais independently selected from halogen, -CN, -OR10, -SR10, - N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one,two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R7, R7a, and R7bare independently selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -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; andp is 0, 1, 2, 3, or 4; wherein the compound of Formula (III) is not28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein X is C(R7) and R7is hydrogen.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein X is N.

30. The compound of claim 27, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Illa):Formula (Illa).

31. The compound of any one of claims 27-30, or a pharmaceutically acceptable salt thereof, wherein Y is O.

32. The compound of any one of claims 27-30, or a pharmaceutically acceptable salt thereof, wherein Y is S.

33. The compound of any one of claims 27-32, or a pharmaceutically acceptable salt thereof, wherein Z is N.

34. The compound of any one of claims 27-32, or a pharmaceutically acceptable salt thereof, wherein Z is C(H).

35. The compound of any one of claims 27-34, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-membered heteroaryl ring.

36. The compound of any one of claims 27-35, or a pharmaceutically acceptable salt thereof, wherein ring B is a pyridyl ring.

37. The compound of any one of claims 27-36, or a pharmaceutically acceptable salt thereof, wherein each R1ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl , C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl , and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.

38. The compound of any one of claims 27-37, or a pharmaceutically acceptable salt thereof, wherein each R1ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl.

39. The compound of any one of claims 27-38, or a pharmaceutically acceptable salt thereof, wherein p is 1.

40. The compound of any one of claims 27-39, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from:Formula (IV); or a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7);J is N, C(H), or C(R1); each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, Ci-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups; each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring;R7is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and m is 0, 1, or 2.

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

43. The compound of claim 41, or a pharmaceutically acceptable salt thereof, having the structure of Formula (Illa)Formula (IVb).

44. The compound of any one of claims 41-43, or a pharmaceutically acceptable salt thereof, wherein X is N.

45. The compound of any one of claims 41-43, or a pharmaceutically acceptable salt thereof, wherein X is C(R7) and R7is hydrogen.

46. A compound of Formula (V):Formula (V); or a pharmaceutically acceptable salt thereof, wherein: each R1is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), - C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11);R2is selected from C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-4 R3groups; each R3is independently selected from halogen, -CN, -OR10, C1-6alkyl, C1 -6haloalky 1, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11);R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups;each R5ais independently selected from halogen, -CN, -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)-, C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl , C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2- C1-9heteroaryl, wherein C1-3alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -CH2-C6- 10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5aare combined to form a C3-6cycloalkyl ring; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10and R11taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently 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 R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, 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, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; andm is 0, 1, 2, 3, or 4.

47. The compound of any one of claims 41-46, or a pharmaceutically acceptable salt thereof, wherein R4bis C1-9heteroaryl optionally substituted with 1-4 R5agroups, wherein the C1-9heteroaryl is a bicyclic heteroaryl.

48. The compound of any one of claims 41-47, or a pharmaceutically acceptable salt thereof, wherein R4bis C1-9heteroaryl substituted with 1 R5agroup, wherein the C1-9heteroaryl is a bicyclic heteroaryl.

49. The compound of any one of claims 41-48, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl , C2-9heterocycloalkyl, -OR10, and -S(O)2R13, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl , and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.

50. The compound of any one of claims 41-49, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, unsubstituted C3-6cycloalkyl, unsubstituted C2-9heterocycloalkyl, -OR10, and - S(O)2R13, each R10is independently selected from C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl , and each R13is independently selected from C1-6alkyl and C1-6haloalkyl.

51. The compound of any one of claims 41-50, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halogen, unsubstituted C1-6alkyl, C1-6haloalkyl, and -OR10, and each R10is independently selected from C1-6alkyl.

52. The compound of any one of claims 41-51, or a pharmaceutically acceptable salt thereof, wherein R4bis selected from:

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl optionally substituted with 1-4 R3groups.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 1-4 R3groups.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 1 or 2 R3groups.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halogen.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from C1-6alkyl.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein each R1is -CH3.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, wherein m is 2.

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

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

67. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof.

69. A method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof.

70. The method of claim 69, wherein the neurological disorder is a neurodegenerative disease.

71. The method of claim 70, wherein the neurodegenerative disease is Alzheimer’s disease, frontotemporal dementia, or amyotrophic lateral sclerosis.

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