Covalent SARM1 inhibitors

Abstract

This disclosure is drawn to covalent SARM1 inhibitors, compositions thereof, and associated methods, useful for inhibition of SARM1 activity and / or for treating or preventing neurological disorders.

Description

COVALENT SARM1 INHIBITORSCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 592,477 filed on October 23, 2023, and U.S. Provisional Patent Application No. 63 / 706,556 filed on October 11, 2024, each of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] Described herein are compounds and compositions, and associated methods, useful for inhibition of SARM1 activity and / or for treating or preventing a neurological disorder.BACKGROUND OF THE INVENTION

[0003] Aging constitutes the main risk factor for the development of neurodegenerative diseases. Axonal degeneration is an important pathological event in many neurodegenerative and neurological disorders, including peripheral neuropathy and traumatic brain injury (Gerdts, J. et al., Neuron, 2016, 89, 449-60). Axonal degeneration has also been implicated in, for example, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis, where degeneration precedes symptom onset and widespread neuronal loss (Kurowska, Z. et al., J. Parkinson’s Dis., 2016, 6, 703-07). While these neurological conditions have unique underlying etiologies, inhibition of axonal degeneration in the conditions’ early stages may slow or prevent their progression by preventing the loss of functional synapses and maintaining neuronal connectivity (Essuman, K. et al., Neuron, 2017 Mar. 22, 93(6), 1334-43).

[0004] Axonal degeneration after injury occurs both toward the proximal cell body (termed retrograde degeneration) and toward the distal axon terminal (termed Wallerian or orthograde degeneration) (Kanamori A. et al., Am. J. Pathol. 2012 Jul; 18 l(l):62-73). Wallerian degeneration, which occurs in that section of the axon that is distal to the site of injury, occurs after axonal injury’ in both the peripheral nervous system (PNS) and the central nervous system (CNS). Wallerian degeneration usually begins within 24-36 hours of a lesion. Prior to degeneration, the distal section of the axon tends to remain electrically excitable, while after injury, the axonal skeleton disintegrates and the axonal membrane breaks apart.

[0005] T lie processes of death of the cell body and degeneration of the axon are independent events. As alluded to above, evidence exists indicating that the degeneration of axons precedes clinical symptoms in neurodegenerative diseases and occurs before cell body loss. Thus, axonal degeneration constitutes an early event in pathological processes and provides a potential therapeutic target to treat neurodegeneration prior to neuronal cell death (Salvadores, N. et al., Front. Neurosci., 2017, 11, 451).

[0006] In view of the above, new modalities are needed for the treatment of neurological disorders such as neurodegenerative disease by the prevention of axonal degeneration.SUMMARY OF THE INVENTION

[0007] In one aspect is a compound of Formula (I’):Formula (F); or a pharmaceutically acceptable salt thereof, wherein: each Y is C(R3a)2; each Z is C(R3b)2;R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R3ais independently selected from hydrogen and C1-6alkyl; each R3bis independently selected from hydrogen and C1-6alkyl; each R4is independently selected from halogen, oxo, -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, -CTU-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-10aryl, -CF2-C1-10aryl, C1- 9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CTU-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -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, C1-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, and C1-9heteroaryl; n is 1 or 2; and p is 1, 2, or 3.

[0008] In another aspect described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R4is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted withone, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, and C1-9heteroaryl; n is 1 or 2; and p is 1, 2, or 3.

[0009] In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt thereof, having Formula (la):Formula (la).

[0010] In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt thereof, having Formula (lb):Formula (lb).

[0011] In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt thereof, having Formula (Ic):( )

[0012] In some embodiments is a compound of Formula (F), (F), (I), (la), (lb), or (Ic), wherein R1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (F), (F), (I), (la), (lb), or (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, - C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), (I), (la), (lb),or (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (I’), (I), (la), (lb), or (Ic), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CF2-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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3- ecycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is selected from:

[0013] In some embodiments is a compound of Formula (I’), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C i -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, - OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, - OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic),wherein R2is selected from:

[0014] In some embodiments is a compound of Formula (I’), (I), (la), (lb), or (Ic), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), - C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2.9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is C1-9heteroaryl substituted with 1- 5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C i -6haloalky 1, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is C1-9heteroaryl substituted with 1- 3 R5groups and each R5is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is unsubstituted C1-9heteroaryl. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R2is selected from. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R6is hydrogen. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I’), (I),(la), (lb), or (Ic), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R7is hydrogen and R8is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R7is hydrogen and R8is hydrogen. In some embodiments is a compound of Formula (F), (I), (la), (lb), or (Ic), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (F), (I), (la),(lb), or (Ic), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound ofcompound of Formula (F), (I), (la), (lb), or (Ic), wherein R9is hydrogen.

[0015] 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.

[0016] In another aspect is a method of inhibiting SARM1 comprising contacting the SARM1 with a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of inhibiting SARM1 comprising contacting the SARM1 with a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the contacting is carried out in vitro. In some embodiments is a method of inhibiting SARM1 comprising contacting the SARM1 with a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the contacting is carried out in vivo.

[0017] In another aspect is a method of inhibiting axonal degeneration in a patient in need thereof comprising administering to the patient an inhibiting amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of inhibiting axonal degeneration in a patient in need thereof comprising administering to the patient an inhibiting amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the axonal degeneration is caused by abnormal reduction or depletion of NAD+ in the axons.

[0018] In another aspect is a method of treating or preventing 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 someembodiments is a method of treating or preventing 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.

[0019] In some embodiments is a method of treating or preventing 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.

[0020] In some embodiments is a use of a compound described herein, or a pharmaceutically acceptable salt thereof, in treating or preventing a neurological disorder in a patient in need thereof.

[0021] In some embodiments is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating or preventing a neurological disorder in a patient in need thereof.DETAILED DESCRIPTION

[0022] Similar to programmed cell death pathways (e.g., apoptosis), axonal degeneration in response to injury or disease stimulates a local signaling cascade that causes destruction of the injured axon segment (Summers D. W., et al., PNAS USA, 2016 Oct 11, 113 (41 ):E6271— E6280). Following injury, the axonal skeleton disintegrates, and the axonal membrane breaks apart. Subsequent to axonal degeneration, the myelin sheath degrades and infiltration by macrophages follows; the macrophages, along with Schwann cells, clear the cellular debris resulting from the degeneration (Coleman M.P., et al., PNAS USA, 1998 Aug, 95( 17): 9985-90).

[0023] SARM1 (sterile alpha and TIR motif-containing 1) protein (NP 055892) is a 724 amino acid protein involved in axon degeneration. It has also been implicated in infectious and inflammatory disorders. The SARM1 protein, also known as FLJ36296, KIAA0524, MyD88-5, SAM domain-containing protein 2, and SAMD2, comprises four domains, i) a mitochondrial localization signal, ii) an auto-inhibitory N-terminus region consisting of armadillo / HEAT motifs, iii) two sterile alpha motifs responsible for multimerization, and iv) a C-terminus Toll / Interleukin-1 receptor that possesses enzymatic activity (Essuman K., et al., Neuron 2017 Mar., 93(6): 1334-43.e5).

[0024] SARM1 protein plays a critical role in the Wallerian degeneration pathway. Activation of SARM1 triggers a rapid collapse of NAD+levels in the distal section of the injured axon, which then undergoes degeneration (Gerdts J. et al., Science 2015 Apr. 348(6233):453-57).Promoting dimerization of the Toll / interleukin receptor (TIR) domain of SARM1 has been shown to be sufficient to promote NAD+loss and axon degeneration.

[0025] SARMl’s activity is responsible for, at least in part, the protective nature of the survival factor NMNAT2, as NMKNAT enzymes have been found to prevent SARM1 -mediated depletion of NAD+. Other pro-degeneration signaling pathways, including the MAP kinase pathway, have been linked to SARM1 activation. MAPK signaling has been shown to promote the loss of NMNAT2, which promotes SARM1 activation (See, e.g., Yang J. et al., C6ll 2015 Jan 160(1-2): 161-76).

[0026] SARM1 is involved in the innate immune response. It promotes neuronal cell death in response to stress and other stimuli. SARM1 acts as a negative regulator of TICAM1 / TRIF- dependent Toll-like receptor signaling by inhibiting induction of TLR3- and TLR4-dependent genes, which play a pivotal role in activating axonal degeneration following injury. In addition, SARM1 specifically blocks TICAM1 / TRIF -dep endent transcription factor activation and gene induction, without affecting the MYD88- dependent pathway or non-TLR signaling. It is also a negative regulator of NF- kappa-B and IRF activation. (See, e.g., Summers, D.W. et al., J Neurosci., 2014 Jul 9, 34(28):9338-50).

[0027] In some embodiments described herein are inhibitors of SARM1. SARM1 activation can cause a rapid reduction in NAD+levels in injured axons, which then undergo degeneration. In particular embodiments, the compounds inhibit axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+(e.g., inhibition of SARM1 NADase).

[0028] Further described herein are active-site SARM1 NAD hydrolase inhibitors. In some aspects, the inhibitors described herein act in the catalytic pocket but do not directly compete with substrate binding. In some aspects, the inhibitors are uncompetitive, pro-inhibitors that function by opportunistically intercepting the NAD hydrolysis reaction and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). In some embodiments, the resulting small molecule-ADPR adducts confer knock-out like axon protection in vivo - reducing levels of the translatable biomarker neurofilament light and conferring functional protection. In some embodiments, described herein is a mode of pharmacologic inhibition that has implications not just for SARM1 but for a broader panel of related NAD hydrolases linked to age-related decline and disease.Compounds

[0029] Compounds described herein, including pharmaceutically acceptable salts, active metabolites and pharmaceutically acceptable solvates thereof, are inhibitors of SARM1.

[0030] In some embodiments is a compound of Formula (I’):Formula (I’); or a pharmaceutically acceptable salt thereof, wherein: each Y is C(R3a)2; each Z is C(R3b)2;R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R3ais independently selected from hydrogen and C1-6alkyl; each R3bis independently selected from hydrogen and C1-6alkyl; each R4is independently selected from halogen, oxo, -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, -CF2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CF2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring;each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, C1-9heteroaryl, and -CH2-C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, 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 nitrogenatom 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, and C1-9heteroaryl; n is 1 or 2; and p is 1, 2, or 3.

[0031] In some embodiments is a compound of Formula (F), wherein each Y is CH2. In some embodiments is a compound of Formula (F), wherein each Z is CH2.

[0032] In some embodiments is a compound of Formula (F), wherein n is 1 and p is 1. In some embodiments is a compound of Formula (F), wherein n is 1 and p is 2. In some embodiments is a compound of Formula (F), wherein n is 2 and p is 2. In some embodiments is a compound of Formula (F), wherein n is 2 and p is 3.

[0033] In some embodiments is a compound of Formula (F), wherein R1is C1-10aryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (F), wherein R1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (F), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (F), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is acompound of Formula (I’), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (I’), wherein R1is phenyl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I’), wherein R1is phenyl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0034] In some embodiments is a compound of Formula (F), wherein R1is C1-9heteroaryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (I’), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (F), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R1is C1-9heteroaryl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R1is C1-9heteroaryl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0035] In some embodiments is a compound of Formula (F), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, - N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, - S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, -CF2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl,C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, - N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I’), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R2is selected fromFormula (I’), whereinsome embodiments is a compound of Formula(I’), whereinsome embodiments is a compound of Formula (F),

[0036] In some embodiments is a compound of Formula (F), wherein R2is selected from

[0037] In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C 1 -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I’), wherein R2is selected from:,2isn some embodiments is a compound of Formula (I’), wherein R2is

[0038] In some embodiments is a compound of Formula (F), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (I’), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (F), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula(F), wherein R2is selected from. In some embodiments is a compound of Formula (I’), wherein R2isIn some embodiments is a compound of Formula (I’), wherein

[0039] In some embodiments is a compound of Formula (F), wherein R2is selected fromcompound of Formula (I’), whereinsome embodiments is a compound of Formula (I’), whereinsome embodiments is a compound of Formula (I’), wherein

[0040] In some embodiments is a compound of Formula (F), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (I’), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (I’), wherein R3is -S(O)2C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (I’), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (I’), wherein R6is hydrogen. In some embodiments is a compound of Formula (I’), wherein R6is halogen. In some embodiments is a compound of Formula (I’), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is hydrogen. In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is C1-6alkyl substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R7is hydrogen and R8is - CH3.

[0041] In some embodiments is a compound of Formula (F), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (F), wherein R3is -S(O)2C=C(R7). In someembodiments is a compound of Formula (F), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R7is unsubstituted -CH3. In some embodiments is a compound of Formula (F), wherein R7is hydrogen.

[0042] In some embodiments is a compound of Formula (F), wherein R3is selected from. In some embodiments is a compound of Formula (F), wherein R3is . Insome embodiments is a compound of Formula (I’), wherein R3is. In some embodiments is a compound of Formula (F), wherein R3is. In some embodiments is a compound of Formula (F), wherein R3is V In some embodiments is acompound of Formula (F), wherein R3isIn some embodiments is a compoundFormula (F), wherein R3is

[0043] In some embodiments is a compound of Formula (F), wherein R3is -C(O)CH2F.

[0044] In some embodiments is a compound of Formula (F), wherein R9is H. In some embodiments is a compound of Formula (F), wherein R9is C1-6alkyl. In some embodiments is a compound of Formula (F), wherein R9is -CH3. In some embodiments is a compound of Formula (F), wherein R9is C3-6cycloalkyl.

[0045] In some embodiments is a compound of Formula (I):Formula (I); or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R4is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- 6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, and C1-9heteroaryl;n is 1 or 2; and p is 1, 2, or 3.

[0046] In some embodiments is a compound of Formula (I), wherein n is 1 and p is 1. In some embodiments is a compound of Formula (I), wherein n is 1 and p is 2. In some embodiments is a compound of Formula (I), wherein n is 2 and p is 2. In some embodiments is a compound of Formula (I), wherein n is 2 and p is 3.

[0047] In some embodiments is a compound of Formula (I), wherein R1is C1-10aryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (I), wherein R1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R1is phenyl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0048] In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independentlyselected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R1is C1-9heteroaryl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0049] In some embodiments is a compound of Formula (I), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, - N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, - S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, -CF2-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, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C 1 -6haloalky 1, - CH2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CH2-C3- ecycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R2is

[0050] In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected fromhalogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C 1 -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring, In some embodiments is a compound of Formula (I), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is selected from:some embodiments is a compound of Formula (I), wherein R2ise embodiments is a compound of Formula (I), wherein R2is

[0051] In some embodiments is a compound of Formula (I), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (I), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (I), wherein R2is selected from. In some embodiments is a compound of Formula (I), wherein R2is. In some embodiments is a compound of Formula (I), wherein R2is. In some embodiments is a compound of Formula (I), wherein R2is

[0052] In some embodiments is a compound of Formula (I), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (I), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (I), wherein R3is -S(O)2C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (I), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (I), wherein R6is hydrogen. In some embodiments is a compound of Formula (I), wherein R6is halogen. In some embodiments is a compound of Formula (I), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is hydrogen. In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is C1-6alkyl substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R7is hydrogen and R8is -CH3.

[0053] In some embodiments is a compound of Formula (I), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (I), wherein R3is -S(O)2C=C(R7). In some embodiments is a compound of Formula (I), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), wherein R7is unsubstituted -CH3. In some embodiments is a compound of Formula (I), wherein R7is hydrogen.

[0054] In some embodiments is a compound of Formula (I), wherein R3is selected from. In some embodiments is a compound of Formula (I), wherein R3is. InO some embodiments is a compound of Formula (I), wherein R3is. In some embodiments is a compound of Formula (I), wherein R3is. In some embodiments is a compound of.0.Formula (I), wherein R3isIn some embodiments is a compound of Formula (I), wherein R3isIn some embodiments is a compound of Formula (I), wherein R3

[0055] In some embodiments is a compound of Formula (I), wherein R3is -C(O)CH2F.

[0056] In some embodiments is a compound of Formula (I), wherein R9is H. 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. In some embodiments is a compound of Formula (I), wherein R9is C3-6cycloalkyl.

[0057] In some embodiments is a compound of Formula (la):Formula (la); or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R4is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C2-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; and each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, 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, C1-10aryl, and C1-9heteroaryl.

[0058] In some embodiments is a compound of Formula (la), wherein R1is C1-10aryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (la), whereinR1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R1is phenyl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0059] In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R1is C1-9heteroaryl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0060] In some embodiments is a compound of Formula (la), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, - N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, - S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, -CF2-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, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C16haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3- ecycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R2is selected fromsome embodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinembodiments is a compound of Formula (la), whereinsome embodiments is a compound of Formula (la), wherein

[0061] In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1- ealkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C 1 -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is phenyl fused with C2- 9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is selected from:n some embodiments is a compound of Formula (la), wherein R2is

[0062] In some embodiments is a compound of Formula (la), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (la), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (la), wherein R2is selected from. In some embodiments is a compound of Formula (la),

[0063] In some embodiments is a compound of Formula (la), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (la), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (la), wherein R3is -S(O)2C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (la), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (la), wherein R6is hydrogen. In some embodiments is a compound of Formula (la), wherein R6is halogen. In some embodiments is a compound of Formula (la), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is hydrogen. In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is C1-6alkyl substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is unsubstituted C1- ealkyl. In some embodiments is a compound of Formula (la), wherein R7is hydrogen and R8is - CH3.

[0064] In some embodiments is a compound of Formula (la), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (la), wherein R3is -S(O)2C=C(R7). In some embodiments is a compound of Formula (la), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), wherein R7is unsubstituted -CH3. In some embodiments is a compound of Formula (la), wherein R7is hydrogen.

[0065] In some embodiments is a compound of Formula (la), wherein R3is selected fromoIn some embodiments is a compound of Formula (la), wherein R3issome embodiments is a compound of Formula (la), wherein R3is ' F . In someO embodiments is a compound of Formula (la), wherein R3isIn some embodiments is a compound of Formula (la), wherein R3iscompound of Formula (la), wherein R3isIn some embodiments is a compound of Formula (la), wherein R3isIn some embodiments is a compound ofFormula (la), wherein

[0066] In some embodiments is a compound of Formula (la), wherein R3is -C(O)CH2F.

[0067] In some embodiments is a compound of Formula (la), wherein R9is H. 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. In some embodiments is a compound of Formula (la), wherein R9is C3-6cycloalkyl.

[0068] In some embodiments is a compound of Formula (lb):Formula (lb); or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F;each R4is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- ealkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; and each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- ealkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl.

[0069] In some embodiments is a compound of Formula (lb), wherein R1is C1-10aryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (lb), wherein R1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selectedfrom halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R1is phenyl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0070] In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R1is C1-9heteroaryl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0071] In some embodiments is a compound of Formula (lb), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, - S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3.6cycloalkyl, -CH2-C3.6cycloalkyl, C2.9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3. ecycloalkyl, -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, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C1-6haloalkyl, -CH2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CH2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3. ecycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2.9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2.9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R2isembodiments is a compound of Formula (lb), whereinembodiments is a compound of Formula (lb), whereinembodiments is a compound of Formula (lb), whereinembodiments is a compound of Formula (lb), whereinembodiments is a compound of Formula (lb), whereinsome embodiments is a compound of Formula (lb), wherein

[0072] In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1- ealkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C 1 -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb),

[0073] In some embodiments is a compound of Formula (lb), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (lb), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CF2-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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (lb), wherein R2is selected from. In some embodiments is a compound ofFormula (lb), wherein R2is. In some embodiments is a compound of Formula(lb), wherein R2is. In some embodiments is a compound of Formula (lb), wherein R2is. In some embodiments is a compound of Formula (lb), wherein

[0074] In some embodiments is a compound of Formula (lb), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (lb), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (lb), wherein R3is -S(O)2C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (lb), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (lb), wherein R6is hydrogen. In some embodiments is a compound of Formula (lb), wherein R6is halogen. In some embodiments is a compound of Formula (lb), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R7is hydrogen andR8is hydrogen. In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8is C1-6alkyl substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8is unsubstituted C1- ealkyl. In some embodiments is a compound of Formula (lb), wherein R7is hydrogen and R8is -CH3.

[0075] In some embodiments is a compound of Formula (lb), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (lb), wherein R3is -S(O)2C=C(R7). In some embodiments is a compound of Formula (lb), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (lb), wherein R7is unsubstituted -CH3. In some embodiments is a compound of Formula (lb), wherein R7is hydrogen.

[0076] In some embodiments is a compound of Formula (lb), wherein R3is selected fromIn some embodiments is a compound of Formula (lb), whereinsome embodiments is a compound of Formula (lb), whereinembodiments is a compound of Formula (lb), whereinIn some embodiments is a compound of Formula (lb), whereincompound of Formula (lb), wherein In some embodiments is a compoundof Formula (lb), wherein . In some embodiments is a compound ofFormula (lb), wherein

[0077] In some embodiments is a compound of Formula (lb), wherein R3is -C(O)CH2F.

[0078] In some embodiments is a compound of Formula (lb), wherein R9is H. 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. In some embodiments is a compound of Formula (lb), wherein R9is C3-6cycloalkyl.

[0079] In some embodiments is a compound of Formula (Ic):Formula (Ic); or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R4is independently selected from halogen, oxo, -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, -CF2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, C1- 9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CF2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring;each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- ealkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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 nitrogenatom 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; and each R13is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- ealkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl.

[0080] In some embodiments is a compound of Formula (Ic), wherein R1is C1-10aryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R1is phenyl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0081] In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl optionally substituted with 1-5 R4groups. In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independentlyselected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl substituted with 1-2 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R1is C1-9heteroaryl substituted with 2 R4groups and one R4is halogen and one R4is unsubstituted C1-6alkyl.

[0082] In some embodiments is a compound of Formula (Ic), wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, - N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, - S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, -CF2-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, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CF2-C3-6cycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups andeach R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3- ecycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R2isembodiments is a compound of Formula (Ic), whereinembodiments is a compound of Formula (Ic), wherein

[0083] In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ringR2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1- ealkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C 1 -6haloalky 1, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring, In some embodiments is a compound of Formula (Ic), wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is selected from:

[0084] In some embodiments is a compound of Formula (Ic), wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments is a compound of Formula (Ic), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is C1-9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring. In some embodiments is a compound of Formula (Ic), wherein R2is selected from. In some embodiments is a compound of Formula (Ic),

[0085] In some embodiments is a compound of Formula (Ic), wherein R3is selected from - C(O)C(R6)=C(R7)(R8) and -C(O)C=C(R7). In some embodiments is a compound of Formula (Ic), wherein R3is -C(O)C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (Ic), wherein R3is -S(O)2C(R6)=C(R7)(R8). In some embodiments is a compound of Formula (Ic), wherein R6is selected from hydrogen and halogen. In some embodiments is a compound of Formula (Ic), wherein R6is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R6is halogen. In some embodiments is a compound of Formula (Ic), wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is C1-6alkyl optionally substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is C1-6alkyl substituted with one group selected from C2-9heterocycloalkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is unsubstituted C1- ealkyl. In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen and R8is - CH3.

[0086] In some embodiments is a compound of Formula (Ic), wherein R3is -C(O)C=C(R7). In some embodiments is a compound of Formula (Ic), wherein R3is -S(O)2C=C(R7). In someembodiments is a compound of Formula (Ic), wherein R7is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), wherein R7is unsubstituted -CH3. In some embodiments is a compound of Formula (Ic), wherein R7is hydrogen.

[0087] In some embodiments is a compound of Formula (Ic), wherein R3is selected fromIn some embodiments is a compound of Formula (Ic), wherein R3isosome embodiments is a compound of Formula (Ic), wherein R3is F . In some embodiments is a compound of Formula (Ic), wherein R3isIn some embodiments is a compound of Formula (Ic), wherein R3iscompound of Formula (Ic), wherein R3isIn some embodiments is a compound of Formula (Ic), wherein R3isIn some embodiments is a compound ofFormula (Ic), wherein

[0088] In some embodiments is a compound of Formula (Ic), wherein R3is -C(O)CH2F.

[0089] In some embodiments is a compound of Formula (Ic), wherein R9is H. 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. In some embodiments is a compound of Formula (Ic), wherein R9is C3-6cycloalkyl.

[0090] In some embodiments is a compound selected from:acceptable salt thereof.

[0091] In some embodiments is a compound selected from:pharmaceutically acceptable salt thereof.

[0092] 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.

[0093] 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 ranges include 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.

[0094] 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.

[0095] 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)-.

[0096] The term “n-membered,” where “n” is an integer, typically describes the number of ring-forming 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, pyridyl 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.

[0097] 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.

[0098] As used herein, the phrase “optionally substituted” means unsubstituted or substituted.

[0099] As used herein, the term “substituted” means that a hydrogen atom is replaced by a non-hydrogen 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.

[0100] As used herein, the term “C1-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.

[0101] 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. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n / -pentyl, 2-methyl-l -butyl, 3-pentyl, / / -hexyl, 1,2,2-trimethylpropyl, eptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl. In some embodiments, the alkyl group is methyl.

[0102] 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.

[0103] 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, CHCH,2C2CI5, and the like.

[0104] 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.

[0105] 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.

[0106] As used herein, “amino,” employed alone or in combination with other terms, refers to NH2.

[0107] 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 bridg6head 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 group is a C3-7monocyclic 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.

[0108] 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 bridg6head heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridg6head 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.

[0109] 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 aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0110] 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. In some embodiments, the heteroaryl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, and the monocyclic heteroaryl group is fused with a heterocycloalkyl group.

[0111] 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, pyridyl, 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.

[0112] 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.

[0113] 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 isomericprotonation states having the same empirical formula and total charge. Example prototropic tautomers 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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 acceptablesalts 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.Synthesis of Compounds

[0120] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0121] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0122] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0123] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5;Larock, R. C. "Compr6hensive Organic Transformations: A Guide to Functional GroupPreparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley- VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0124] In some embodiments, compounds are prepared as described in Scheme 1.Scheme 1

[0125] In some embodiments, compounds are prepared as described in the Examples. Methods of Use

[0126] Compounds described herein can inhibit the activity of SARM1. For example, the compounds described herein can be used to inhibit activity or a function of SARM1 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.

[0127] Compounds described herein, as SARM1 inhibitors, can increase levels of NAD+ in a cell. Accordingly, the present disclosure is further directed to a method of increasing the level of NAD+ in a sample or in a patient, comprising contacting the sample or administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the increased level of NAD+ is relative to the level of NAD+ prior to the contacting or administering.

[0128] Compounds described herein, as SARM1 inhibitors, can inhibit axonal degeneration. Accordingly, the present disclosure is further directed to a method of inhibiting axonal degeneration in a sample or in a patient, comprising contacting the sample or administering to the patient an inhibiting amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0129] The compounds described herein are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of SARM1. For example, the compounds described herein are useful in the treatment and prevention of 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. The term "neurological disorder" generally refers to a disorder affecting the nervous system, including the central nervous system or the peripheral nervous system. The term “neurological disorder” also includes ocular indications having a nexus to the nervous system.

[0130] In some embodiments, the neurological disorder treatable or preventable by administration of a compound described herein includes neurodegenerative diseases. In some embodiments, the compounds described herein are useful in the treatment of neurodegenerative diseases. In some embodiments, the compounds described herein are useful in the prevention of neurodegenerative diseases. Neurodegenerative diseases are characterized by damage to the central nervous system and can be identified by progressive dysfunction, degeneration and death of specific populations of neurons which are often synaptically interconnected. Examples of neurodegenerative diseases include Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), prion disease, motor neuron diseases (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and epilepsy.

[0131] Examples of neurological disorders treatable or preventable according to the methods described herein include spinal muscular atrophy (SMA), Chemotherapy Induced Peripheral Neuropathy (representative chemotherapeutic agents include vinca-alkaloids, taxols and platins), multiple sclerosis (MS), traumatic brain injury (TBI), spinal cord injury, stroke, Parkinson’ disease, glaucoma, Huntington’s disease, Alzheimer’s disease, Char cot-Marie-Tooth disease (CMT), retinitis pigmentosa (RP), age-related macular degeneration (AMD), small fiber neuropathies, peripheral neuropathy (e.g., viral neuropathy), spinocerebellar ataxias, cystic fibrosis, familial amyloidotic polyneuropathy, spongiform encephalopathies, spinal and bulbar muscular atrophy, hereditary dentatorubral-pallidoluysian atrophy, adrenoleukodystrophy, adrenomyeloneuropathy, Alexander’s disease, amyotrophic lateral sclerosis (ALS), Bassen- Kornzweig syndrome, Bell’s palsy, progressive supra nuclear palsy (PSP), central pontinemyelolysis, cluster headache, congenital hypomyelination, corticobasal degeneration, Creutzfeldt- Jakob disease, epilepsy, dementia (e.g., frontotemporal dementia and Lewy body dementia), demyelination disorders (e.g., ischemic demyelination), encephalomyelitis, Friedrich’s ataxia, Gaucher’s disease, hereditary sensory and autonomic neuropathy (HSAN), Hurler syndrome, Krabbe’s disease, metachromatic leukodystrophy, migraine and tension headaches, mild cognitive impairment, motor spinoneuron disease, neuromyelitis optica, Niemann-Pick disease, optic neuritis, Pelizaeus Merzbacher disease, peripheral neuropathy, periventricular leukomalacia, post-herpetic neuralgia, prion disease, progressive supranuclear palsy, progressive multifocal leukoencephalopathy, Tay-Sacks disease, thoracic disc herniation, traverse myelitis, trigeminal neuralgia, Wallerian degeneration, cerebellar degeneration, chiari malformation, dystonia, encephalitis (e.g., pediatric viral encephalitis and La Crosse virus encephalitis), hyperekplexia, multifocal motor neuropathy, muscular dystrophy, myasthenia gravis, myopathy, neurofibromatosis, neuronal ceroid lipofuscinosis, neuropathies (e.g., peripheral neuropathy), pseudobulbar affect, restless legs syndrome, spina bifida, syringomyelia, thoracic outlet syndrome, and transverse myelitis.

[0132] In other embodiments, the neurological disorder treatable or preventable by administration of a compound described herein is a neuropathy. As used herein, the term “neuropathy” refers broadly to diseased conditions of the nervous system, including polyneuropathy; neuropathy, ataxia, and retinosa pigmentosa (NARP); familial amyloid neuropathies; diabetic neuropathy (peripheral neuropathy due to diabetes mellitus); peripheral neuropathy (e.g., chemotherapy-induced peripheral neuropathy (CIPN), including CIPN caused by vinca alkaloids, bortezomib, ixabepilone, thalidomide and its analogs, taxanes, and platinumbased agents); and cranial neuropathy (e.g., auditory neuropathy and optic neuropathy). The term also includes other neuropathies associated with genetic disorders (e.g., NMNAT2 genetic mutation disorders).

[0133] In still other embodiments, the neurological disorder treatable or preventable by administration of a compound described herein is an ocular neuropathy (e.g., optic neuropathy). The term “optic neuropathy” refers to damage to the optic nerve from a number of causes. Types of optic neuropathy include ischemic optic neuropathy (e.g., anterior and posterior ischemic optic neuropathy); optic neuritis (e.g., chronic relapsing inflammatory optic neuropathy (CRION), single isolated optic neuritis (SION), and relapsing isolated optic neuritis); compressive optic neuropathy; infiltrative optic neuropathy; traumatic optic neuropathy; mitochondrial optic neuropathies; and hereditary optic neuropathies (e.g., Leber’s hereditary optic neuropathy (LHON), hereditary neuropathy with liability to pressure palsy (HNPP), and dominant optic atrophy).

[0134] In still other embodiments, the neurological disorder treatable or preventable by administration of a compound described herein is multiple sclerosis (MS), chemotherapy- induced peripheral neuropathy (CIPN), amyotrophic lateral sclerosis (ALS), glaucoma, traumatic brain injury (TBI), or stroke.

[0135] 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.

[0136] 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” SARM1 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 SARM1, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing SARM1.

[0137] 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.

[0138] 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.

[0139] As used herein, the phrase “inhibiting amount” refers to the amount of active compound or pharmaceutical agent that elicits a measurable SARM1 inhibition or axonal degeneration in a tissue, system, animal, individual or human.

[0140] 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).

[0141] 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

[0142] 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.

[0143] 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.

[0144] 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

[0145] 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.

[0146] These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Pharmaceutical compositions may be 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 & Wilkins 1999), herein incorporated by reference for such disclosure.

[0147] 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.

[0148] 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 v6hicle, 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.

[0149] 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 andother mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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 v6hicles.

[0154] 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 pressurebreathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0155] 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.

[0156] 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.

[0157] 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:

[0158] 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 inhibitors of SARM1 according to one or more of the assays provided herein.

[0159] 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 fromsuppliers such as Sigma-Aldrich (MilliporeSigma), Combi-Blocks, Enamine, Sinopharm Chemical Reagent Co. (SCRC), and Alfa Aesar and were used without purification unless otherwise noted. Proton 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-d6), acetonitrile (CD3CN) or methanol (CD3OD).Chemical shifts are recorded in parts per million (ppm) and are referenced to the centerline of deuterochloroform (5 7.26 ppm), of DMSO-d6(5 2.50 ppm), of CD3CN (5 1.94 ppm) or of CD3OD (5 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). 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 carbonyl BOC2O Boc-anhydride or di-tert-butyl dicarbonateCDI l,l’-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-1λ5,2-benziodoxole-l,l,l(3H)-triyl triacetateDEA diethylamineDHP 3,4-dihydropyranDIAD diisopropyl azodicarboxylateDIPEA A,A-diisopropylethylamineDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethylsulfoxideDPPA diphenyl phosphoryl azideEDC HC1A-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]-lH-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-chlorosuccinimideOTf trifluoromethanesulfonatePd / C palladium on carbonPE petroleum etherPh phenylPTSA p -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 chromatographyT3P propylphosphonic anhydrideTBAF tetrabutyl ammonium fluorideTBPH tert-butyl hydroperoxide solution (Luperox®, TBH70X)TBUP tri-tert-butylphosphonium tetrafluoroborate t-BuOK potassium tert-butoxideTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTHP tetrahydropyranTLC thin layer chromatographyTol tolueneTosMIC p-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 1-8):Synthesis of tert-butyl 3-amino-3-(3-chloro-2-methylphenyl)azetidine-l-carboxylate (Int- 1):

[0160] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-hydroxyazetidine-l- carboxylate (Int-la): To a 2 L 4-necked round-bottom flask were added l-bromo-3 -chi oro-2 - methylbenzene (70 g, 340.6 mmol, 1 eq.) and THF (700 mL) at room temperature. Followed bythe addition of n-BuLi (149.9 mL, 374.7 mmol, 1.1 eq.) dropwise at -78 °C. The mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added tertbutyl 3 -oxoazetidine- 1 -carboxylate (64.1 g, 374.7 mmol, 1.1 eq.) in THF (210 mL) dropwise over 10 min at -78 °C. The resulting mixture was stirred for additional Ih at -78 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (350 mL) at -78 °C. The resulting mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with (EtOAc / n-heptane=l :5) (600 mL) to afford the title compound as a white solid (72.1 g, 66% yield).1H NMR (400 MHz, CHLOROFORM-td) δ 7.43 - 7.33 (m, IH), 7.21 - 7.11 (m, 2H), 4.59 - 4.45 (m, 2H), 4.33 - 4.12 (m, 2H), 2.38 (s, 3H), 1.47 (s, 9H). LCMS ELMS m / z: = 298 [M+H]+.

[0161] Preparation of tert-butyl 3 -azido-3 -(3 -chloro-2-methylphenyl)azetidine-l -carboxylate (Int-lb): To a 1 L 3 -necked round-bottom flask were added tert-butyl 3 -(3 -chi oro-2 - methylphenyl)-3-hydroxyazetidine-l -carboxylate (Int-la) (35 g, 117.5 mmol, 1 eq.), THF (350 mL), and PBus (47.6 g, 235.0 mmol, 2 eq.) at room temperature. Followed by the addition of DIAD (47.5 g, 235.0 mmol, 2 eq.) dropwise at -10 °C. Finally, to the above mixture was added DPPA (64.7 g, 235.0 mmol, 2 eq.) dropwise at -10 °C. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The crude was directly used to the next step.

[0162] Preparation of tert-butyl 3 -amino-3 -(3 -chloro-2-methylphenyl)azetidine-l -carboxylate (Int-1): To the crude reaction (Int-lb) was added PBus (71.4 g, 353.1 mmol) dropwise at room temperature. The resulting mixture was stirred for additional Ih at room temperature. Followed by the addition of H2O (210 mL) dropwise at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (lx 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (column, YMC 50*250mm lOum; mobile phase, MeCN in Water (0.1% NH3.H2O + lOmmol / L NH4HCO3), 20% to 80% gradient in 12 min; detector, UV 220 nm.) to afford the title compound as a white solid (10.7 g, 31% yield).1H NMR (300 MHz, DMSO-dZ6): δ 7.33 (dt, J= 8.1, 4.0 Hz, IH), 7.19 (q, J= 4.2, 3.5 Hz, 2H), 4.28 (d, J= 8.6 Hz, 2H), 3.90 (d, J= 8.6 Hz, 2H), 2.25 (s, 3H), 1.37 (s, 9H). LCMS ES-MS m / z = 297 [M+H]+.Synthesis of tert-butyl 3-amino-3-(2-chloro-3-methylphenyl)azetidine-l-carboxylate (Int-2):

[0163] Preparation of tert-butyl 3 -(2-chl oro-3 -methylphenyl)-3 -hy droxyazeti dine- 1- carboxylate (Int-2a): Compound Int-2a was synthesized by using l-bromo-2-chl oro-3 - methylbenzene (6 g, 29.2 mmol, 1 eq.) and tert-butyl 3-oxoazetidine-l-carboxylate (5 g, 29.2 mmol, 1 eq.) by following the procedure from Compound Int-la. The crude mixture was purified by reversed-phase chromatography to afford the title compound as a brown solid (3 g, 34% yield). LCMS ESI-MS m / z = 298 [M+H]+.

[0164] Preparation of tert-butyl 3 -azido-3-(2-chloro-3-methylphenyl)azetidine-l -carboxylate (Int-2b): Compound Int-2b was synthesized by using tert-butyl 3 -(2-chl oro-3 -methylphenyl)-3- hydroxyazeti dine- 1 -carboxylate (Int-2a) (3 g, 10.1 mmol, 1 eq.) by following the procedure from Compound Int-lb to afford the title compound that was used in the next step directly without purification. LCMS ESI-MS m / z = 323 [M+H]+.

[0165] Preparation of tert-butyl 3 -amino-3 -(2-chl oro-3 -m ethylphenyl)azeti dine- 1 -carboxylate (Int-2): Compound Int-2 was synthesized by using crude tert-butyl 3 -azido-3 -(2-chl oro-3 - methylphenyl)azetidine-l -carboxylate (Int-2b) by following the procedure from Compound Int- 1 to afford the title compound as a white solid (470 mg, 16% yield over 2 steps). LCMS ESI-MS m / z = 297 [M+H]+.Synthesis of tert-butyl 3-amino-3-(2,3-dichlorophenyl)azetidine-l-carboxylate (Int-3):

[0166] Preparation of tert-butyl 3-(2,3-dichlorophenyl)-3-hydroxyazetidine-l-carboxylate (Int-3a): Compound Int-3a was synthesized using l-bromo-2,3-dichlorobenzene (2.26 g, 10.0 mmol, 1.0 eq) and tert-butyl 3 -oxoazetidine- 1 -carboxylate (2.05 g, 12.0 mmol, 1.2 eq) by following the procedure from Compound Int-la to afford the title compound as a white solid (1.55 g, 49% yield). LCMS ES-MS m / z. = 659 [2M+Na]+.

[0167] Preparation of tert-butyl 3-(2,3-dichlorophenyl)-3-((methylsulfonyl)oxy)azetidine-l- carboxylate (Int-3b): To a solution of tert-butyl 3-(2,3-dichlorophenyl)-3-hydroxyazetidine-l- carboxylate (Int-3a) (318 mg, 1.0 mmol, 1 eq.) in DCM was added pyridine (395 mg, 5.0 mmol,5 q.) and MsCl (172 mg, 1.5 mmol, 1.5 eq.) dropwise at 0 °C. The resulting mixture was allowed to stir for 18 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (1 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4.After filtration, the filtrate was concentrated under reduced pressure to afford the title compound. The crude was directly used to the next step. LCMS ES-MS m / z = 815 [2M+Na]+.

[0168] Preparation of tert-butyl 3-azido-3-(2,3-dichlorophenyl)azetidine-l-carboxylate (Int- 3c): A solution of tert-butyl 3-(2,3-dichlorophenyl)-3-((methylsulfonyl)oxy)azetidine-l- carboxylate (Int-3b) (909 mg, 2.09 mmol, 1 eq.) in DMF (8 mL) was added NaNs (746 mg, 11.5 mmol, 5 eq.) at room temperature, then heated at 50 °C overnight. After cooling down, the reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with H2O (20 mL x 5), washed with brine, dried over anhydrous U. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography with (EtOAc / n-hexane =10:8) to afford the title compound as an oil (640 mg, 81% yield). LCMS ES-MS m / z. = 343 [M]+.

[0169] Preparation of tert-butyl 3-amino-3-(2,3-dichlorophenyl)azetidine-l-carboxylate (Int-3): A solution of tert-butyl 3-azido-3-(2,3-dichlorophenyl)azetidine-l-carboxylate (Int-3c) (640 mg, 1.86 mmol, 1 eq.) was added trimethyl phosphine (5.59 mL, 5.59 mmol, 1 M in THF, 3 eq.) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature, followed by the addition of H2O (1 mL) dropwise at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography with (MeOH / DCM = 1 :9 with 0.1% NH3H2O) to afford the title compound as a white foam (365 mg, 61%). LCMS ES-MS m / z = 635 [2M + H]+.Synthesis of tert-butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl)azetidine-l-carboxylate

[0170] Preparation of tert-butyl 3-(2,3-dichloro-6-fluorophenyl)-3-hydroxyazetidine-l- carboxylate (Int-4a): Compound Int-4a was synthesized using 2-bromo-3,4-dichloro-l-fluorobenzene (530 mg, 2.17 mmol, 1 eq.) and tert-butyl 3 -oxoazetidine- 1 -carboxylate (372 mg, 2.17 mmol, 1.0 eq.) by following the procedure from Compound Int-la to afford the title compound as a white solid (350 mg, 48% yield). LCMS ES-MS m / z = 695 [2M + Na]+.

[0171] Preparation of tert-butyl 3-(2,3-dichloro-6-fluorophenyl)-3- ((methylsulfonyl)oxy)azetidine-l -carboxylate (Int-4b): Compound Int-4b was synthesized using tert-butyl 3 -(2, 3 -dichloro-6-fluorophenyl)-3-hydroxyazeti dine- 1 -carboxylate (Int-4a) (360 mg, 1.07 mmol, 1 eq.) and (chlorosulfonyl)methane (184 mg, 1.61 mmol, 1.5 eq.) by following the procedure from Compound Int-3b to afford the title compound as crude white foam that was used for next step without further purification. LCMS ES-MS m / z = 851 [2M + Na]+.

[0172] Preparation of tert-butyl 3-azido-3-(2,3-dichloro-6-fluorophenyl)azetidine-l- carboxylate (Int-4c): Compound Int-4c was synthesized using tert-butyl 3-(2,3-dichloro-6- fluorophenyl)-3 -((methyl sulfonyl)oxy)azetidine-l -carboxylate (Int-4b) (169 mg, 0.41 mmol, 1 eq.) and sodium azide (42 mg, 0.65 mmol, 1.6 eq.) by following the procedure from Compound Int-3c to afford the title compound as an oil (85 mg, 57% yield). LCMS ES-MS m / z = 745 [2M + Na]+.

[0173] Preparation of tert-butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl)azetidine-l- carboxylate (Int-4): Compound Int-4 was synthesized using tert-butyl 3-azido-3-(2,3-dichloro- 6-fluorophenyl)azetidine-l -carboxylate (Int-4c) (110 mg, 0.27 mmol, 1 eq.) and trimethyl phosphine (0.79 mL, 0.79 mmol, 1 M in THF, 3 eq.) by following the procedure from Int-3 to afford the title compound as foam in (60 mg, 67% yield). LCMS ES-MS m / z 693 [2M + Na]+.Synthesis of benzyl (3-amino-3-(3-chloro-2-methylphenyl)cyclobutyl)carbamate (Int-5):

[0174] Preparation of benzyl (3-(3-chloro-2-methylphenyl)-3-hydroxycyclobutyl)carbamate (Int-5a): Compound Int-5a was synthesized using l-bromo-3-chloro-2-m ethylbenzene (10 g, 48.7 mmol, 2 eq.) and benzyl N-(3-oxocyclobutyl)carbamate (5.3 g, 24.3 mmol, 1 eq.) by following the procedure from Compound Int-la to afford the title compound as a yellow oil (3.8 g, 45% yield).

[0175] Preparation of benzyl (3-azido-3-(3-chloro-2-methylphenyl)cyclobutyl)carbamate (Int- 5b): To a stirred solution of benzyl (3-(3-chloro-2-methylphenyl)-3- hydroxycyclobutyl)carbamate (Int-5a) (3.8 g, 11.0 mmol, 1 eq.) and TMSN3 (3.8 g, 33.0 mmol, 3 eq.) in toluene (38 mL) was added BF3.Et2O (4.7 g, 33.0 mmol, 3 eq.) dropwise at rt undernitrogen atmosphere. The reaction mixture was stirred for 2 h at rt. The resulting mixture was poured into ice water (150 mL) and the organics were extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as a brown solid (4 g). The crude product was used in the next step directly without further purification.

[0176] Preparation of benzyl (3-amino-3-(3-chloro-2-methylphenyl)cyclobutyl)carbamate (Int-5): To a stirred solution of benzyl (3-azido-3-(3-chloro-2- methylphenyl)cyclobutyl)carbamate (Int-5b) (4 g, 10.8 mmol, 1 eq.) in THF (120 mL) and H2O (4 mL) was added PMe3(32.4 mL, 32.4 mmol, 3 eq.) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was warmed to rt and stirred 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous NH3H2O, filtered, and concentrated under reduced pressure to afford a yellow solid. The resulting mixture was purified by reversed-phase flash chromatography to afford the title compound as a yellow oil (650 mg, 17% yield (2 steps)).Synthesis of tert-butyl 3-amino-3-(3-chloro-2-methylphenyl)pyrrolidine-l-carboxylate (Int- 6):

[0177] Preparation of tert-butyl 3 -(3 -chi oro-2-methylphenyl)-3 -hydroxypyrrolidine- 1- carboxylate (Int-6a): Compound Int-6a was synthesized using l-bromo-3 -chi oro-2 - methylbenzene (10 g, 48.7 mmol, 1 eq.) and tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (9.0 g, 48.7 mmol, 1 eq.) by following the procedure from Compound Int-la to afford the title compound as a white solid (7 g, 46% yield). LCMS ESI-MS m / z: = 312 [M+H]+.

[0178] Preparation of tert-butyl 3-azido-3-(3-chloro-2-methylphenyl)pyrrolidine-l- carboxylate (Int-6b): Compound Int-6b was synthesized using tert-butyl 3-(3-chloro-2- methylphenyl)-3 -hydroxypyrrolidine- 1 -carboxylate (Int-6a) (5 g, 16 mmol) by following the procedure from Compound Int-lb to afford the title compound. The reaction was used in the next step directly without purification. LCMS ESI-MS m / z: = 337 [M+H]+.

[0179] Preparation of tert-butyl 3-amino-3-(3-chloro-2-methylphenyl)pyrrolidine-l- carboxylate (Int-6): Compound Int-6 was synthesized using tert-butyl 3-azido-3-(3-chloro-2- methylphenyl)pyrrolidine-l-carboxylate (Int-6b) from previous step by following the procedure from Compound Int-1 to afford the title compound as a white solid (900 mg, 18% over 2 steps). LCMS ESI-MS m / z: = 311 [M+H]+.

[0180] The racemic compound (Int-6) was purified by Prep-Chiral-HPLC to afford tert-butyl (R)-3 -amino-3 -(3 -chloro-2-methylphenyl)pyrrolidine-l -carboxylate (Int-6-(R)) and methylphenyl)pyrrolidine-l-carboxylate (Int-6-(S)). The absolute stereochemistry was assigned arbitrarily.Synthesis of benzyl 3-amino-3-(3-chloro-2-methylphenyl)pyrrolidine-l-carboxylate (Int-7):

[0181] Preparation of benzyl 3 -(3 -chi oro-2-methylphenyl)-3 -hydroxypyrrolidine- 1- carboxylate (Int-7a): Compound Int-7a was synthesized using l-bromo-3 -chi oro-2 - methylbenzene (20 g, 97.3 mmol, 1 eq.) and benzyl 4-oxopiperidine-l -carboxylate (27.3 g, 116.8 mmol, 1.2 eq.) by following the procedure from Compound Int-la to afford the title compound as a white solid (19 g, 51% yield). LCMS ESI-MS m / z = 346 [M+H]+.

[0182] Preparation of benzyl 3-(3-chloro-2-methylphenyl)-3-(2-chloroacetamido)pyrrolidine- 1-carboxylate (Int-7b): Into a 500mL round-bottom flask were added benzyl 4-(3-chloro-2- methylphenyl)-4-hydroxypiperidine-l -carboxylate (Int-7a) (15 g, 41.7 mmol, 1 eq.) and 2- chloroacetonitrile (450 mL) at room temperature. To the above mixture was added H2SO4 (2.04 g, 0.5 eq.) dropwise at 0 °C. The resulting mixture was stirred for additional 4 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford the title compound as a white solid (9.4 g, 48% yield). LCMS ESI-MS m / z = 421 [M+H]+.

[0183] Preparation of benzyl 3 -amino-3 -(3 -chloro-2-methylphenyl)pyrrolidine-l -carboxylate (Int-7): Into a 250 mL 3-necked round-bottom flask were added benzyl 3-(3-chloro-2- methylphenyl)-3-(2-chloroacetamido)pyrrolidine-l-carboxylate (Int-7b) (9 g, 21.4 mmol, 1 eq.), thiourea (1.95 g, 25.6 mmol, 1.2 eq.) and AcOH (18 mL) in EtOH (90 mL).The resulting mixture was stirred for 48 h at 85 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reversed-phase chromatography to afford the title compound as a yellow solid (3.5 g, 45% yield). LCMS ESI- MS m / z = 345 [M+H]+.Synthesis of benzyl 4-amino-4-(3-chloro-2-methylphenyl)piperidine-l-carboxylate (Int-8):

[0184] Preparation of benzyl 4-(3 -chi oro-2-methylphenyl)-4-hydroxypiperi dine- 1 -carboxylate (Int-8a): Compound Int-8a was synthesized using l-bromo-3-chloro-2-m ethylbenzene (26 g, 126.5 mmol, 1 eq.) and benzyl 4-oxopiperidine-l -carboxylate (35.42 g, 151.8 mmol, 1.2 eq.) by following the procedure from Compound Int-la to afford the title compound as a white solid (22 g, 48% yield). LCMS ESI-MS m / z. = 360 [M+H]+.

[0185] Preparation of benzyl 4-(3 -chi oro-2-methylphenyl)-4-(2-chloroacetamido)piperi dine- 1- carboxylate (Int-8b): Compound Int-8b was synthesized using benzyl 4-(3 -chi oro-2 - methylphenyl)-4-hydroxypiperidine-l -carboxylate (Int-8a) (13 g, 36.1 mmol, 1 eq.) and 2- chloroacetonitrile (390 mL) by following the procedure from Compound Int-7b to afford the title compound as a white solid (9 g, 57%). LCMS ESI-MS m / z = 435 [M+H]+.

[0186] Preparation of benzyl 4-amino-4-(3 -chi oro-2-methylphenyl)piperi dine- 1 -carboxylate (Int-8): Compound Int-8 was synthesized using benzyl 4-(3-chloro-2-methylphenyl)-4-(2- chloroacetamido)piperidine-l -carboxylate (Int-8b) (9 g, 20.7 mmol, 1 eq.) by following the procedure from Compound Int-7 to afford the title compound as a yellow solid (2.5 g, 34% yield). LCMS ESI-MS m / z = 359 [M+H]+.Synthesis of tert-butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl) pyrrolidine-l-carboxylate(Int-9)

[0187] Preparation of tert-butyl 3-(2,3-dichloro-6-fluorophenyl)-3-hydroxypyrrolidine-l- carboxylate (Int-9a): To a stirred solution of l,2-dichloro-4-fluorobenzene (50 g, 304.8 mmol) in THF (1000 mL) was added LDA (227.2 mL, 2M in THF, 243.9 mmol) dropwise at -65 °C under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at -65 °C. To the above mixture was added tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (56 g, 304.8 mmol) in three portions over at -65 °C. The resulting mixture was warmed to rt and stirred for 1 h. The reaction was quenched by the addition of sat. NH4CI (aq.) (500 mL) at 0 °C and the resulting mixture was extracted with EA (2 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford the title compound as an off-white solid (27.5 g, 25.9% yield). LCMS ELMS m / z = 350 [M+H]+.

[0188] Preparation of tert-butyl 3-azido-3-(2,3-dichloro-6-fluorophenyl) pyrrolidine- 1- carboxylate (Int-9b): A solution of tert-butyl 3-(2,3-dichloro-6-fluorophenyl)-3- hydroxypyrrolidine-1 -carboxylate (27.5 g, 78.7 mmol) and PBus (31.8 g, 157.4 mmol) in THF (275 ml) was treated with DIAD (31.8 g, 157.4 mmol) at -30 °C for 5 min under a nitrogen atmosphere followed by the addition of DPPA (43.3 g, 157.4 mmol) dropwise at -30 °C. The resulting mixture was warm to rt and stirred for 3 h. The reaction mixture was used for next step directly without workup.

[0189] Preparation of tert-butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl) pyrrolidine- 1- carboxylate (Int-9): To the reaction mixture from the previous step was added PBus (47.7 g, 236.3 mmol) dropwise at rt. The resulting mixture was stirred for additional Ih at rt. To the above mixture, H2O (160 mL) was added at rt and the solution was allowed to stirred for 16 h at rt. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PEZEA (20: 1 to 9: 1) to afford 40 g crude. The 40 g crude was further purified by slurry with PEZEA (20: 1) for 1 h. The solid was removed by filtration and the filtrate was concentrated under vacuum to afford 30 g crude. The crude product was dissolved in Et2O (600 mL). Oxalate (3.8 g, 43.1 mmol) in EtOH (15 mL) was added dropwise to the above mixture at rt and the mixture was stirred for 16 h. The precipitated solids were collected by filtration. The solids were dissolved in H2O (100 mL) and then the solution was basified to pH 8-9 with sat. Na2CO3. The mixture was extracted with EA (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-amino-3- (2,3 -dichloro-6-fluorophenyl)pyrrolidine-l -carboxylate as a white solid (13 g, 47% for 2 steps).1H NMR (300 MHz, DMSO-d6): δ 7.62 (dd, J= 9.0, 5.0 Hz, IH), 7.27 (ddd, J= 12.4, 9.0, 1.8 Hz, IH), 4.06 (dd, J= 20.6, 11.2 Hz, IH), 3.53 - 3.32 (m, 3H), 2.60 (m, IH), 2.28 (m, 3H), 1.41 (s, 9H). LCMS ESI-MS m / z = 349 [M+H]+.

[0190] The racemic compound (Int-9) was purified by Prep-Chiral-HPLC to afford tert-butyl (R)-3-amino-3 -(3 -chloro-2-methylphenyl)pyrrolidine-l -carboxylate (Int-9-(R)) and methylphenyl)pyrrolidine-l-carboxylate (Int-9-(S)). The absolute stereochemistry was assigned arbitrarily.Synthesis of l-benzyl-3-(3-chloro-2-methylphenyl) piperidin-3-amine (Int-10)

[0191] Preparation of l-benzyl-3-(3-chloro-2-methylphenyl)piperidin-3-ol (Int-lOa): A solution of l-bromo-3-chloro-2- methylbenzene (15 g, 73 mmol) in THF (350 mL) was treated with n-BuLi (5.61 g, 87.6 mmol) for 30 min at -78 °C under nitrogen atmosphere followed by the addition of 1-benzylpiperi din-3 -one (13.8 g, 73 mmol) in THF (25 mL) dropwise at -78 °C. The resulting mixture was stirred for 2 h at -78 °C. The reaction mixture was allowed to warm up to rt, quenched with NH4CI (aq.) (1.8 L) and extracted with EA (3 x 600 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford the title compound as a yellow oil (10.1 g, 43%). LCMS ESI-MS m / z. = 316 [M+H]+.

[0192] Preparation of N-[l-benzyl-3-(3-chloro-2-methylphenyl)piperidin-3-yl]-2- chloroacetamide (Int-lOb): To a solution of l-benzyl-3-(3-chloro-2-methylphenyl)piperidin-3-ol (2.2 g, 6.96 mmol) in CICH2CN (44 mL) was added H2SO4(14.7 mL) at rt. The mixture was stirred for 1 h at rt. The resulting mixture was diluted with H2O (200 mL), basified to pH 9 with Na2CO3(aq.) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column to afford the title compound as a white solid (1.6 g, 58%). LCMS ESI-MS m / z. = 391 [M+H]+.

[0193] Preparation of l-benzyl-3 -(3 -chi oro-2-methylphenyl)piperi din-3 -amine (lnt-10): To a stirred solution of N-[l-benzyl-3-(3-chloro-2-methylphenyl)piperidin-3-yl]-2-chloroacetamide (1.6 g, 4.08 mmol) and thiourea (0.47 g, 6.13 mmol) in EtOH (16 mL) was added AcOH (3.2 mL) at rt. The mixture was heated to 80 °C and stirred for 16 h. The resulting mixture was cooled to rt, diluted with H2O (80 mL), basified to pH 9 with Na2CO3(aq.) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford the title compound as a brown oil (840 mg, 65%). LCMS ESI-MS m / z = 315 [M+H]+.Synthesis of (rac)-(2R,65)-l-benzyl-4-(3-chloro-2-methylphenyl)-2,6-dimethylpiperidin-4- amine (Int-11)

[0194] Preparation of (rac)-(2R,6S)-l-benzyl-2,6-dimethylpiperidin-4-one (Int-lla): To a solution of acetonedicarboxylic acid (30 g, 205 mmol) in water (60 mL) was added acetald6hyde (18.1 g, 411 mmol) at 20 °C. The reaction was stirred at 20 °C for 20 min. Then cooled to 0 °C and benzylamine (22 g, 205 mmol) was added dropwise. The reaction solution was allowed to warm to rt and stirred for 36 h. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude mixture was purified by silica gel column to afford the title compound as a yellow oil (2 g, 4%, confirmed by 2D NMRs). LCMS ESI-MS m / z =218 [M+H]+.

[0195] Preparation of (rac)-(2R,6S)-l-benzyl-4-(3-chloro-2-methylphenyl)-2,6- dimethylpiperidin-4-ol (Int-llb): To a stirred solution of l-bromo-3 -chi oro-2-m ethylbenzene (1.9 g, 9.2 mmol) in THF (40 mL) was added n-BuLi (4.4 mL, 11 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C. Then to the above mixture was added (rac)-(2R,6S)-l-benzyl-2,6- dimethylpiperidin-4-one (2 g, 9.2 mmol) in THF (10 mL) dropwise at -78 °C. The reaction mixture was stirred 2 h at -78° C. The resulting mixture was warmed to rt and poured into sat. NH4CI (aq.) (200 mL). The organics were extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The resulting mixture was purified by reversed-phase flash to afford the title compound as a yellow oil (2.7 g, 85%, yield). LCMS ESI-MS m / z. =344 [M+H]+.

[0196] Preparation of (rac)-(N-[(2R,6S)-l -benzyl -4-(3-chloro-2-methylphenyl)-2, 6- dimethylpiperidin-4-yl]acetamide (Int-llc): To a stirred solution of (rac)-(2R,6S)-l-benzyl-4- (3-chloro-2-methylphenyl)-2,6-dimethylpiperidin-4-ol (2.7 g, 7.9 mmol) in ACN (27 mL) was added H2SO4 (5.4 mL) dropwise at 0 °C. The reaction was allowed to warm to rt and stirred 4 h at rt. The mixture was poured into ice water (150 mL) and basified to pH 8 with saturated Na2CO3(aq.). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil. The resulting mixture was purified by reversed-phase flash to afford the title compound as a yellow oil (2 g, 66%, yield). LCMS ESI-MS m / z =385[M+H]+.

[0197] Preparation of (rac)-(2R,6S)-l-benzyl-4-(3-chloro-2-methylphenyl)-2,6- dimethylpiperidin-4-amine (Int-11): A solution of (rac)-N-[(2R,6S)-l-benzyl-4-(3-chloro-2-methylphenyl)-2,6-dimethylpiperidin-4-yl]acetamide (2 g, 5.2 mmol) in HC1(20 mL, 6 M) was heated to 100 °C and stirred for 5 days. The reaction was allowed to cool down to rt. The mixture was poured into ice water (100 mL), basified to pH 8 with saturated Na2CO3(aq.) and extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil. The resulting mixture was purified by reversed-phase flash to afford the title compound as a yellow oil (550 mg, 30.8%, yield). LCMS ESLMS m / z =343 [M+H]+.Synthesis of tert-butyl 3-amino-3-(2,3-dichlorophenyl) pyrrolidine-l-carboxylate (Int-12)

[0198] Preparation of tert-butyl 3-(2,3-dichlorophenyl)-3-hydroxypyrrolidine-l-carboxylate (12a): To a stirred solution of l-bromo-2,3-di chlorobenzene (10 g, 44.3 mmol) in THF (200 mL) was added n-BuLi (19.5 mL, 48.7 mmol) dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C. Then to the above mixture was added tertbutyl 3-oxopyrrolidine-l-carboxylate (8.2 g, 44.3 mmol) in THF (25 mL) dropwise at -78 °C. The reaction mixture was stirred for 2 h at -78 °C. The resulting mixture was warmed to rt and then was poured into ice water (500 mL). The organics were extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The resulting mixture was purified by Silica gel column to afford the title compound as a yellow oil (7 g, 48%). LCMS ESI-MS m / z =332 [M+H]+.

[0199] Preparation of tert-butyl 3 -azido-3 -(2,3 -dichlorophenyl) pyrrolidine- 1 -carboxylate (12b): To a stirred solution of tert-butyl 3-(2,3-dichlorophenyl)-3-hydroxypyrrolidine-l- carboxylate (7 g, 21.1 mmol), PBus (8.5 g, 42.1 mmol) in THF (70 mL) was added DIAD (8.5 g, 42.1 mmol) dropwise at -40 °C under nitrogen atmosphere. Then to the above mixture was added DPPA (11.6 g, 42.1 mmol) dropwise at -40 °C. The resulting mixture was stirred for 16 h at rt. The reaction was used in the next step directly without purification.

[0200] Preparation of tert-butyl 3-amino-3-(2,3-dichlorophenyl) pyrrolidine- 1 -carboxylate (Int-12): To the reaction from the previous step was added PBus (8.5 g, 42.1 mmol) dropwise at rt. The resulting mixture was stirred for 1 h at rt. H2O (42 mL) was added dropwise at rt to the above reaction system. The resulting mixture was stirred for 16 h at rt. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x 30 mL), dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The crude product was purified by silica gel column to afford the title compound as a white solid (1.4 g, 20% yield for 2 steps). LCMS ESI-MS m / z =331 [M+H]+.

[0201] Synthesis of tert-butyl N-[2-amino-2-(2,3-dichloro-6-fluorophenyl) ethyl] carbamate (Int-13)lnt-13a lnt-13b lnt-13c Int-13

[0202] Preparation of tert-butyl N-[2-(2,3-dichloro-6-fluorophenyl)-2-oxoethyl] carbamate (Int-13a): To a stirred solution of l,2-dichloro-4-fluorobenzene (10 g, 60.6 mmol) in THF (200 mL) was added LDA (33.3 mL, 66.67 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at -78 °C. To the above mixture was added tert-butyl N-{[methoxy(methyl)carbamoyl] methyl} carbamate (13.2 g, 60.6 mmol) in THF (10 mL) dropwise at -78 °C. The resulting mixture was stirred for additional Ih at rt. The reaction was quenched by the addition of sat. NH4CI (100 mL) at 0 °C and extracted with EA (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (5 g, 24%). LCMS ESI-MS m / z. = 322 [M+H]+.

[0203] Preparation of tert-butyl N-[2-(2,3-dichloro-6-fluorophenyl)-2-hydroxyethyl]carbamate (Int-13b): To a stirred solution of tert-butyl N-[2-(2,3-dichloro-6-fluorophenyl)-2- oxoethyl]carbamate (1 g, 3.104 mmol, Int-13a) in methanol (15 mL) was added NaBH4 (0.23 g, 6.208 mmol) at rt under nitrogen atmosphere. The reaction mixture was heated to 60 °C and stirred for 4 h. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (30 mL) and extracted with DCM (5 x 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by reverse phase chromatography to afford the title compound as a white solid (520 mg, 51% yield). LCMS ESI-MS m / z = 324 [M+H]+.

[0204] Preparation of tert-butyl N-[2-azido-2-(2,3-dichloro-6-fluorophenyl) ethyl] carbamate (Int-13c): To a stirred solution of tert-butyl N-[2-(2,3-dichloro-6-fluorophenyl)-2-hydroxy ethyl] carbamate (520 mg, 1.6 mmol, Int-13b) and PBus (649 mg, 3.2 mmol) in THF (5.2 mL) were added DIAD (648 mg, 3.2 mmol) and DPPA (882 mg, 3.2 mmol) at -10 °C under nitrogenatmosphere. The resulting mixture was warm up to rt and stirred for 3 h at rt. The resulting mixture was used in the next step directly without further purification. LCMS ESI-MS m / z = 349 [M+H]+.

[0205] Preparation of tert-butyl N-[2-amino-2-(2,3-dichloro-6-fluorophenyl) ethyl] carbamate (Int-13): A solution of Int-13c was treated with NaOH (3 mL, IM) and heated to 60 °C and stirred for 16 h. The mixture was cooled to rt and was diluted with water (30 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by reverse phase chromatography to afford tert-butyl N-[2-amino-2-(2,3-dichloro-6-fluorophenyl) ethyl] carbamate as an off-white oil (200 mg, 41% for 2 steps). LCMS ESI-MS m / z = 323[M+H]+Synthesis of tert-butyl 3-amino-3-(2,3-dichloro-4-tolyl)-l-pyrrolidinecarboxylate (Int-14)

[0206] Preparation of tert-butyl 3-(2,3-dichloro-4-tolyl)-3-hydroxy-l-pyrrolidinecarboxylate (Int-14a): To a 250 mL round-bottom flask were added 2,3 -di chlorotoluene (1.91 g, 11.9 mmol, 1.1 eq.) and THF (20 mL) at room temperature. Followed by the addition of n-BuLi (4.75 mL, 2.5 M, 374.7 mmol, 1.1 eq.) dropwise at -78 °C. The mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. To the above mixture was added tert-butyl 3-oxo-l- pyrrolidinecarboxylate (2 g, 10.8 mmol, 1.0 eq.) in THF (6 mL) dropwise over 10 min at -78°C. The resulting mixture was stirred for additional Ih at -78 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq.) (50 mL) at -78 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, 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 white solid (1.5 g, 40% yield). LCMS EI-MS m / z 713.3 [2M+Na]+.

[0207] Preparation of tert-butyl 3-azido-3-(2,3-dichloro-4-tolyl)-l-pyrrolidinecarboxylate (Int-14b): To a 250 ml round-bottom flask were added tert-butyl 3-(2,3-dichloro-4-tolyl)-3-hydroxy- 1-pyrrolidinecarboxylate (Int-a) (1.19 g, 3.44 mmol, 1 eq.), THF (12 mL), and PBus (1.39 g, 6.87 mmol, 2 eq.) at room temperature. Followed by the addition of DIAD (1.39 g, 6.87 mmol, 2 eq.) dropwise at -10 °C. Finally, to the above mixture was added DPPA (1.89 g, 6.87 mmol, 2 eq.) dropwise at -10 °C. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The crude was directly used to the next step.

[0208] Preparation of tert-butyl 3-amino-3-(2,3-dichloro-4-tolyl)-l-pyrrolidinecarboxylate (Int-c): To the crude reaction (Int-b) was added PBus (2.09 g, 10.3 mmol) dropwise at room temperature. The resulting mixture was stirred for additional Ih at room temperature. Followed by the addition of H2O (7 mL) dropwise at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the title compound as a white solid (190 mg, 16% yield). LCMS ELMS m / z. 711 [2M+Na]+.1H NMR (400 MHz, CHLOROFORM-d) δ 7.20 - 7.10 (m, 2H), 4.14 - 3.96 (m, IH), 3.68 - 3.46 (m, 3H), 2.41 (s, 3H), 2.40 - 2.24 (m, 2H), 1.48 (s, 9H).

[0209] The racemic compound (Int-14c) (190 mg) was purified by Prep-Chiral-HPLC to afford Peak 1 (RT1 = 29.9 min, 73 mg) tert-butyl-(R)-3-amino-3-(2,3-dichloro-4-tolyl)-l- pyrrolidinecarboxylate (Int-14-(R)) as a white solid and Peak 2 (39.0 min, 73 mg) tert-butyl-(S)- 3-amino-3-(2,3-dichloro-4-tolyl)-l-pyrrolidinecarboxylate (Int-14-(S)) as a white solid. The absolute stereochemistry was assigned arbitrarily.Example 1 : 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 1)

[0210] Preparation of tert-butyl 6-bromo-3, 3 -dimethyl-2-oxoindoline-l -carboxylate (la): A solution of 6-bromo-3,3- dimethyl-lH-indol-2-one (1 g, 4.16 mmol, 1 eq.) in THF (10 mL) was treated with NaH (0.11 g, 4.58 mmol, 1.1 eq) for 0.5 h at 0 °C under a nitrogen atmospherefollowed by the addition of BOC2O (1 g, 4.58 mmol, 1.1 eq.) dropwise at 0 °C. The resulting mixture was warmed to rt and stirred for 16 h. The mixture was diluted with water (50 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford as the title compound as a brown solid (1.1 g, 77% yield).

[0211] Preparation of tert-butyl 6-((l-(tert-butoxycarbonyl)-3-(3-chloro-2- methylphenyl)azetidin-3-yl)amino)-3,3-dimethyl-2-oxoindoline-l-carboxylate (lb): To a solution of tert-butyl 6-bromo-3,3-dimethyl-2-oxoindole-l-carboxylate (la) (2.2 g, 6.46 mmol, 1 eq.), tert-butyl 3-amino-3-(3-chloro-2- methylphenyl)azetidine-l -carboxylate (Int-1) (1.02 g, 6.46 mmol, 1 eq.), Qphos (460 mg, 0.65 mmol, 0.1 eq.) and Cs2CO3(5.26 g, 16.15 mmol, 2.5 eq.) in 1,4-dioxane (66 mL) was added Qphos Pd G3 (620 mg, 0.65 mmol, 0.1 eq.) at rt under a nitrogen atmosphere. The mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to rt, diluted with water (300 mL) and extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford the title compound as a white solid (850 mg, 23% yield).

[0212] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (1c): A solution of tert-butyl 6-((l-(tert-butoxycarbonyl)-3-(3-chloro-2- methylphenyl)azetidin-3-yl)amino)-3,3- dimethyl-2-oxoindole-l -carboxylate (lb) (850 mg, 1.53 mmol) in DCM (4.3 mL) was treated with HCl / dioxane (4.3 mL) for 2 h at rt. The resulting mixture was diluted with water (20 mL), basified to pH 8-9 with POCI3(aq.) and extracted with EA (3 x 7 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as a white solid (460 mg, crude). The crude product was used for the next step without further purification.

[0213] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 1): A solution of 6-((3-(3-chloro-2-methylphenyl)azetidin- 3-yl)amino)-3,3-dimethyl-lH-indol-2- one (1c) (460 mg, 1.29 mmol, 1 eq.) and TEA (261 mg, 2.44 mmol, 1.9 eq.) in DCM (4.6 mL) was treated with acryloyl chloride (116 mg, 1.29 mmol, 1 eq.) for 1 h at 0 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford the title compound as a white solid (406.8 mg, 76% yield (2 steps)).1H NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 7.67 (dd, J= 7.9, 1.3 Hz, 1H), 7.37 (dd, J= 8.0, 1.1 Hz, 1H), 7.25 (t, J= 7.9 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J= 8.0Hz, 1H), 6.39 (dd, J= 17.0, 10.3 Hz, 1H), 6.18 - 6.07 (m, 2H), 5.98 (dd, J= 8.1, 2.1 Hz, 1H), 5.70 (dd, J= 10.3, 2.2 Hz, 1H), 4.92 (s, 1H), 4.60 - 4.41 (m, 2H), 4.32 (d, J= 10.3 Hz, 1H), 2.32 (s, 3H), 1.11 (s, 6H). LCMS ELMS m / z = 410 [M+H]+.Example 2: 6-((3-(3-Chloro-2-methylphenyl)-l-(2-fluoroacetyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 2)1c Compound 2

[0214] Preparation of 6-((3-(3-chloro-2-methylphenyl)-L(2-fluoroacetyl)azetidin-3- yl)amino)-3,3-dimethylindolin-2-one (Compound 2): A solution of 6-((3-(3-chloro-2- methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (1c) (30 mg, 0.084 mmol, 1 eq.) in DCE (1.5 mL) was treated with AlMe3(6.08 mg, 0.084 mmol, 1 eq.) for 0.5 h at rt under nitrogen atmosphere followed by the addition of ethyl 2 -fluoroacetate (7.16 mg, 0.067 mmol, 0.8 eq.) dropwise at rt. The resulting mixture was heated to 80 °C and stirred for 16 h. The mixture was cooled to rt, diluted with water (8 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by reversed-phase chromatography to afford the title compound as a white solid (13.1 mg, 34% yield).1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.66 (d, J= 7.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 - 7.18 (m, 1H), 6.92 (s, 1H), 6.84 (d, J= 8.1 Hz, 1H), 6.09 (d, J= 2.1 Hz, 1H), 5.98 (dd, J= 8.1, 2.1 Hz, 1H), 5.05 (s, 1H), 4.95 - 4.85 (m, 2H), 4.57 - 4.39 (m, 2H), 4.36 - 4.27 (m, 1H), 2.34 - 2.27 (m, 3H), 1.11 (s, 6H). LCMS ELMS m / z = 416 [M+H]+.Example 3: (E)-6-((l-(But-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 3)

[0215] Preparation of (E)-6-((l-(but-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3- yl)amino)-3,3-dimethylindolin-2-one (Compound 3): Compound 3 was synthesized by usingthe crude 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (1c) (16 mg, 0.05 mmol, 1 eq.) and crotonyl chloride (4.7 mg, 0.05 mmol, 1 eq.) by following the procedure from Compound 1 to afford the title compound as a white solid (12 mg, 61% yield).XH NMR (400 MHz, METHANOL-d4) δ 7.57 (d, J= 7.6 Hz, 1H), 7.33 (d, J= 7.9 Hz, 1H), 7.21 (t, J= 7.9 Hz, 1H), 6.91 - 6.81 (m, 2H), 6.21 - 6.07 (m, 3H), 4.88 (d, J= 14.0 Hz, 1H), 4.67 - 4.51 (m, 2H), 4.41 (d, J= 10.5 Hz, 1H), 2.39 (s, 3H), 1.89 (dd, J= 6.9, 1.5 Hz, 3H), 1.22 (s, 6H). LCMS ES-MS m / z = 424 [M+H]+.Example 4: 6-((3-(3-Chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 4)Compound 4

[0216] Preparation of 6-((3-(3-chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3- yl)amino)-3,3-dimethylindolin-2-one (Compound 4): To a solution of 6-((3-(3-chloro-2- methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (1c) (17 mg, 0.05 mmol, 1 eq.) in dry acetonitrile (1 mL) was added sodium 2-fluoroacrylate (8.4 mg, 0.07 mmol, 1.4 eq.), DIEA (30 mg, 0.25 mmol, 5 eq.), and T3P (44 mg, 0.15 mmol, 3 eq.) at rt and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with DI water (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (11 mg, 55% yield).1H NMR (400 MHz, METHANOL-d4) δ 7.58 (d, J= 7.8 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.20 (dd, J= 8.1, 1.8 Hz, 1H), 6.15 (d, J= 1.5 Hz, 1H), 5.66 - 5.48 (m, 1H), 5.23 (dd, J= 16.1, 3.5 Hz, 1H), 5.10 - 4.92 (m, 1H), 4.83 - 4.74 (m, 1H), 4.67 (br d, J= 10.5 Hz, 1H), 4.45 (br d, J= 10.8 Hz, 1H), 2.38 (s, 3H), 1.22 (s, 6H). LCMS ES-MS m / z = 428 [M+H]+.Example 5: 6-((3-(3-Chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 5)Compound 5

[0217] Preparation of 6-((l-(but-2-ynoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)- 3,3-dimethylindolin-2-one (Compound 5): Compound 5 was synthesized using crude 6-((3-(3- chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (1c) (15 mg, 0.041 mmol, 1 eq.) and 2-butynoyl chloride (4.2 mg, 0.041 mmol, 1 eq.) by following the procedure from Compound 1 to afford the title compound as a white solid (12 mg, 66% yield).1H NMR (400 MHz, METHANOL-d4) δ 7.56 (d, J= 7.6 Hz, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 6.87 (d, J= 8.1 Hz, 1H), 6.19 (dd, J= 8.1, 2.1 Hz, 1 H), 6.15 (d, J= 2.0 Hz, 1 H), 4.84 - 4.73 (m, 1H), 4.64 - 4.48 (m, 2H), 4.38 (d, J=10.6 Hz, 1H), 2.38 (s, 3H), 2.02 (s, 3H), 1.22 (s, 6H). LCMS ES-MS m / z = 422 [M+H]+.Example 6: 6-((l-Acryloyl-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 6)

[0218] Preparation of tert-butyl 6-(( l-(tert-butoxycarbonyl)-3-(2-chl oro-3 - methylphenyl)azetidin-3-yl)amino)-3,3-dimethyl-2-oxoindoline-l-carboxylate (6a): Compound 6a was synthesized using tert-butyl 3-amino-3-(2-chloro-3- methylphenyl)azetidine-l- carboxylate (Int-2) (450 mg, 1.52 mmol, 1 eq.) and tert-butyl 6-bromo-3,3-dimethyl-2- oxoindole-1 -carboxylate (la) (516 mg, 1.52 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (400 mg, 47% yield). LCMS ESIMS m / z = 556 [M+H]+.

[0219] Preparation of 6-((3-(2-chl oro-3 -methylphenyl)azeti din-3 -yl)amino)-3, 3- dimethylindolin-2-one hydrochloride (6b): To a stirred solution of tert-butyl 6-((l-(tert- butoxycarbonyl)-3-(2-chl oro-3 -methylphenyl)azeti din-3 -yl)amino)-3, 3 -dimethyl-2-oxoindoline- 1-carboxylate (6a) (400 mg, 0.719 mmol) in DCM (2 mL) was added HC1(2 mL, 4 M in dioxane) at rt. The reaction mixture was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to afford the title compound as a brown solid (350 mg). The crude product was used for next step without further purification. LCMS ESI-MS m / z = 356 [M+H]+.I l l

[0220] Preparation of 6-((l-acryloyl-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 6): To a stirred solution of 6-((3-(2-chloro-3- methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one hydrochloride (6b) (180 mg, 0.51 mmol, 1 eq.) and acryloyl chloride (54.9 mg, 0.61 mmol, 1.2 eq.) in DCM (1.8 mL) was added TEA (256 mg, 2.53 mmol, 5 eq.) at rt. The resulting mixture was stirred for 3 h and then was concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford the title compound as a white solid (90.0 mg, 27% yield (2 steps)).1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.66 (dd, J= 7.3, 2.1 Hz, 1H), 7.34 - 7.21 (m, 2H), 6.93 - 6.78 (m, 2H), 6.39 (dd, J= 17.0, 10.3 Hz, 1H), 6.13 (dd, J= 16.9, 2.1 Hz, 2H), 5.98 (dd, J= 8.1, 2.1 Hz, 1H), 5.69 (dd, J= 10.4, 2.2 Hz, 1H), 4.90 (s, 1H), 4.52 (d, J= 9.4 Hz, 2H), 4.29 (d, J = 10.4 Hz, 1H), 2.31 (s, 3H), 1.11 (s, 6H). LCMS EI-MS m / z = 410 [M+H]+.Example 7 : 6-((l-Acryloyl-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 7)ODCompound 7

[0221] Preparation of 6-((3 -(2-chl oro-3 -methylphenyl)- l-(2-fluoroacryloyl)azeti din-3 - yl)amino)-3,3-dimethylindolin-2-one (Compound 7): A solution of 6-((3 -(2-chl oro-3 - methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one hydrochloride (6b) (85 mg, 0.22 mmol, 1 eq.) and 2-fluoroprop-2-enoic acid (23.4 mg, 0.26 mmol, 1.2 eq.) in DMF (0.9 mL) was treated with DIEA (140 mg, 1.08 mmol, 5 eq.) and T3P (103 mg, 0.33 mmol, 1.5 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was warmed to rt and stirred for 3 h. The mixture was diluted with water (5 mL) and extracted with DCM (3 x 2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by reversed-phase chromatography to afford the title compound as a white solid (40.6 mg, 43% yield).1H NMR (300 MHz, DMSO-cf) 5 10.03 (s, 1H), 7.69 (dd, J = 7.2, 2.3 Hz, 1H), 7.33 - 7.21 (m, 2H), 6.92 - 6.81 (m, 2H), 6.11 (d, J= 2.0 Hz, 1H), 5.99 (dd, J = 8.1, 2.1 Hz, 1H), 5.63 - 5.27 (m, 2H), 5.01 (s, 1H), 4.66 (d, J = 9.4 Hz, 2H), 4.33 (d, J= 10.7 Hz, 1H), 2.31 (s, 3H), 1.11 (s, 6H).19F NMR (282 MHz, DMSO-d6): δ - 114.54. LCMS EI-MS m / z = 428 [M+H]+.Example 8: (E)-6-((l-(But-2-enoyl)-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 8)Comound 8

[0222] Preparation of (E)-6-((l-(but-2-enoyl)-3-(2-chl oro-3 -m ethylphenyl)azeti din-3 - yl)amino)-3,3-dimethylindolin-2-one (Compound 8): Compound 8 was synthesized by using 6-((3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one hydrochloride (6b) (85 mg, 0.22 mmol, 1 eq.) and 2-butenoyl chloride (27.1 mg, 0.26 mmol, 1.2 eq.) by following the procedure from Compound 1 to afford the title compound as a white solid (30 mg, 31% yield).1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 7.72 - 7.63 (m, 1H), 7.32 - 7.20 (m, 2H), 6.93 - 6.79 (m, 2H), 6.74 - 6.60 (m, 1H), 6.17 - 6.05 (m, 2H), 5.98 (dd, J= 8.0, 2.1 Hz, 1H), 4.85 (s, 1H), 4.48 (d, J = 9.4 Hz, 2H), 4.26 (d, J= 10.5 Hz, 1H), 2.31 (s, 3H), 1.89 - 1.77 (m, 3H), 1.11 (s, 6H). LCMS ELMS m / z = 424 [M+H]+.Example 9: 6-((l-Acryloyl-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (Compound 9)

[0223] Preparation of tert-butyl 3-(2,3-dichlorophenyl)-3-((3,3-dimethyl-2-oxoindolin-6- yl)amino)azetidine-l -carboxylate (9a): To a solution of tert-butyl 3-(2,3-dichlorophenyl)-3- ((methylsulfonyl)oxy)azetidine-l -carboxylate (Int-3b) (74 mg, 0.19 mmol, 1.1 eq.) in DMF (dry, 0.8 mL) was added 6-amino-3,3-dimethylindolin-2-one (30 mg, 0.17 mmol, 1.0 eq.), Na2CO3(54 mg, 0.51 mmol, 3.0 eq.). The reaction mixture was heated at 60 °C in microwave for 4 h. The reaction was then diluted with EtOAc (30 mL). The organic layers were washed with water (5 mL x 5), brine (15 mL), and dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (21 mg, 25% yield). LCMS ESMS m / z = 476 [M]+.

[0224] Preparation of 6-((3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2- one TFA (9b): To a solution of tert-butyl 3-(2,3-dichlorophenyl)-3-((3,3-dimethyl-2-oxoindolin- 6-yl)amino)azetidine-l -carboxylate (9a) (25 mg, 0.07 mmol) in DCM (dry, 1 mL) was cooled to 0 °C. TFA (0.2 mL, in large excess) was added dropwise to the solution at 0 °C. The resultingsolution was stirred at 0 °C for 30 minutes, then stirred at rt for 2h. The reaction was monitored by LCMS. The crude mixture was concentrated to dryness and used for next step without further purification. LCMS ES-MS m / z = 376 [M]+.

[0225] Preparation of 6-((l-acryloyl-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 9): To a solution of crude 6-((3-(2,3- dichlorophenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one TFA (9b) (25 mg, 0.066 mmol, 1 eq.) in dry DCM (1 mL) was cooled to 0 °C. Diisopropylethylamine (34 μL, 0.2 mmol, 3 eq.) was added dropwise at 0 °C, followed by acryloyl chloride (9.02 mg, 0.10 mmol, 1.5 eq.). The resulting solution was stirred at rt for 1 h. The reaction was monitored by LCMS. The resulting solution was diluted with ethyl acetate (15 mL), washed with DI water (3x5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with (EtOAc / hexane =10:5) to afford the title compound as white solid (12.0 mg, 40% yield).1H NMR (400 MHz, CD3OD): δ 7.70 (d, J= 7.4 Hz, 1H), 7.46 (d, J= 7.5 Hz, 1H), 7.31 (t, J= 7.9 Hz, 1H), 6.88 (d, J= 7.8 Hz, 1H), 6.40 - 6.30 (m, 2H), 6.21 - 6.16 (m, 2H), 5.77 (dd, .7= 10.4, 1.6 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.72 - 4.63 (m, 2H), 4.43 (d, J= 10.8 Hz, 1H), 1.21 (s, 6H). LCMS ES-MS m / z = 430 [M]+.Example 10: 6-((3-(2,3-Dichlorophenyl)-l-(2-fluoroacryloyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 10)Compound 10

[0226] Preparation of 6-((3 -(2,3 -dichlorophenyl)- l-(2-fluoroacryloyl)azeti din-3 -yl)amino)- 3,3-dimethylindolin-2-one (Compound 10): Compound 10 was synthesized using crude 6-((3- (2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one TFA (9b) (15 mg, 0.04 mmol, 1 eq.) and sodium 2 -fluoroacrylate (8.04 mg, 0.07 mmol, 1.8 eq.) by following the procedure from Compound 4 to afford the title compound as white solid (7.5 mg, 42% yield).1H NMR (400 MHz, METHANOL-d4): δ 7.71 (d, J= 7.8 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.31 (t, J= 7.9 Hz, 1H), 6.88 (d, J= 7.8 Hz, 1H), 6.21 - 6.16 (m, 2H), 5.64 - 5.53 (d, J= 3.5 Hz, 1H), 5.24 (dd, J= 16.0, 3.6 Hz, 1H), 5.10 (m, 1H), 4.78 - 4.63 (m, 3H), 4.44 (d, J= 10.8 Hz, 1H), 1.22 (s, 6H).19F NMR (376 MHz, METHANOL-d4) δ - 116.9 (s, IF). LCMS ES-MS m z\ m / z = 448 [M]+.Example 11 : (E)-6-((l-(But-2-enoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 11)

[0227] Preparation of (E)-6-((l-(but-2-enoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-3,3- dimethylindolin-2-one (Compound 11): Compound 11 was synthesized using 6-((3-(2,3- dichlorophenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one TFA (9b) (10 mg, 0.027 mmol, 1 eq.) and crotonyl chloride (3.33 mg, 0.032 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as white solid (5.0 mg, 42% yield).1H NMR (400 MHz, CD3OD): δ 7.70 (d, J= 6.8 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.19 - 6.07 (m, 3H), 4.94 (m, 1H), 4.68 - 4.53 (m, 3H), 4.40 (d, J= 10.8 Hz, 1H), 1.90 (dd, J= 6.9, 1.4 Hz, 3 H), 1.22 (s, 6H). LCMS ES-MS m / z = 444 [M]+.Example 12: 6-(3-(3-Chloro-2-tolyl)-l-crotonoyl-3-azetidinylamino)-l-methyl-3,3- dimethyl-2-indolinone (Compound 12)

[0228] Preparation of tert-butyl 3-(3-chloro-2-tolyl)-3-(l-methyl-3,3-dimethyl-2-oxo-6- indolinylamino)-l-azetidinecarboxylate (12a): Compound 12a was synthesized using 6-bromo- l-methyl-3,3-dimethyl-2-indolinone (43 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3- chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb. The crude reaction was purified by silica gel column chromatography to afford the title compound as a white solid (55 mg, 69% yield).

[0229] Preparation of 6-(3-(3-chloro-2-tolyl)-3-azetidinylamino)-l-methyl-3,3-dimethyl-2- indolinone TFA (12b): Compound 12b was synthesized by using tert-butyl 3-(3-chloro-2-tolyl)- 3-(l-methyl-3,3-dimethyl-2-oxo-6-indolinylamino)-l-azetidinecarboxylate (12a) (15 mg, 0.03 mmol) by following the procedure from Compound 9b to afford the title compound as a brownish oil and was used in the next step without further purification.

[0230] Preparation of 6-(3-(3-chloro-2-tolyl)-l-crotonoyl-3-azetidinylamino)-l-methyl-3,3- dimethyl-2-indolinone (Compound 12): Compound 12 was synthesized using crude 6-(3-(3-chloro-2-tolyl)-3-azetidinylamino)-l-methyl-3,3-dimethyl-2-indolinone TFA (12b) (11 mg, 0.03 mmol, 1 eq.) and crotonyl chloride (3.3 mg, 0.03 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (5 mg, 35% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.40 (d, J= 7.9 Hz, 1H), 7.34 (d, J= 7.5 Hz, 1H), 5 7.26 - 7.19 (m, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.28 (dd, J= 7.9, 2.0 Hz, 1H), 6.08 (d, J= 1.9 Hz, 1H), 5.78 - 5.63 (m, 1 H), 5.20 (dd, J= 15.6, 3.4 Hz, 1H), 4.87 (br dd, J= 10.4, 4.1 Hz, 1H), 4.71 (br d, J =11.1 Hz, 1H), 4.60 (br d, J= 11.3 Hz, 1H), 4.60 (br d, J= 11.3 Hz, 1H), 3.08 (s, 3H), 2.38 (s, 3 H), 1.31 (s, 6 H). LCMS ES-MS m / z = 442 [M+H]+.Example 13: 6-(3-(3-Chloro-2-tolyl)-l-crotonoyl-3-azetidinylamino)-l-methyl-3,3- dimethyl-2-indolinone (Compound 13)Compound 13

[0231] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,3,3- trimethylindolin-2-one (Compound 13): Compound 13 was synthesized using 6-(3-(3-chloro- 2-tolyl)-3-azetidinylamino)-l-methyl-3,3-dimethyl-2-indolinone TFA (12b) (10 mg, 0.02 mmol, 1 eq.) and acryloyl chloride (1.9 mg, 0.02 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (5 mg, 56% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.47 - 7.30 (m, 2H), 7.27 - 7.17 (m, 1H), 6.95 (d, J= 7.9 Hz, 1H), 6.48 - 6.35 (m, 1H), 6.35 - 6.21 (m, 2H), 6.09 (d, J= 2.0 Hz, 1H), 5.75 (dd, J= 10.3, 1.8 Hz, 1H), 4.85 (br d, J= 8.6 Hz, 1H), 4.78 - 4.52 (m, 3H), 3.08 (s, 3H), 2.41 (s, 3H), 1.31 (s, 6H). LCMS ES-MS m / z = 424 [M+H]+.Example 14: 6-((l-Acryloyl-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-l,3,3- trimethylindolin-2-one (Compound 14)Compound 6 Compound 14

[0232] Preparation of 6-((l-acryloyl-3-(2-chloro-3-methylphenyl)azetidin-3-yl)amino)-l,3,3- trimethylindolin-2-one (Compound 14): To a stirred solution of 6-((l-acryloyl-3-(2-chloro-3- methylphenyl)azetidin-3-yl)amino)-3,3-dimethylindolin-2-one (Compound 6) (76 mg, 0.19mmol, 1 eq.) and Mel (57.9 mg, 0.41 mmol, 2.1 eq.) in DMF (0.7 mL) was added Cs2CO3(121 mg, 0.37 mmol, 2 eq.) at rt. The reaction mixture was stirred for 4 h at rt. The reaction was quenched with water (1 mL) and the resulting homogeneous mixture was purified by reversed- phase flash chromatography to afford the title compound as an off-white solid (36.9 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J= 6.6, 2.7 Hz, 1H), 7.36 - 7.23 (m, 2H), 6.98 (s, 1H), 6.91 (d, J= 8.0 Hz, 1H), 6.39 (dd, J= 17.0, 10.3 Hz, 1H), 6.21 - 6.03 (m, 3H), 5.70 (dd, J= 10.3, 2.2 Hz, 1H), 4.91 (s, 1H), 4.56 (d, J= 9.2 Hz, 2H), 4.31 (s, 1H), 3.01 (s, 3H), 2.31 (s, 3H), 1.13 (s, 6H). LCMS EI-MS m / z = 424 [M+H]+.Example 15: 6-((3-(3-Chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3-yl)amino)- l,3,3-trimethylindolin-2-one (Compound 15)

[0233] Preparation of 6-((3-(3-chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3- yl)amino)-l,3,3-trimethylindolin-2-one (Compound 15): To a solution of 6-(3-(3-chloro-2- tolyl)-3-azetidinylamino)-l-methyl-3,3-dimethyl-2-indolinone TFA (12b) (11 mg, 0.03 mmol, 1 eq.) in dry THF (1 mL) was added DIPEA (19 mg, 0.15 mmol, 3 eq.), HATU (22 mg, 0.59 mmol, 1.2 eq.), and 2-fluoroacrylic acid (4.4 mg, 0.05 mmol, 1 eq.). The resulting solution was stirred at rt for 20 h. The resulting solution was diluted with ethyl acetate (15 mL), washed with DI water (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and Prep-HPLC to afford title compound as a white solid (4 mg, 18% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.34 - 7.10 (m, 4H), 6.86 (d, J= 8.0 Hz, 1H), 6.19 (dd, J= 7.9, 2.0 Hz, 1H), 5.99 (d, J= 1.9 Hz, 1H), 5.67 - 5.55 (m, 1 H), 5.11 (dd, J= 15.6, 3.4 Hz, 1H), 4.94 (br d, J= 9.5 Hz, 1H), 4.78 (br dd, J =10.4, 4.1 Hz, 1H), 4.62 (br d, J = 11.1 Hz, 1H), 4.51 (br d, J= 11.3 Hz, 1H), 3.05 - 2.92 (m, 3H), 2.29 (s, 3 H), 1.28 - 1.16 (m, 6 H). LCMS ES-MS, m / z = 442 [M+H]+.Example 16: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- (cyclopropylmethyl)-3,3-dimethylindolin-2-one (Compound 16)

[0234] Preparation of 6-bromo-l-(cyclopropylmethyl)-3,3-dimethylindolin-2-one (16a): To a solution of 6-bromo-3,3-dimethylindolin-2-one (60 mg, 0.25 mmol, 1 eq.) in DMF (1 mL), Cs2CO3(204mg, 0.63mmol, 2.5 eq.) and l-(bromomethyl)cyclopropane (51 mg, 0.38 mmol, 1.5 eq.) were added to the solution. The resulting solution was stirred at rt for 16 h. The resulting mixture was diluted with ethyl acetate (15 mL) and washed with DI water (3 x 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography as a white solid (58 mg, 79% yield). LCMS ES-MS m / z = 294 [M+H]+.

[0235] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-(cyclopropylmethyl)-3,3- dimethyl-2-oxoindolin-6-yl)amino)azetidine-l-carboxylate (16b): Compound 16b was synthesized using 6-bromo-l-(cyclopropylmethyl)-3,3-dimethylindolin-2-one (16a) (50 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (58 mg, 66% yield). LCMS ES-MS m / z = 454 [M-C4H7]+.

[0236] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- (cyclopropylmethyl)-3,3-dimethylindolin-2-one TFA (16c): Compound 16c was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-(cyclopropylmethyl)-3,3-dimethyl-2- oxoindolin-6-yl)amino)azetidine-l -carboxylate (16b) (26 mg, 0.05 mmol, 1 eq.) by following the procedure from Compound 9b to afford the title compound as a brownish oil and was used for the next step without further purification. LCMS ES-MS m / z = 410 [M+H]+.

[0237] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- (cyclopropylmethyl)-3,3-dimethylindolin-2-one (Compound 16): Compound 16 was synthesized using crude 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- (cyclopropylmethyl)-3,3-dimethylindolin-2-one TFA (16c) (20 mg, 0.05 mmol, 1 eq.) andacryloyl chloride (4.6 mg, 0.05 mmol, 1 eq.) by following the procedure Compound 9 to afford the title compound as a white solid (8 mg, 34% yield).1H NMR (400 MHz, CHLOROFORM-d) 5 7.45 - 7.30 (m, 2H), 7.24 - 7.15 (m, 1H), 6.95 (d, J= 7.9 Hz, 1H), 6.48 - 6.33 (m, 1H), 6.33 - 6.20 (m, 2H), 6.16 (d, J= 1.9 Hz, 1H), 5.74 (dd, J= 10.3, 1.6 Hz, 1H), 4.84 (br d, J= 8.5 Hz, 1H), 4.75 - 4.60 (m, 2H), 4.60 - 4.45 (m, 1H), 3.44 (d, J= 6.9 Hz, 2 H), 2.40 (s, 3H), 1.30 (s, 6H), 1.07 - 0.96 (m, 1H), 0.54 - 0.45 (m, 2H), 0.36 - 0.25 (m, 2H). LCMS ES-MS m / z = 464 [M+H]+.Example 17: (E)-6-((3-(3-Chloro-2-methylphenyl)-l-(4-methoxybut-2-enoyl)azetidin-3- yl)amino)-l-(cyclopropylmethyl)-3,3-dimethylindolin-2-one (Compound 17)

[0238] Preparation of (E)-6-((3-(3-chloro-2-methylphenyl)-l-(4-methoxybut-2-enoyl)azetidin- 3-yl)amino)-l-(cyclopropylmethyl)-3,3-dimethylindolin-2-one (Compound 17): Compound 17 was synthesized using crude 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- (cyclopropylmethyl)-3,3-dimethylindolin-2-one TFA (16c) (23 mg, 0.06 mmol, 1 eq.) and (E)-4- methoxy-2-butenoic acid (7 mg, 0.06 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (16 mg, 56% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.36 (t, J= 7.8 Hz, 2H), 7.23 - 7.15 (m, 1H), 6.99 - 6.90 (m, 2H), 6.29 - 6.12 (m, 3H), 4.85 (br d, J= 8.9 Hz, 1H), 4.74 - 4.58 (m, 2H), 4.58 - 4.49 (m, 1H), 4.17 - 4.05 (m, 2H), 3.44 (d, J= 6.9 Hz, 2H), 3.40 (s, 3H), 2.39 (s, 3H), 1.29 (s, 6H), 1.10 - 0.94 (m, 1H), 0.50 - 0.34 (m, 2H), 0.34 - 0.25 (m, 2H). LCMS ES-MS m / z = 508 [M+H]+.Example 18: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3-dimethyl- l-((tetrahydro-2H-pyran-4-yl)methyl)indolin-2-one (Compound 18)

[0239] Preparation of 6-bromo-3, 3 -dimethyl- l-((tetrahydro-2H-pyran-4-yl)methyl)indolin-2- one (18a): Compound 18a was synthesized using 6-bromo-3,3-dimethylindolin-2-one (100 mg, 0.42 mmol, leq.) and 4-(bromomethyl)tetrahydro-2H-pyran (112 mg, 0.63 mmol, 1.5 eq.) by following the procedure from Compound 16a to afford the title compound as a white solid (106 mg, 75% yield). LCMS ES-MS m / z. = 338 [M+H]+.

[0240] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((3,3-dimethyl-2-oxo-l- ((tetrahydro-2H-pyran-4-yl)methyl)indolin-6-yl)amino)azetidine-l-carboxylate (18b): Compound 18b was synthesized using 6-bromo-3,3-dimethyl-l-((tetrahydro-2H-pyran-4- yl)methyl)indolin-2-one (18a) (35 mg, 0.10 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2- tolyl)-l-azetidinecarboxylate (Int-1) (31 mg, 0.10 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (36 mg, 63% yield). LCMS ES-MS m / z = 498 [M-C4H7]+.

[0241] Preparation of 6-((3 -(3 -chi oro-2-methylphenyl)azeti din-3 -yl)amino)-3, 3 -dimethyl- 1- ((tetrahydro-2H-pyran-4-yl)methyl)indolin-2-one TFA (18c): Compound 18c was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((3,3-dimethyl-2-oxo-l-((tetrahydro-2H-pyran- 4-yl)methyl)indolin-6-yl)amino)azetidine-l -carboxylate (18b) (36 mg, 0.07 mmol, 1 eq.) by following the procedure from Compound 9b to afford the title compound as a brownish oil and was used for the next step without further purification. LCMS ES-MS m / z = 454 [M+H]+.

[0242] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethyl-l-((tetrahydro-2H-pyran-4-yl)methyl)indolin-2-one (Compound 18): Compound 18 was synthesized by using crude 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethyl-l-((tetrahydro-2H-pyran-4-yl)methyl)indolin-2-one TFA (18c) (30 mg, 0.065 mmol, 1 eq.) and acryloyl chloride (5.9 mg, 0.065 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (15 mg, 45% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.40 (d, J= 7.9 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.25 - 7.17 (m,1H), 6.95 (d, J= 8.0 Hz, 1H), 6.44 - 6.34 (m, 1H), 6.31 - 6.21 (m, 2H), 6.05 (d, J= 1.9 Hz, 1H), 5.74 (dd, J= 10.3, 1.50 Hz, 1H), 4.92 - 4.75 (m, 1H), 4.72 - 4.60 (m, 2H), 4.60 - 4.48 (m, 1H), 4.00 - 3.88 (m, 2H), 3.33 (d, J= 7.4 Hz, 2H), 3.30 (t, J= 1.0 Hz, 2H), 2.41 (s, 3H), 1.86 (dddt, J = 15.0, 11.3, 7.5, 3.6, 3.6 Hz, 1H), 1.51 - 1.44 (m, 2H), 1.41 - 1.32 (m, 2H), 1.29 (s, 6H). LCMS ES-MS m / z = 508 [M+H]+.Example 19: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3-dimethyl- l-(2,2,2-trifluoroethyl)indolin-2-one (Compound 19)

[0243] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((3,3-dimethyl-2-oxo-l-(2,2,2- trifluoroethyl)indolin-6-yl)amino)azetidine-l -carboxylate (19a): Compound 19a was synthesized using 6-bromo-3,3-dimethyl-l-(2,2,2-trifluoroethyl)indolin-2-one (39 mg, 0.12 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (36 mg, 0.12 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (36 mg, 63% yield). LCMS ES-MS, m / z = 482 [M-C4H?]+.

[0244] Preparation of 6-((3 -(3 -chi oro-2-methylphenyl)azeti din-3 -yl)amino)-3, 3 -dimethyl- 1- (2,2,2-trifluoroethyl)indolin-2-one TFA (19b): Compound 19b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((3,3-dimethyl-2-oxo-l-(2,2,2-trifluoroethyl)indolin-6- yl)amino)azetidine-l -carboxylate (19a) (10 mg, 0.02 mmol, 1 eq.) by following the procedure from Compound 9b to afford the title compound as a brownish oil and was used for the next step without further purification. LCMS ES-MS m / z = 438.2 [M+H]+.

[0245] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-3,3- dimethyl-l-(2,2,2-trifluoroethyl)indolin-2-one (Compound 19): Compound 19 was synthesized by using crude 6-((3 -(3 -chi oro-2-methylphenyl)azeti din-3 -yl)amino)-3, 3 -dimethyl- 1 -(2,2,2- trifluoroethyl)indolin-2-one TFA (19b) (8 mg, 0.02 mmol, 1 eq.) and acryloyl chloride (1.7 mg, 0.02 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (5 mg, 56% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.39 (d, J= 7.9 Hz, 1H), 7.35 (d, J= 73. Hzu, 1H), 7.24 - 7.18 (m, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.44 - 6.30 (m, 2H), 6.29 - 6.21 (m, 1H), 6.20 (s, 1H), 5.74 (dd, J= 10.4, 1.8 Hz, 1H), 4.85 (br d, J= 8.6 Hz, 1H), 4.73 - 4.59 (m, 2H), 4.59 - 4.48 (m, 1H), 4.23 - 4.06 (m, 2H), 2.39 (s, 3H), 1.33 (s, 6H). LCMS ES-MS m / z = 492 [M+H]+.Example 20: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-isopropyl- 3,3-dimethylindolin-2-one (Compound 20)

[0246] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-isopropyl-3,3-dimethyl-2- oxoindolin-6-yl)amino)azetidine-l -carboxylate (20a). Compound 20a was synthesized using 6- bromo-l-isopropyl-3,3-dimethylindolin-2-one (50 mg, 0.18 mmol, 1 eq.) and tert-butyl 3- amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (53 mg, 0.18 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as white solid (26 mg, 29% yield). LCMS ES-MS m / z. = 498 [M+H]+.

[0247] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-isopropyl-3,3- dimethylindolin-2-one TFA (20b): Compound 20b was synthesized using tert-butyl 3-(3-chloro- 2-methylphenyl)-3-((l-isopropyl-3,3-dimethyl-2-oxoindolin-6-yl)amino)azetidine-l-carboxylate (20a) (26 mg, 0.05 mmol, 1 eq.) by following the procedure from Compound 9b to afford the title compound as a brownish oil and crude was used without further purification. LCMS ES-MS m / z = 398 [M+H]+.

[0248] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l- isopropyl-3,3-dimethylindolin-2-one (Compound 20): Compound 20 was synthesized using crude 6-((3 -(3 -chloro-2-methylphenyl)azeti din-3 -yl)amino)- 1 -isopropyl-3,3 -dimethylindolin-2- one TFA (20b) (20 mg, 0.05 mmol, 1 eq.) and acryloyl chloride (4.7 mg, 0.05 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (16 mg, 66% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (t, J= 8.1 Hz, 2H), 7.20 (t, J= 7.9 Hz, 1H), 6.94 (d, J= 7.8 Hz, 1H), 6.45 - 6.33 (m, 1H), 6.33 - 6.21 (m, 3H), 5.73 (dd, J= 10.2, 1.7 Hz, 1H), 4.84 (br d, J= 8.8 Hz, 1H), 4.73 - 4.61 (m, 2H), 4.60 - 4.50 (m, 2H), 2.40 (s, 3H), 1.34 (d, J= 6.6 Hz, 6H), 1.27 (s, 6H). LCMS ES-MS m / z = 452 [M+H]+.Example 21: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-(2- methoxyethyl)-3,3-dimethylindolin-2-one (Compound 21)

[0249] Preparation of 6-bromo-l-(2-methoxyethyl)-3,3-dimethylindolin-2-one (21a): Compound 21a was synthesized using 6-bromo-3,3-dimethylindolin-2-one (57 mg, 0.24 mmol, leq.) and l-bromo-2-methoxy ethane (40 mg, 0.29 mmol, 1.2 eq.) by following the procedure from Compound 16a to afford the title compound as a white solid (55 mg, 76% yield). LCMS ES-MS m / z: = 298 [M+H]+.

[0250] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-(2-methoxyethyl)-3,3- dimethyl-2-oxoindolin-6-yl)amino)azetidine-l-carboxylate (21b): Compound 21b was synthesized using 6-bromo-l-(2-methoxyethyl)-3,3-dimethylindolin-2-one (21a) (55 mg, 0.18 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (55 mg, 0.18 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (53 mg, 56% yield). LCMS ES-MS m z. = 514 [M+H]+.

[0251] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-(2- methoxyethyl)-3,3-dimethylindolin-2-one TFA (21c): Compound 21c was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-(2-methoxyethyl)-3,3-dimethyl-2-oxoindolin-6- yl)amino)azetidine-l -carboxylate (21b) (29 mg, 0.06 mmol, 1 eq.) by following the procedure from Compound 9b to afford the title compound as brownish oil and was used for the next step without further purification. LCMS ES-MS m z. = 414 [M+H]+.

[0252] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-(2- methoxyethyl)-3,3-dimethylindolin-2-one (Compound 21): Compound 21 was synthesized by using crude 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l-(2-methoxyethyl)-3,3- dimethylindolin-2-one TFA (21c) (23 mg, 0.06 mmol, 1 eq.) and acryloyl chloride (5 mg, 0.06 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (18 mg, 66% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (d, J= 8.0 Hz, 2H), 7.20 (t, J= 7.9 Hz, 1H), 6.92 (d, J= 8.6 Hz, 1H), 6.43 - 6.34 (m, 1H), 6.30 - 6.20 (m, 3H), 5.73 (dd, J= 10.3, 1.8 Hz, 1H), 4.84 (br d, J= 8.8 Hz, 1H), 4.72 - 4.59 (m, 2H), 4.59 - 4.48 (m,1H), 3.84 - 3.64 (m, 2H), 3.51 (t, J= 5.6 Hz, 2H), 3.32 (s, 3H), 2.39 (s, 3H), 1.29 (s, 6H).LCMS ES-MS m / z = 468 [M+H]+.Example 22: 6'-((l-(But-2-ynoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'- methylspiro[cyclopropane-l,3'-indolin]-2'-one (Compound 22)

[0253] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l'-methyl-2'- oxospiro[cyclopropane-l,3'-indolin]-6'-yl)amino)azetidine-l-carboxylate (22a): Compound 22a was synthesized using 6'-bromo-l'-methylspiro[cyclopropane-l,3'-indolin]-2'-one (42 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a pink solid (65 mg, 82% yield).

[0254] Preparation of 6'-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'- methylspiro[cyclopropane-l,3'-indolin]-2'-one TFA (22b): Compound 22b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l'-methyl-2'-oxospiro[cyclopropane-l,3'- indolin]-6'-yl)amino)azetidine-l-carboxylate (22a) (27 mg, 0.05 mmol) by following the procedure from Compound 9b to afford the title compound that was used for the next step without purification.

[0255] Preparation of 6'-((l-(but-2-ynoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)- l'-methylspiro[cyclopropane-l,3'-indolin]-2'-one (Compound 22): Compound 22 was synthesized using 6'-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'- methylspiro[cyclopropane-l,3'-indolin]-2'-one TFA (22b) (25 mg, 0.068 mmol, 1 eq.) and 2- butynoyl chloride (6.9 mg, 0.068 mmol, 1.2 eq) by following the procedure from Compound 9 to afford the title compound as a white solid (14 mg, 48% yield).1H NMR (400 MHz, METHANOL-d4) δ 7.60 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 7.7 Hz, 1H), 7.23 (t, J= 7.9 Hz, 1H), 6.60 (d, J= 8.7 Hz, 1H), 6.24 - 6.20 (m, 2H), 4.63 - 4.54 (m, 3H), 4.41 (d, J= 10.4 Hz, 1H), 3.14 (s, 4H), 2.39 (s, 3H), 2.03 (s, 3H), 1.50 - 1.45 (m, 2H), 1.42 - 1.38 (m, 2H). LCMS EI-MS m / z = 434 [M+H]+.Example 23: 6'-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'- methylspiro[cyclopropane-l,3'-indolin]-2'-one (Compound 23)Compound 23

[0256] Preparation of 6'-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'- methylspiro[cyclopropane-l,3'-indolin]-2'-one (Compound 23): Compound 23 was synthesized using 6'-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l'-methylspiro[cyclopropane-l,3'- indolin]-2'-one TFA (22b) (15 mg, 0.04 mmol, leq.) and acryloyl chloride (6 mg, 0.06 mmol, 1.5 eq) using the procedure from Compound 9 to afford the title compound as a white solid (12 mg, 45% yield).1H NMR (400 MHz, METHANOL-d4) δ 7.60 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.27 - 7.19 (m, 1H), 6.60 (d, J= 8.8 Hz, 1H), 6.47 - 6.37 (m, 1H), 6.31 - 6.22 (m, 3H), 5.77 (dd, J= 10.3, 1.8 Hz, 1H), 4.96 (br d, J= 9.13 Hz, 1H), 4.72 - 4.57 (m, 2H), 4.47 (d, J = 10.6 Hz, 1H), 3.13 (s, 3H), 2.40 (s, 3H), 1.50 - 1.46 (m, 2H), 1.42 - 1.38 (m, 2H). LCMS EIMS m / z = 423 [M+H]+.Example 24: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoindolin-l-one (Compound 24)

[0257] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-methyl-3-oxoisoindolin-5- yl)amino)azetidine-l -carboxylate (24a): Compound 24a was synthesized using 6-bromo-2- methylisoindolin-l-one (38 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l- azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure fromCompound lb to afford the title compound as a white solid (55 mg, 74% yield).

[0258] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoindolin-l-one TFA (24b): Compound 24b was synthesized using tert-butyl 3-(3- chloro-2-methylphenyl)-3-((2-methyl-3-oxoisoindolin-5-yl)amino)azetidine-l -carboxylate (24a) (30 mg, 0.07 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification.

[0259] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoindolin-l-one (Compound 24): Compound 24 was synthesized using 6-((3-(3-chloro- 2-methylphenyl)azetidin-3-yl)amino)-2-methylisoindolin-l-one TFA (24b) (29 mg, 0.084 mmol, 1 eq.) and acryloyl chloride (8.2 mg, 0.1 mmol, 1.2 eq) by following the procedure fromd4mpound 9 to afford the title compound as a white solid (17 mg, 40% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.70 (d, J= 7.7 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.26 - 7.13 (m, 2H), 6.86 - 6.79 (m, 2H), 6.80 - 6.38 (m, 1H), 5.77 (dd, J= 10.3, 1.8 Hz, 1H), 5.01 (br d, J= 9.2 Hz, 2H), 4.68 - 4.61 (m, 2H), 4.47 (d, J=10.6 Hz, 1H), 4.28 (s, 2H), 3.11 (s, 3H), 2.65 (s, 1H), 2.38 (s, 3H). LCMS ELMS m / z = 396 [M+H]+.Example 25: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2,3,3- trimethylisoindolin-l-one (Compound 25)

[0260] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l,l,2-trimethyl-3- oxoisoindolin-5-yl)amino)azetidine-l -carboxylate (25a): Compound 25a was synthesized using 6-bromo-2,3,3-trimethylisoindolin-l-one (43 mg, 0.17 mmol, 1 eq) and tert-butyl 3-amino-3-(3- chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (60 mg, 76% yield).

[0261] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2,3,3- trimethylisoindolin-l-one TFA (25b): Compound 25b was synthesized using tert-butyl 3-(3- chloro-2-methylphenyl)-3-((l,l,2-trimethyl-3-oxoisoindolin-5-yl)amino)azetidine-l -carboxylate (25a) (35 mg, 0.07 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification.

[0262] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2,3,3- trimethylisoindolin-l-one (Compound 25): Compound 25 was synthesized by using 6-((3-(3- chloro-2-methylphenyl)azetidin-3-yl)amino)-2,3,3-trimethylisoindolin-l-one TFA (25b) (28 mg, 0.075 mmol, 1 eq.) and acryloyl chloride (8.2 mg, 0.09 mmol, 1.2 eq) by following the procedure from Compound 9 to afford the title compound as a white solid (15 mg, 37% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.71 (d, J= 7.6 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.27 - 7.19 (m, 2H), 6.85 - 6.80 (m, 2H), 6.46 - 6.38 (m, 1H), 6.31 - 6.24 (m, 1H), 5.76 (dd, J= 10.3, 1.8 Hz, 1H), 5.01 (br d, J= 9.0 Hz, 1H), 4.68 - 4.60 (m, 2H), 4.47 (d, J= 10.6 Hz, 1H), 2.96 (s, 3H), 2.39 (s, 3H), 1.37 (s, 6H). LCMS ELMS m / z = 424 [M+H]+.Example 26: (E)-6-((3-(3-Chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2,3,3-trimethylisoindolin-l-one (Compound 26)Compound 26

[0263] Preparation of (E)-6-((3-(3-chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2,3,3-trimethylisoindolin-l-one (Compound 26): Compound 26 was synthesized using (E)-4-(dimethylamino)-2-butenoic acid hydrochloride (13.4 mg, 0.081 mmol, 1 eq.) and 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2,3,3- trimethylisoindolin-l-one TFA (25b) (30 mg, 0.081 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (19 mg, 49% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.71 (d, J= 7.6 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.27 - 7.18 (m, 2H) 6.86 - 6.77 (m, 3H), 6.27 (d, J= 15.4 Hz, 1H), 5.00 (br d, J= 9.6 Hz, 1H), 4.67 - 4.58 (m, 2H), 4.46 (d, J = 10.6 Hz, 1H), 3.18 - 3.14 (m, 2H), 2.96 (s, 3H), 2.39 (s, 3H), 2.27 (s, 6H), 1.37 (s, 6H). LCMS EI-MS m / z = 481 [M]+.Example 27 : 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)-3,3-dimethylisoindolin-l-one (Compound 27)

[0264] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-(2-methoxyethyl)-l,l- dimethyl-3-oxoisoindolin-5-yl)amino)azetidine-l-carboxylate (27a): Compound 27a was synthesized using 6-bromo-2-(2-m ethoxy ethyl)-3, 3 -dimethylisoindolin-1 -one (45 mg, 0.15 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (45 mg, 0.15 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (52 mg, 67% yield).

[0265] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- m ethoxy ethyl)-3, 3 -dimethylisoindolin-1 -one TFA (27b): Compound 27b was synthesized using tert-butyl 3-(3-chl oro-2-methylphenyl)-3-((2-(2-methoxy ethyl)- 1,1 -dimethyl-3-oxoisoindolin-5- yl)amino)azetidine-l -carboxylate (27a) (35 mg, 0.07 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without any further purification.

[0266] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)-3,3-dimethylisoindolin-l-one (Compound 27): Compound 27 was synthesized using 6-((3 -(3 -chloro-2-methylphenyl)azeti din-3 -yl)amino)-2-(2-methoxy ethyl)-3 , 3 - dimethylisoindolin-l-one TFA (27b) (31 mg, 0.075 mmol, 1 eq.) and acryloyl chloride (8.2 mg, 0.09 mmol, 1.2 eq) by following the procedure from Compound 9 to afford the title compound as a white solid (8 mg, 18% yield).1H NMR (400 MHz, METHANOL-d4): δ 7.71 (d, J= 7.5 Hz, 1H), 7.33 (d, J= 7.5 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.86 - 6.78 (m, 2H), 6.47 - 6.38 (m, 1H), 6.31 - 6.28 (m, 1H), 5.76 (dd, J= 10.4, 1.9 Hz, 1H), 5.01 (br d, J= 9.0 Hz, 1H), 4.65 (br d, J= 9.1 Hz, 2H), 4.46 (br d, J= 10.6 Hz, 1H), 3.59 (t, J= 4.3 Hz, 4H), 3.34 (s, 3H), 2.39 (s, 3H), 1.39 (s, 6H). LCMS EI-MS m / z = 468 [M+H]+.Example 28: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)isoquinolin- l(2H)-one (Compound 28)

[0267] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-oxo-2-((2-(trimethylsilyl)ethoxy)m ethyl)- 1 ,2-dihydroisoquinolin-7-yl)amino)azetidine- 1 -carboxylate(28a): Compound 28a was synthesized using 7-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-l(2H)-one (59.7 mg, 0.17 mmol, 1 eq.) and tert-butyl3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (53 mg, 55% yield).

[0268] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)isoquinolin-l(2H)- one TFA (28b): Compound 28b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)- 3-((l-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-l,2-dihydroisoquinolin-7-yl)amino)azetidine-l- carboxylate (28a) (30 mg, 0.05 mmol) by following the procedure from Compound 9b to afford the title compound and was used without further purification.

[0269] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3- yl)amino)isoquinolin-l(2H)-one (Compound 28): Compound 28 was synthesized using 7-((3- (3-chloro-2-methylphenyl)azetidin-3-yl)amino)isoquinolin-l(2H)-one TFA (28b) (15 mg, 0.05 mmol, 1 eq) and acryloyl chloride (4 mg, 0.05 mmol, 1 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (7 mg, 42% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.5 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H), 7.35 - 7.30 (m,1H), 7.28 - 7.22 (m, 2H), 7.09 (dd, J= 8.6, 2.6 Hz, 1H), 6.89 (d, J= 7.1 Hz, 1H), 6.53 - 6.38 (m, 2H), 6.32 - 6.24 (m, 1H), 5.77 (dd, J= 10.3, 1.8 Hz, 1H), 5.07 (br d, J= 9.2 Hz, 1H), 4.72 - 4.59 (m, 2H), 4.52 (d, J= 10.7 Hz, 1H), 2.40 (s, 3H). LCMS EI-MS m / z = 394 [M+H]+.Example 29: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- isopropylisoquinolin-l(2H)-one (Compound 29)

[0270] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-isopropyl-l-oxo-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (29a): Compound 29a was synthesized using 7-bromo-2-isopropylisoquinolin-l(2H)-one (36 mg, 0.13 mmol, 1 eq.) and tert-butyl 3- amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (40 mg, 0.13 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (50 mg, 77% yield).

[0271] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- isopropylisoquinolin-l(2H)-one TFA (29b): Compound 29b was synthesized using tert-butyl 3- (3-chloro-2-methylphenyl)-3-((2-isopropyl-l-oxo-l,2-dihydroisoquinolin-7-yl)amino)azetidine- 1-carboxylate (29a) (35 mg, 0.06 mmol) by following the procedure from Compound 9b to afford the title compound and was used for next step without further purification.

[0272] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- isopropylisoquinolin-l(2H)-one (Compound 29): Compound 29 was synthesized using 7-((3- (3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-isopropylisoquinolin-l(2H)-one TFA (29b) (32 mg, 0.08 mmol, 1 eq.) and acryloyl chloride (11 mg, 0.12 mmol, 1.5 eq) by following the procedure from Compound 9 to afford the title compound as a white solid (13 mg, 35% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.5 Hz, 1H), 7.34 (t, J= 8.3 Hz, 2H), 7.29 - 7.24 (m, 2H), 7.15 (d, J= 7.4 Hz, 1H), 7.07 (dd, J= 8.6, 2.5 Hz, 1H), 6.57 (d, J= 7.5 Hz, 1H), 6.47 - 6.38 (m, 1H), 6.31 - 6.24 (m, 1H), 5.77 (dd, J= 10.4, 1.9 Hz, 1H), 5.30 - 5.24 (m, 1H), 5.07 (br d, J= 9.5 Hz, 1H), 4.72 - 4.57 (m, 3H), 4.51 (d, J= 10.7 Hz, 1H), 4.28 - 4.27 (m, 1H), 2.40 (s, 3H), 1.37 (d, J= 6.9 Hz, 6H). LCMS EI-MS m / z = 436 [M+H]+.Example 30: 7-((l-Acryloyl-3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2- isopropylisoquinolin-l(2H)-one (Compound 30)

[0273] Preparation of tert-butyl 3-(2,3-dichloro-6-fluorophenyl)-3-((2-isopropyl-l-oxo-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (30a): Compound 30a was synthesized using 7-bromo-2-isopropyl-l,2-dihydro-l-isoquinolinone (22 mg, 0.084 mmol, 1 eq.) and tert- butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl)azetidine-l-carboxylate (Int-4) (28 mg, 0.18 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (12 mg, 28% yield). LCMS ES-MS m / z = 520 [M]+.

[0274] Preparation of 7-((3 -(2,3 -di chi oro-6-fluorophenyl)azeti din-3 -yl)amino)-2- isopropylisoquinolin-l(2H)-one TFA (30b): Compound 30b was synthesized using tert-butyl 3- (2,3-dichloro-6-fluorophenyl)-3-((2-isopropyl-l-oxo-l,2-dihydroisoquinolin-7- yl)amino)azetidine-l -carboxylate (30a) (12 mg, 0.022 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LCMS ES-MS m / z = 420 [M]+.

[0275] Preparation of 7-((l-acryloyl-3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2- isopropylisoquinolin-l(2H)-one (Compound 30): Compound 30 was synthesized using 7-((3- (2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2-isopropylisoquinolin-l(2H)-one TFA (30b) (10 mg, 0.023 mmol, 1 eq.) and acryloyl chloride (2.47 mg, 0.027 mmol, 1.2 eq.) by following the procedure for Compound 9 to afford the title compound as white solid (4.5 mg, 37% yield).1H NMR (400 MHz, METHANOL-d4): δ 7.55 - 7.47 (m, 2H), 7.38 (d, J= 8.8 Hz, 1H), 7.23 - 7.14 (m, 3H), 6.59 (d, J =7.5 Hz, 1H), 6.47 - 6.39 (m, 1H), 6.26 (d, J= 1.8 Hz, 1H), 5.77 (dd, J = 10.4, 1.6 Hz, 1H), 5.34 - 5.23 (m, 1H), 4.64 - 4.54 (br s, 4H), 1.38 (d, J= 6.9 Hz, 6H).19F NMR (376 MHz, METHANOL-d4): 6 - 107.9 (s, IF). LCMS ES-MS m / z = 474 [M]+.Example 31: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)isoquinolin-l(2H)-one (Compound 31)

[0276] Preparation of 7-bromo-2-(2-methoxyethyl)-l,2-dihydro-l-isoquinolinone (31a): Compound 31a was synthesized using 6-bromo-3,3-dimethyl-l-isoindolinone (0.2 g, 0.89 mmol, 1 eq.) and l-bromo-2-m ethoxy ethane (86 mg, 89 mmol, 1 eq.) by following the procedure from Compound la to afford the title compound as a white solid (160 mg, 63% yield).

[0277] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-(2-methoxyethyl)-l-oxo- l,2-dihydroisoquinolin-7-yl)amino)azetidine-l-carboxylate (31b): Compound 31b was synthesized using 7-bromo-2-(2-methoxyethyl)-l,2-dihydro-l-isoquinolinone (31a) (47 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (65 mg, 77% yield).

[0278] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)isoquinolin-l(2H)-one TFA (31c): Compound 31c was synthesized using tert- butyl 3-(3-chl oro-2 -methylphenyl)-3-((2-(2 -methoxy ethyl)- 1-oxo- 1,2-dihy droisoquinolin-7- yl)amino)azetidine-l -carboxylate (31b) (30 mg, 0.06 mmol) by following the procedure from Compound 9b to afford the title compound and was used for next step without further purification.

[0279] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)isoquinolin-l(2H)-one (Compound 31): Compound 31 was synthesized using 7- ((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2-methoxyethyl)isoquinolin-l(2H)-one TFA (31c) (30 mg, 0.07 mmol, 1 eq.) and acryloyl chloride (7.5 mg, 0.08 mmol, 1.2 eq) by following the procedure from Compound 9 to afford the title compound as a white solid (15 mg, 44% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.1 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.29 - 7.23 (m, 2H), 7.10 - 7.03 (m, 2H), 6.49 - 6.39 (m, 2H), 6.32 - 6.22 (m, 1H), 5.76 (dd, J= 10.4, 1.9 Hz, 1H), 5.07 (br d, J= 9.3 Hz, 1H), 4.72 - 4.57 (m, 3H), 4.51 (d, J=10.6 Hz, 1H), 4.18 - 4.12 (m, 2H), 3.67 (t, J= 5.2 Hz, 2H), 3.31 (br s, 3H), 2.40 (s, 3H). LCMS EI-MS m / z = 452 [M+H]+.Example 32: (E)-7-((l-(But-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)isoquinolin-l(2H)-one (Compound 32)

[0280] Preparation of (E)-7-((l-(but-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3- yl)amino)-2-(2-methoxyethyl)isoquinolin-l(2H)-one (Compound 32): Compound 32 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2- methoxyethyl)isoquinolin-l(2H)-one TFA (31c) (30 mg, 0.07 mmol, leq.) and crotonyl chloride (8 mg, 0.07 mmol, 1 eq.) by using the procedure for Compound 9 to afford the title compound as a white solid (15 mg, 42% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.77 (d, J= 7.6 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.28 - 7.23 (m, 2 H), 7.09 - 7.02 (m, 2H), 6.92 - 6.80 (m, 1H), 6.47 (d, .7= 7.2 Hz, 1H), 6.11 (dd, J= 15.3, 1.6 Hz, 1H), 5.02 (br d, J= 9.1 Hz, 1H), 4.68 - 4.59 (m, 2H), 4.48 (br d, J= 10.5 Hz, 1H), 4.17 - 4.12 (m, 2H), 3.67 (t, J= 5.2 Hz, 2H), 3.31 (br s, 3H), 2.40 (s, 3H), 1.89 (d, J = 6.9 Hz, 3H). LCMS EI-MS m / z = 466 [M+H]+.Example 33: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- ((tetrahydro-2H-pyran-4-yl)methyl)isoquinolin-l(2H)-one (Compound 33)

[0281] Preparation of 7-bromo-2-((tetrahydro-2H-pyran-4-yl)methyl)isoquinolin-l(2H)-one (33a): Compound 33a was synthesized by using 7-bromoisoquinolin-l(2H)-one (180 mg, 0.80 mmol, 1.0 eq.) and 4-(bromomethyl)tetrahydro-2H-pyran (288 mg, 1.60 mmol, 2.0 eq.) byfollowing the procedure from Compound 16a to afford the title compound as an oil (158 mg, 61% yield). LCMS ES-MS m / z. = 322 [M]+.

[0282] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-oxo-2-((tetrahydro-2H- pyran-4-yl)methyl)-l,2-dihydroisoquinolin-7-yl)amino)azeti dine- 1 -carboxylate (33b): Compound 33b was synthesized using tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l- azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) and 7-bromo-2-((tetrahydro-2H-pyran-4- yl)methyl)isoquinolin-l(2H)-one (33a) (54 mg, 0.16 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (28 mg, 31% yield). LCMS ES-MS m / z = 538 [M]+.

[0283] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-((tetrahydro- 2H-pyran-4-yl)methyl)isoquinolin-l(2H)-one TEA (33c): Compound 33c was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (33b) (25 mg, 0.046 mmol) by following the procedure from Compound 9b to afford the title compound as a white solid (27 mg, 100% yield). LCMS ES-MS m / z = 438 [M]+.

[0284] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- ((tetrahydro-2H-pyran-4-yl)methyl)isoquinolin-l(2H)-one (Compound 33): Compound 33 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-((tetrahydro-2H- pyran-4-yl)methyl)isoquinolin-l(2H)-one (33c) (15 mg, 0.032 mmol, 1 eq.) and acryloyl chloride (3.4 mg, 0.038 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as white solid (3.6 mg, 23% yield).1H NMR (400 MHz, Methanol-d4): δ 7.78 (d, J= 7.0 Hz, 1H), 7.37 - 7.24 (m, 4H), 7.11 - 7.00 (m, 2H), 6.49 - 6.31 (m, 2H), 6.35 - 6.21 (m, 1H), 5.85 - 5.77 (m, 1H), 5.06 (br d, J= 9.0 Hz, 1H), 4.70 - 4.55 (m, 2H), 4.51 (d, J= 10.9 Hz, 1H), 3.96 - 3.82 (m, 4H), 3.41 - 3.32 (m, 2H), 2.40 (s, 3H), 2.22 - 2.08 (m, 1H), 1.58 - 1.47 (m, 2H), 1.43 - 1.33 (m, 2H). LCMS ES-MS m / z = 492 [M]+.Example 34: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2,2,2- trifluoroethyl)-isoquinolin- l(2H)-one (Compound 34)trifluoroethyl)- 1 ,2-dihydroisoquinolin-7-yl)amino)azetidine- 1 -carboxylate (34a) : Compound 34a was synthesized using 7-bromo-2-(2,2,2-trifluoroethyl)-l,2-dihydro-l-isoquinolinone (62mg, 0.20 mmol, 1.0 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int- 1) (60 mg, 0.20 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as an oil (86 mg, 76% yield). LCMS ES-MS m / z = 522 [M]+.

[0286] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2,2,2- trifluoroethyl)isoquinolin-l(2H)-one TFA (34b): Compound 34b was synthesized using tertbutyl 3-(3-chloro-2-methylphenyl)-3-((l-oxo-2-(2,2,2-trifluoroethyl)-l,2-dihydroisoquinolin-7- yl)amino)azetidine-l -carboxylate (34a) (40 mg, 0.08 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LCMS ES-MS m / z = 422 [M]+.

[0287] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- (2,2,2-trifluoroethyl)-isoquinolin- l(2H)-one (Compound 34): Compound 34 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-(2,2,2-trifluoroethyl)isoquinolin- l(2H)-one TFA (34b) (17 mg, 0.041 mmol, 1 eq.) and acryloyl chloride (5.9 mg, 0.065 mmol, 1.2 eq.) by following the procedure for Compound 9 to afford the title compound as white solid (13.5 mg, 70% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.55 (d, J= 7.6 Hz, 1H), 7.45 (d, J= 2.5 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.27 - 7.21 (m, 2H), 6.96 (dd, J= 8.5, 2.4 Hz, 1H), 6.84 (d, .7= 7.4 Hz, 1H), 6.44 - 6.31 (m, 2H), 6.29 - 6.10 (m, 1H), 5.72 (dd, J= 10.3, 1.8 Hz, 1H), 5.12 (br s, 1H), 4.99 (br d, J= 8.8 Hz, 1H), 4.73 - 4.53 (m, 5H), 2.37 (s, 3H).19F NMR (376 MHz, CHLOROFORM-d): δ - 70.5 (s, IF). LCMS ES-MS m / z = 476 [M]+.Example 35: (E)-7-((3-(3-Chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2-(2,2,2-trifluoroethyl)isoquinolin-l(2H)-one (Compound 35)CF335

[0288] Preparation of (E)-7-((3-(3-chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2-(2,2,2-trifluoroethyl)isoquinolin-l(2H)-one (Compound 35): Compound 35 was synthesized by using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)- 2-(2,2,2-trifluoroethyl)isoquinolin-l(2H)-one (34b) (18 mg, 0.041 mmol, 1 eq.) and (E)-4- (dimethylamino)-2-butenoic acid (6.85 mg, 0.053 mmol, 1.3 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid, (15.5 mg, 73% yield).1HNMR (400 MHz, CHLOROFORM-d): δ 7.55 (d, J= 7.6 Hz, 1H), 7.44 (d, J= 2.5 Hz, 1H), 7.35 - 7.21 (m, 3H), 6.99 - 6.81 (m, 3H), 6.39 (d, J= 7.4 Hz, 1H), 6.16 - 6.07 (m, 1H), 4.99 (br d, J= 8.8 Hz, 1H), 4.68 - 4.45 (m, 5H), 3.07 - 3.00 (m, 2H), 2.37 (s, 3H), 2.24 (s, 6H).19F NMR (376 MHz, CHLOR.OFOR.M-d / CH L O ROFO RM- DF). LCMS ES-MS m / z = 533 [M]+.Example 36: 7-((l-Acryloyl-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 36)

[0289] Preparation of tert-butyl 3-(2,3-dichlorophenyl)-3-((2-methyl-l-oxo-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (36a): Compound 36a was synthesized using tert-butyl 3-amino-3-(2,3-dichlorophenyl)azetidine-l-carboxylate (Int-3) (43 mg, 0.14 mmol, 1 eq.) and 7-bromo-2-methylisoquinolin-l(2H)-one (33 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (50 mg, 87% yield). LCMS ES-MS m / z. = 474 [M]+.

[0290] Preparation of 7-((3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin- l(2H)-one TFA (36b): Compound 36b was synthesized using tert-butyl 3-(2,3-dichlorophenyl)- 3-((2-methyl-l-oxo-l,2-dihydroisoquinolin-7-yl)amino)azetidine-l-carboxylate (36a) (50 mg, 0.105 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LCMS ES-MS m / z. = 374 [M]+.

[0291] Preparation of 7-((l-acryloyl-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 36): Compound 36 was synthesized using 7-((3- (2,3-dichlorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (36b) (10 mg, 0.03 mmol, 1 eq.) and acryloyl chloride (3.63 mg, 0.04 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (3.2 mg, 28% yield).1H NMR (400 MHz, METHANOL-d4): δ 7.91 (dd, J= 7.8, 1.2 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.18 (d, J= 2.5 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.52 - 6.39 (m, 2H), 6.32 - 6.23 (m, 1H), 5.77 (dd, J= 10.3, 1.8 Hz, 1H), 5.1 (br d, J= 9.0 Hz, 1H), 4.72 - 4.50 (m, 4H), 3.55 (s, 3H). LCMS ES-MS m / z = 429 [M]+.Example 37 : 7-((l-Acryloyl-3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 37)

[0292] Preparation of tert-butyl 3-(2,3-dichloro-6-fhiorophenyl)-3-((2-methyl-l-oxo-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l-carboxylate (37a): Compound 37a was synthesized using by 7-bromo-2-methyl-l,2-dihydro-l-isoquinolinone (43 mg, 0.18 mmol, 1 eq.) and tert- butyl 3-amino-3-(2,3-dichloro-6-fluorophenyl)azetidine-l-carboxylate (Int-4) (60 mg, 0.18 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (49 mg, 36% yield). LCMS ES-MS m / z = 492 [M]+.

[0293] Preparation of 7-((3 -(2,3 -di chloro-6-fluorophenyl)azeti din-3 -yl)amino)-2- methylisoquinolin-l(2H)-one TFA (37b): Compound 37b was synthesized using tert-butyl 3- (2,3-dichloro-6-fluorophenyl)-3-((2-methyl-l-oxo-l,2-dihydroisoquinolin-7-yl)amino)azetidine- 1-carboxylate (37a) (36 mg, 0.073 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LCMS ESMS m / z = 392 [M]+.

[0294] Preparation of 7-((l-acryloyl-3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 37): Compound 37 was synthesized using 7-((3- (2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (37b) (10 mg, 0.026 mmol, 1 eq.) and acryloyl chloride (2.54 mg, 0.028 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (4.0 mg, 35% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.61 (s, 1 H), 7.36 (dd, J= 8.9, 5.1 Hz, 1H), 7.33 (d, J= 8.6 Hz, 1H), 7.12 - 6.90 (m, 2H), 6.87 (d, J= 13 Hz, 1H), 6.40 - 6.32 (m, 2H), 6.31 - 6.17 (m, 1H), 5.72 (dd, J= 10.3, 1.8 Hz, 1H), 5.23 (br s, 2H), 4.72 (br d, J= 8.4 Hz, 1H), 4.59 (br s, 2H), 3.57 (s, 3H).19F NMR (376 MHz, CHLOROFORM-d): δ - 106.7 (s, IF). LCMS ESMS m / z = 446 [M]+.Example 38: (E)-7-((l-(But-2-enoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 38)Compound 38

[0295] Preparation of (E)-7-((l-(but-2-enoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 38): Compound 38 was synthesized using 7-((3- (2,3-dichlorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (36b) (13 mg, 0.035 mmol, 1 eq.) and crotonyl chloride (3.63 mg, 0.040 mmol, 1.2 eq.) by following the procedure for Compound 9 to afford the title compound as a white solid (8.1 mg, 53% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.71 (d, J= 7.5 Hz, 1H), 7.40 - 7.23 (m, 4H), 6.97 - 6.81 (m, 3H), 6.34 (d, J= 73 Hz, 1H), 5.94 (br d, J= 15.1 Hz, 1H), 5.32 (s, 1H), 4.96 (br d, J = 7.6 Hz, 1H), 4.75 - 4.56 (m, 2H), 4.50 (br d, J= 10.5 Hz, 1H), 3.56 (s, 3H), 1.88 (d, J= 6.4 Hz, 3 H). LCMS ES-MS m / z = 442 [M]+.Example 39: 7-((l-(But-2-ynoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 39)Compound 39

[0296] Preparation of 7-((l-(but-2-ynoyl)-3-(2,3-dichlorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 39): Compound 39 was synthesized using 7-((3- (2,3-dichlorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (36b) (13 mg, 0.035 mmol, 1 eq.) and 2-butynoyl chloride (3.56 mg, 0.035 mmol, 1.2 eq.) by following the procedure for Compound 9 to afford the title compound as white solid (7.2 mg, 46% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.70 (dd, J= 7.8, 1.4 Hz, 1H), 7.40 - 7.24 (m, 4H), 6.92 (dd, J= 8.6, 2.6 Hz, 1H), 6.86 (d, J= 7.3 Hz, 1H), 6.35 (d, J = 7.3 Hz, 1H), 5.31 (s, 1H), 4.97 (br d, J= 9.5 Hz, 1H), 4.64 - 4.59 (m, 2H), 4.47 (d, J= 10.6 Hz, 1H), 3.56 (s, 3H), 2.00 (s, 3H). LCMS ES-MS m / z = 440 [M]+.Example 40: 7-((l-(But-2-ynoyl)-3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 40)Compound 40

[0297] Preparation of 7-((l-(but-2-ynoyl)-3-(2,3-dichloro-6-fluorophenyl)azetidin-3- yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 40): Compound 40 was synthesized using 7-((3-(2,3-dichloro-6-fluorophenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (37b) (13 mg, 0.033 mmol, 1 eq.) and 2-butynoyl chloride (3.74 mg, 0.036 mmol, 1.2 eq.) by following the procedure for Compound 9 to afford the title compound as a white solid (5.0 mg, 33% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.61 (d, J= 2.5 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.07 (t, J= 9.9 Hz, 1H), 6.99 (dd, J= 8.6, 2.6 Hz, 1H), 6.88 (d, J= 7.3 Hz, 1H), 6.36 (d, J= 7.3 Hz, 1H), 5.25 (br s, 2H), 4.69 (br d, J= 9.1 Hz, 1H), 4.55 (br d, J= 9.9 Hz, 2H), 3.57 (s, 3H), 2.00 (s, 3H).19F NMR (376 MHz, CHLOROFORM-d): δ - 106.5 (s, IF). LCMS ES-MS m / z = 458 [M]+.Example 41: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)oxy)-2- methylisoquinolin-l(2H)-one (Compound 41), dihydroisoquinolin-7-yl)oxy)azetidine-l-carboxylate (41a): To a stirred solution of 7-bromo-2- methylisoquinolin-l-one (150 mg, 0.63 mmol, 1 eq.), Cs2CO3(411 mg, 1.26 mmol, 2 eq.), Dppf (69.60 mg, 0.12 mmol, 0.2 eq.) and tert-butyl 3-(3-chloro-2-methylphenyl)-3-hydroxyazetidine- 1-carboxylate (Int-la) (225 mg, 0.75 mmol, 1.2 eq.) in toluene (7.5 mL) was added Dppf Pd G3 (58.2 mg, 0.06 mmol, 0.1 eq.) at rt under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred for 6 h. The mixture was allowed to cool down to rt and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography to afford the title compound as a brown oil (180 mg, 57% yield).

[0299] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)oxy)-2-methylisoquinolin- l(2H)-one hydrochloride (41b): Compound 41b was synthesized using tert-butyl 3-(3-chloro-2- methylphenyl)-3 -((2-methyl- 1 -oxo- 1 ,2-dihydroisoquinolin-7-yl)oxy)azetidine- 1 -carboxylate (41a) (80 mg, 0.17 mmol) by following the procedure from Compound 1c to afford the title compound as a light yellow solid (70 mg, crude). The crude product was used in the next step directly without further purification.

[0300] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)oxy)-2- methylisoquinolin-l(2H)-one (Compound 41): Compound 41 was synthesized using crude 7- ((3-(3-chloro-2-methylphenyl)azetidin-3-yl)oxy)-2-methylisoquinolin-l(2H)-one hydrochloride(41b) (50 mg, 0.12 mmol, 1 eq.) and acryloyl chloride (13.9 mg, 0.15 mmol, 1.25 eq.) by following the procedure from Compound 1 to afford the title compound as a grey solid (21.4 mg, 43% yield (2 steps)).1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.59 - 7.47 (m, 4H), 7.32 (d, J= 13 Hz, 1H), 7.26 (t, J= 7.9 Hz, 1H), 6.70 (d, J= 16.7 Hz, 1H), 6.50 (d, J= 13 Hz, 1H), 6.15 (dd, J= 16.7, 2.3 Hz, 1H), 5.65 (dd, J= 10.5, 2.3 Hz, 1H), 4.81 (s, 2H), 4.71 (s, 2H), 3.48 (s, 4H), 2.29 (s, 3H). LCMS ESI-MS m / z = 409 [M+H]+.Example 42: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 42)

[0301] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-methyl-l-oxo-l,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (42a): Compound 42a was synthesized using 7-bromo-2-methyl-l,2-dihydro-l-isoquinolinone (40 mg, 0.17 mmol, 1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (55 mg, 73% yield).

[0302] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one TFA (42b): Compound 42b was synthesized using tert-butyl 3-(3- chl oro-2-methylphenyl)-3-((2-methyl-l -oxo-1, 2-dihydroisoquinolin-7-yl)amino)azeti dine- 1- carboxylate (42a) (30 mg, 0.07 mmol) by following the procedure from Compound 9b to afford the title compound and was used for next step without further purification.

[0303] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 42): Compound 42 was synthesized using 7-((3-(3- chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (42b) (30 mg, 0.08 mmol, 1 eq.) and acryloyl chloride (11.5 mg, 0.12 mmol, 1.5 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (20 mg, 58% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.59 - 7.52 (m, 2H), 7.38 - 7.31 (m, 2H), 7.28 - 7.25 (m, 1H), 6.94 (dd, J= 8.6, 2.5 Hz, 1H), 6.88 (s, 1H), 6.43 - 6.36 (m, 2H), 6.30 - 6.20 (m, 1H), 5.74 (dd, .J=10.2, 1.4 Hz, 1H), 4.98 (br s, 1H), 4.72 - 4.53 (m, 3H), 3.59 (s, 3H), 2.39 (s, 3H). LCMS ELMS m / z = 408 [M+H]+.Example 43: (E)-7-((l-(But-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 43)Compound 43

[0304] Preparation of (E)-7-((l-(but-2-enoyl)-3-(3-chloro-2-methylphenyl)azetidin-3- yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 43): Compound 43 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (42b) (20 mg, 0.06 mmol, 1 eq.) and crotonyl chloride (6 mg, 0.06 mmol, 1 eq.) by using the procedure from Compound 9 to afford the title compound as a white solid (11 mg, 45% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.7 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.28 - 7.22 (m, 2H), 7.09 - 7.03 (m, 2H), 6.87 (dd, J= 15.2, 6.9 Hz, 1H), 6.50 (d, J= 7.2 Hz, 1H), 6.12 (dd, J= 15.2, 1.5 Hz, 1H), 5.03 (br d, J = 9.4 Hz, 1H), 4.68 - 4.58 (m, 2H), 4.52 - 4.44 (m, 1H), 3.59 - 3.51 (m, 3H), 2.39 (s, 3H), 1.89 (s, 3H). LCMS EI-MS m / z = 422 [M+H]+.Example 44: 7-((3-(3-Chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 44)Compound 44

[0305] Preparation of 7-((3-(3-chloro-2-methylphenyl)-l-(2-fluoroacryloyl)azetidin-3- yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 44): Compound 44 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (42b) (10 mg, 0.03 mmol, 1 eq.) and 2-fluoroacrylic acid (2.4 mg, 0.03 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (6.5 mg, 54% yield).1H NMR (400 MHz, CHLOROFORM-d) 7.50 - 7.43 (m, 2H), 7.29 - 7.20 (m, 2H), 6.86 - 6.78 (m, 2H), 6.29 (d, J= 7.2 Hz, 1H), 5.63 (d, J= 3.2 Hz, 1H), 5.52 (d, J= 3.1 Hz, 1H), 5.07 (d, J= 3.2 Hz, 1H), 5.03 (br d, J= 3.2 Hz, 1H), 4.74 (br dd, J= 9.9, 3.9 Hz, 1H), 4.63 (br d, J= 10.7 Hz, 1H), 4.47 (br d, J= 11.0 Hz, 1H), 3.49 (s, 3H), 2.29 (s, 3H). LCMS EI-MS m / z = 426 [M+H]+.Example 45: 7-((l-(But-2-ynoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 45)

[0306] Preparation of 7-((l-(but-2-ynoyl)-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one (Compound 45): Compound 45 was synthesized using 7-((3-(3- chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (42b) (20 mg, 0.06 mmol, 1 eq.) and 2-butynoic acid (5 mg, 0.06 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (17 mg, 56% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.28 - 7.20 (m, 2H), 7.09 - 7.03 (m, 2H), 6.51 (d, J =7.2 Hz, 1H), 4.61 (br d, J= 9.6 Hz, 3H), 4.45 (br d, J =10.5 Hz, 1H), 3.55 (s, 3H), 2.38 (s, 3H), 2.03 (s, 3H). LCMS EI-MS m / z = 420 [M+H]+.Example 46: (E)-7-((3-(3-Chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2-methyl-3,4-dihydroisoquinolin-l(2H)-one (Compound 46)

[0307] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-methyl-l-oxo- 1,2- dihydroisoquinolin-7-yl)amino)azetidine-l -carboxylate (46a): A solution of tert-butyl 3-amino- 3-(3-chloro-2-methylphenyl)azetidine-l-carboxylate (Int-1) (100 mg, 0.337 mmol, 1 eq.) in 1,4- dioxane (2.5 mL) was treated with 7-bromo-2-methylisoquinolin-l-one (80.2 mg, 0.337 mmol, 1 eq.), Cphos (14.7 mg, 0.034 mmol, 0.1 eq.), Cphos Pd G3 (27.7 mg, 0.034 mmol, 0.1 eq.) and Cs2CO3(274 mg, 0.843 mmol, 2.5 eq.) at rt under nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to rt, diluted with water (15 mL) and extracted with EtOAc (3 x 6 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford the title compound as a white solid (80 mg, 52% yield).

[0308] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one hydrochloride (46b): Compound 46b was synthesized using tertbutyl 3-(3-chloro-2-methylphenyl)-3-[(2-methyl-l-oxoisoquinolin-7-yl) amino]azetidine-l- carboxylate (46a) (80 mg, 0.176 mmol) by following the procedure from Compound 1c to afford the title compound as a white solid (80 mg, crude). The crude product was used for the next step without further purification.

[0309] Preparation of (E)-7-((3-(3-chloro-2-methylphenyl)-l-(4-(dimethylamino)but-2- enoyl)azetidin-3-yl)amino)-2-methyl-3,4-dihydroisoquinolin-l(2H)-one (Compound 46): Compound 46 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one hydrochloride (46b) (80 mg, 0.164mmol, 1 eq.) and (E)-4- (dimethylamino)but-2-enoic acid hydrochloride (33.8 mg, 0.20 mmol, 1.3 eq.) by following the procedure from Compound 7 to afford the title compound as white solid (29.7 mg, 37% yield (2 steps)).1H NMR (300 MHz, DMSO-d6): δ 7.80 - 7.72 (m, 1H), 7.40 - 7.34 (m, 2H), 7.28 (dd, J = 15.6, 7.7 Hz, 2H), 7.20 (d, J= 2.5 Hz, 1H), 7.12 (d, J= 7.2 Hz, 1H), 6.97 (dd, J= 8.6, 2.5 Hz, 1H), 6.68 - 6.55 (m, 1H), 6.38 (d, J= 7.3 Hz, 1H), 6.20 (dt, J= 15.4, 1.5 Hz, 1H), 4.98 (s, 1H), 4.55 (d, J= 8.9 Hz, 2H), 4.35 (d, J= 10.1 Hz, 1H), 3.42 (s, 3H), 3.01 (dd, J= 6.1, 1.6 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 6H). LCMS EI-MS m / z = 465 [M+H]+.Example 47 : (E)-7-((3-(3-Chloro-2-methylphenyl)-l-(4-(piperidin-l-yl)but-2- enoyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 47)Compound 47

[0310] Preparation of (E)-7-((3-(3-chloro-2-methylphenyl)-l-(4-(piperidin-l-yl)but-2- enoyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 47): Compound 47 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methylisoquinolin-l(2H)-one TFA (42b) (25 mg, 0.07 mmol, 1 eq.) and (E)-4-piperidino-2- butenoic acid (14.5 mg, 0.07 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (20 mg, 56% yield).1H NMR (400 MHz, METHANOL-d4) δ 8.51 (d, J= 4.2 Hz, 2H), 8.17 (dd, J= 8.4, 1.2 Hz, 2H), 7.76 (d, J= 7.6 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.31 - 7.25 (m, 3H), 7.09 - 7.04 (m, 2H), 6.84 - 6.74 (m, 1H), 6.53 -6.44 (m, 2H), 5.08 (br d, J= 9.4 Hz, 1H), 4.71 (br d, J= 9.4 Hz, 1H), 4.66 - 4.50 (m, 2H), 3.80 - 3.63 (m, 4H), 3.55 (s, 3H), 3.22 (q, J= 7.4 Hz, 3H), 2.39 (s, 3H), 1.80 - 1.75 (m, 3H). LCMS EI-MS m / z = 506 [M+H]+.Example 48: (E)-7-((3-(3-Chloro-2-methylphenyl)-l-(4-methoxybut-2-enoyl)azetidin-3- yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 48)Compound 48

[0311] Preparation of (E)-7-((3-(3-chloro-2-methylphenyl)-l-(4-methoxybut-2-enoyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one (Compound 48): Compound 48 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methylisoquinolin-l(2H)-one TFA (42b) (28 mg, 0.08 mmol, 1 eq.) and (E)-4-methoxy-2-butenoic acid (9 mg, 0.08 mmol, 1 eq.) by following the procedure from Compound 15 to afford the title compound as a white solid (18 mg, 50% yield).1H NMR (400 MHz, METHANOL-4d) δ 7.78 (d, J= 7.5 Hz, 1H),7.38 - 7.30 (m, 2H), 7.28 - 7.23 (m, 2H), 7.08 - 7.03 (m, 2H), 6.84 (dt, J= 15.5, 4.3 Hz, 1H), 6.50 (d, J= 7.1 Hz, 1H), 6.30 (dt, J= 15.4, 2.0 Hz, 1H), 5.05 (br d, J= 9.1 Hz, 1H), 4.71 - 4.58 (m, 3H), 4.50 (d, J= 10.6 Hz, 1H), 4.11 (dd, J= 4.2, 1.9 Hz, 2H), 3.54 (s, 3H), 3.38 (s, 3H),2.39 (s, 3H). LCMS EI-MS m / z = 453 [M+H]+.Example 49: l-(3-(3-Chloro-2-methylphenyl)-3-((l-((tetrahydro-2H-pyran-4- yl)oxy)isoquinolin-7-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 49)

[0312] Preparation of 7-bromo-l-((tetrahydro-2H-pyran-4-yl)oxy)isoquinoline (49a): To a solution of 7-bromo-l,2-dihydro-l-isoquinolinone (180 mg, 0.80 mmol, 1.0 eq.) in DMF (dry, 0.8 mL) was added sodium hydride (29 mg, 60%, 1.2 mmol, 1.5 eq.). After stirred for 20 minutes, 4-bromotetrahydro-2H-pyran (398 mg, 2.41 mmol, 3.0 eq) was added. Then the reaction mixture was heated at 50 °C for 4 h. After diluted with ethyl acetate (30 mL). The organic layers were washed with water (5 mL x 5), brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by purified by silica gel column chromatography to afford the title compound as an oil (22 mg, 8.9% yield). LCMS ES-MS m / z = 308 [M]+.

[0313] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-((tetrahydro-2H-pyran-4- yl)oxy)isoquinolin-7-yl)amino)azetidine-l -carboxylate (49b): Compound 49b was synthesized using tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (20 mg, 0.067 mmol, 1 eq.) and 7-bromo-l-((tetrahydro-2H-pyran-4-yl)oxy)isoquinoline (49a) (21 mg, 0.067 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as white solid (15 mg, 43% yield). LCMS ES-MS m / z = 524 [M]+.

[0314] Preparation of N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)-l-((tetrahydro-2H-pyran- 4-yl)oxy)isoquinolin-7-amine TFA (49c): Compound 49c was synthesized using tert-butyl 3-(3- chloro-2-methylphenyl)-3-((l-((tetrahydro-2H-pyran-4-yl)oxy)isoquinolin-7- yl)amino)azetidine-l -carboxylate (49b) (15 mg, mmol) by following the procedure from Compound 9b to afford the title compound as white solid (14 mg, 100% yield). The compound was used for the next step without further purification. LCMS ES-MS m / z. = 424 [M]+.

[0315] Preparation of l-(3-(3-chloro-2-methylphenyl)-3-((l-((tetrahydro-2H-pyran-4- yl)oxy)isoquinolin-7-yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 49): Compound 49 was synthesized using N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)-l-((tetrahydro-2H-pyran-4- yl)oxy)isoquinolin-7-amine TFA (49c) (14 mg, 0.028 mmol, 1 eq.) and acryloyl chloride (3.3 mg, 0.037 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as white solid (7.3 mg, 50% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.74 (d, J= 5.8 Hz, 1H), 7.51 (dd, J= 8.1, 4.5 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.05 - 6.98 (m, 2H), 6.42 (d, J= 1.6 Hz, 1H), 6.34 - 6.20 (m, 1H), 5.74 (dd, J= 10.3, 1.6 Hz, 1H), 5.44 (tt, J= 8.0, 3.9 Hz, 1H), 4.92 (br d, J= 8.4 Hz, 1H), 4.78 (br s, 1H), 4.70 (br d, J= 8.5 Hz, 2H), 4.58 (br d, J= 10.8 Hz, 1H), 4.02 (m, 2H), 3.76 - 3.61 (m, 2H), 2.40 (s, 3H), 2.18 - 2.09 (m, 2H), 1.93 - 1.70 (m, 2H). LCMS ES-MS m / z = 478 [M]+.Example 50: l-(3-(3-Chloro-2-methylphenyl)-3-((l-methoxyisoquinolin-7- yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 50)

[0316] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-methoxyisoquinolin-7- yl)amino)azetidine-l -carboxylate (50a): Compound 50a was synthesized using tert-butyl 3- amino-3 -(3 -chloro-2-methylphenyl)azetidine-l -carboxylate (Int-1) (100 mg, 0.337 mmol, 1 eq.) and 7-bromo-l-methoxyisoquinoline (80.2 mg, 0.337 mmol, 1 eq.) by following the procedure from Compound 46a to afford the title compound as a brown solid (60 mg, 39% yield).

[0317] Preparation of N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)-l-methoxyisoquinolin-7- amine (50b): Compound 50b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3- ((l-methoxyisoquinolin-7-yl)amino)azetidine-l-carboxylate (50a) (60 mg, 0.132 mmol) by following the procedure for Compound 1c to afford the title compound as a brown solid (80 mg). The crude product was used for the next step without further purification.

[0318] Preparation of l-(3-(3-chloro-2-methylphenyl)-3-((l-methoxyisoquinolin-7- yl)amino)azetidin-l-yl)prop-2-en-l-one (Compound 50): Compound 50 was synthesized by using N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)-l-methoxyisoquinolin-7-amine (50b) (80 mg, 0.131 mmol, 1 eq.) and acryloyl chloride (14.2 mg, 0.157 mmol, 1.2 eq) by following the procedure from Compound 1 to afford the title compound as a white solid (23.3 mg, 43% yield (2 steps)).1H NMR (300 MHz, DMSO-d6): δ 7.79 (dd, J= 7.8, 1.4 Hz, 1H), 7.66 (d, J= 5.7 Hz, 1H), 7.57 (d, J= 8.8 Hz, 1H), 7.46 (s, 1H), 7.39 (dd, J= 8.0, 1.2 Hz, 1H), 7.31 (t, J= 7.8 Hz, 1H), 7.18 - 7.07 (m, 2H), 6.94 (d, J= 2.3 Hz, 1H), 6.43 (dd, J= 17.0, 10.3 Hz, 1H), 6.15 (dd, J = 17.0, 2.2 Hz, 1H), 5.71 (dd, J= 10.3, 2.2 Hz, 1H), 5.03 (s, 1H), 4.68 - 4.50 (m, 2H), 4.42 (d, J = 10.3 Hz, 1H), 3.96 (s, 3H), 2.34 (s, 3H). LCMS ELMS m / z = 408 [M+H]+.Example 51: l-(3-(3-Chloro-2-methylphenyl)-3-(quinolin-7-ylamino)azetidin-l-yl)-2- fluoroethan-l-one (Compound 51)

[0319] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-(quinolin-7- ylamino)azetidine-l -carboxylate (51a): To a solution of tert-butyl 3-amino-3-(3-chloro-2- methylphenyl)azetidine-l -carboxylate (Int-1) (85 mg, 0.286 mmol, 1 eq.), 7-bromoquinoline(59.5 mg, 0.286 mmol, 1 eq.), Cs2CO3(279 mg, 0.858 mmol, 3 eq.) and Ruphos (13.3 mg, 0.029 mmol, 0.1 eq.) in 1,4-dioxane (1.7 mL) was added Ruphos Pd G3 (23.9 mg, 0.029 mmol, 0.1 eq.) at rt under a nitrogen atmosphere. The mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to rt, diluted with water (10 mL) and extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography to afford the title compound as a white solid (45 mg, 37% yield).

[0320] Preparation of N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)quinolin-7-amine (51b): Compound 51b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-(quinolin-7- ylamino)azetidine-l -carboxylate (51a) (45 mg, 0.11 mmol) by following procedure from Compound 1c to afford the title compound as a white solid (30 mg, crude). The crude product was used for the next step without further purification.

[0321] Preparation of l-(3-(3-chloro-2-methylphenyl)-3-(quinolin-7-ylamino)azetidin-l-yl)-2- fhioroethan-l-one (Compound 51): Compound 51 was synthesized by using N-(3-(3-chloro-2- methylphenyl)azeti din-3 -yl)quinolin-7-amine (51b) (30 mg, 0.093 mmol, 1 eq.) and ethyl 2- fluoroacetate (7.86 mg, 0.074 mmol, 0.8 eq.) by following the procedure from Compound 2 to afford the title compound as a white solid (1.3 mg, 3% yield (2 steps)).1H NMR (400 MHz, DMSO-d6): δ 8.57 (dd, J= 4.3, 1.8 Hz, 1H), 8.01 (dd, J= 8.1, 1.8 Hz, 1H), 7.87 (dd, J= 7.8, 1.4 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.38 (dd, J= 8.1, 1.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.0, 4.3 Hz, 1H), 7.06 (dd, J= 8.8, 2.3 Hz, 1H), 6.61 (d, J= 2.3 Hz, 1H), 5.09 - 4.98 (m, 2H), 4.95 (d, J= 1.8 Hz, 1H), 4.62 (d, J= 9.7 Hz, 2H), 4.44 (d, J= 9.6 Hz, 1H), 2.34 (s, 3H). LCMS EI-MS m / z = 384 [M+H]+.Example 52: l-(3-(3-Chloro-2-methylphenyl)-3-(quinolin-7-ylamino)azetidin-l-yl)prop-2- en-l-one (Compound 52)Compound 52

[0322] Preparation of l-(3-(3-chloro-2-methylphenyl)-3-(quinolin-7-ylamino)azetidin-l- yl)prop-2-en-l-one (Compound 52): Compound 52 was synthesized by using l-(3-(3-chloro-2- methylphenyl)azeti din-3 -yl)quinolin-7-amine (51b) (75 mg, 0.23 mmol, 1 eq.) and acryloyl chloride (21.0 mg, 0.23 mmol, 1 eq.) by following the procedure from Compound 1 to affordthe title compound as a white solid (10.1 mg, 11% yield).1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 7.94 (dd, J= 36.5, 7.8 Hz, 2H), 7.78 - 7.54 (m, 2H), 7.34 (dt, J= 15.6, 7.9 Hz, 2H), 7.09 (dd, J= 15.7, 7.1 Hz, 2H), 6.64 (s, 1H), 6.42 (dd, J= 17.0, 10.5 Hz, 1H), 6.15 (d, J= 16.9 Hz, 1H), 5.71 (d, J= 10.3 Hz, 1H), 5.23 - 4.90 (m, 1H), 5.88 - 4.55 (m, 2H), 4.54 - 4.34 (m, 1H), 2.36 (s, 3H). LCMS ELMS m / z = 378 [M+H]+.Example 53: l-(3-(3-Chloro-2-methylphenyl)-3-(cinnolin-7-ylamino)azetidin-l-yl)prop-2- en-l-one (Compound 53)

[0323] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-(cinnolin-7-ylamino)azetidine- 1-carboxylate (53a): Compound 53a was synthesized using tert-butyl 3-amino-3-(3-chloro-2- methylphenyl) azetidine- 1 -carboxylate (Int-1) (99.3 mg, 0.335 mmol, 1 eq.) and 7- bromocinnoline (70 mg, 0.335 mmol, 1 eq.) by following the procedure from Compound 46a to afford the title compound as a brown solid (60 mg, 42% yield).

[0324] Preparation of N-(3-(3-chloro-2-methylphenyl)azetidin-3-yl)cinnolin-7-amine (53b): Compound 53b was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-(cinnolin-7- ylamino)azetidine-l -carboxylate (53a) (60 mg, 0.141 mmol) by following the procedure from Compound 1c to afford the title compound as a white solid (40 mg). The crude product was used for the next step without further purification.

[0325] Preparation of l-(3-(3-chloro-2-methylphenyl)-3-(cinnolin-7-ylamino)azetidin-l- yl)prop-2-en-l-one (Compound 53): Compound 53 was synthesized using N-(3-(3-chloro-2- methylphenyl)azeti din-3 -yl)cinnolin-7-amine (53b) (40 mg, 0.123 mmol, 1 eq.) and acryloyl chloride (13.3 mg, 0.148 mmol, 1.2 eq.) by following the procedure from Compound 1 to afford the title compound as a yellow solid (1.4 mg, 3% yield (2 steps)).1H NMR (300 MHz, DMSO- d6) 5 8.98 (d, J= 5.5 Hz, 1H), 8.04 - 7.93 (m, 2H), 7.84 (d, J= 5.5 Hz, 1H), 7.74 (d, J= 9.0 Hz, 1H), 7.45 - 7.29 (m, 3H), 6.87 (d, J= 2.2 Hz, 1H), 6.43 (dd, J= 17.0, 10.3 Hz, 1H), 6.16 (dd, J = 17.0, 2.2 Hz, 1H), 5.72 (dd, J= 10.3, 2.2 Hz, 1H), 5.12 (s, 1H), 4.69 (d, J= 9.5 Hz, 2H), 4.48 (d, J= 10.4 Hz, 1H), 2.36 (s, 3H). LCMS ELMS m / z = 379 [M+H]+.Example 54: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,3- dimethylquinazoline-2,4(lH,3H)-dione (Compound 54)

[0326] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydroquinazolin-7-yl)amino)azetidine-l-carboxylate (54a): Compound 54a was synthesized by 7-bromo-l,3-dimethylquinazoline-2,4(lH,3H)-dione (60 mg, 0.22 mmol, 1.1 eq.) and tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (60 mg, 0.20 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (36 mg, 37% yield). LCMS ES-MS m / z. = 485 [M]+.

[0327] Preparation of 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,3- dimethylquinazoline-2,4(lH,3H)-dione TFA (54b): Compound 54b was synthesized using tert- butyl 3-(3-chl oro-2 -methylphenyl)-3-((l, 3-dimethyl-2,4-di oxo-1, 2,3, 4-tetrahy droquinazolin-7- yl)amino)azetidine-l -carboxylate (54a) (36 mg, 0.074 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LCMS ES-MS m / z = 385 [M]+.

[0328] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,3- dimethylquinazoline-2,4(lH,3H)-dione (Compound 54): Compound 54 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,3-dimethylquinazoline-2,4(lH,3H)- dione TFA (54b) (16 mg, 0.041 mmol, 1 eq.) and acryloyl chloride (4.10 mg, 0.045 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as white solid (8.8 mg, 39% yield).1H NMR (400 MHz, METHANOL-d4): δ 7.79 - 7.71 (m, 2H), 7.38 (d, J= 7.9 Hz, 1H), 7.30 (t, J= 7.9 Hz, 1H), 6.54 (dd, J= 8.8, 1.8 Hz, 1H), 6.48 - 6.38 (m, 1H), 6.32 - 6.27 (m, 1H), 6.16 (d, J= 1.6 Hz, 1H), 5.79 (dd, J= 10.3, 1.6 Hz, 1H), 5.17 - 4.95 (m, 1H), 4.84 - 4.60 (m, 2 H), 4.51 (br d, J= 10.7 Hz, 1H), 3.37 (s, 3H), 3.30 (s, 3H), 2.37 (s, 3H). LCMS ES-MS m / z = 439 [M]+.Example 55: 6-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,4-dimethyl- l,4-dihydroquinoxaline-2, 3-dione (Compound 55)

[0329] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l,4-dimethyl-2,3-dioxo- 1,2, 3, 4-tetrahydroquinoxalin-6-yl)amino)azeti dine- 1 -carboxylate (55a): Compound 55a was synthesized using 6-bromo-l,4-dimethyl-l,4-dihydroquinoxaline-2, 3-dione (54 mg, 0.20 mmol, 1 eq.) and tert-butyl 3 -amino-3 -(3 -chi oro-2-methylphenyl)azeti dine- 1 -carboxylate (Int-1) (60 mg, 0.20 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as a white solid (37 mg, 37% yield). LCMS ES-MS m / z = 485 [M]+.

[0330] Preparation of 6-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,4-dimethyl-l,4- dihydroquinoxaline-2, 3-dione TFA (55b): Compound 55b was synthesized using tert-butyl 3-(3- chloro-2-methylphenyl)-3-((l,4-dimethyl-2, 3-di oxo- 1,2,3, 4-tetrahy droquinoxalin-6- yl)amino)azetidine-l -carboxylate (55a) (36 mg, 0.074 mmol) by following the procedure from Compound 9b to afford the title compound and was used for the next step without further purification. LC-MS ES-MS m / z = 385 [M]+.

[0331] Preparation of 6-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-l,4- dimethyl-l,4-dihydroquinoxaline-2,3-dione (Compound 55): Compound 55 was synthesized using 6-((3 -(3 -chloro-2-methylphenyl)azeti din-3 -yl)amino)- 1 ,4-dimethyl- 1,4- dihydroquinoxaline-2, 3-dione TFA (55b) (14 mg, 0.036 mmol, 1 eq.) and acryloyl chloride (3.62 mg, 0.036 mmol, 1.2 eq.) by following the procedure from Compound 9 to afford the title compound as a white solid (9.0 mg, 56% yield).1H NMR (400 MHz, CHLOROFORM-d): δ 7.41 (d, J= 8.0, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.23 (t, J= 8.0 Hz, 1H), 7.01 (d, J= 8.4 Hz, 1H), 6.54 (dd, J= 8.8, 2.4 Hz, 1H), 6.43 - 6.36 (m, 2H), 6.30 - 6.21 (m, 1H), 5.74 (dd, J= 10.3, 1.8 Hz, 1H), 4.86 (br d, J= 8.9 Hz, 1H), 4.72 - 4.51 (m, 4H), 3.57 (s, 3H), 3.43 (s, 3H), 2.40 (s, 3H). LCMS ES-MS m / z = 439 [M]+.Example 56: 7-((l-Acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methyl-3- (2,2,2-trifluoroethyl)quinazolin-4(3H)-one (Compound 56)

[0332] Preparation of 7-bromo-2-methyl-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (56a): Compound 56a was synthesized using 7-bromo-2-methylquinazolin-4(3H)-one (240 mg, 1 mmol, 1 eq.) and l,l,l-trifluoro-2-iodoethane (316 mg, 1.5 mmol, 1.5 eq.) by following the procedure from Compound 16a to afford the title compound as an oil (120 mg, 37% yield). LCMS ES-MS m / z = 321 and 323 [M]+.

[0333] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-methyl-4-oxo-3-(2,2,2- trifluoroethyl)-3,4-dihydroquinazolin-7-yl)amino)azetidine-l-carboxylate (56b): Compound 56b was synthesized using tert-butyl 3-amino-3-(3-chloro-2-tolyl)-l-azetidinecarboxylate (Int-1) (50 mg, 0.17 mmol, 0.8 eq.) and 7-bromo-2-methyl-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (56a) (65 mg, 0.20 mmol, 1 eq.) by following the procedure from Compound lb to afford the title compound as white solid (30 mg, 28% yield). LCMS ES-MS m / z = 537 [M]+.

[0334] Preparation of 7-((3 -(3 -chi oro-2-methylphenyl)azeti din-3 -yl)amino)-2-methyl-3 -(2,2,2- trifluoroethyl)quinazolin-4(3H)-one TFA (56c): Compound 56c was synthesized using tert-butyl 3-(3-chloro-2-methylphenyl)-3-((2-methyl-4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin- 7-yl)amino)azetidine-l -carboxylate (56b) (30 mg, 0.056 mmol) by following the procedure from Compound 9b to afford the title compound as white solid (26 mg, 100% yield). The compound was used for next step without further purification. LCMS ES-MS m / z = 437 [M]+.

[0335] Preparation of 7-((l-acryloyl-3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2- methyl-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (Compound 56): Compound 56 was synthesized using 7-((3-(3-chloro-2-methylphenyl)azetidin-3-yl)amino)-2-methyl-3-(2,2,2- trifluoroethyl)quinazolin-4(3H)-one TFA (56c) (16 mg, 0.037 mmol, 1 eq.) and acryloyl chloride (5.4 mg, 0.059 mmol, 1.6 eq.) by following the procedure for Compound 9 to afford the title compound as white solid (5.6 mg, 25% yield).1H NMR (400 MHz, CHLOROFORM- d): 5 7.99 (d, J= 8.6 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.67 (br d, J= 8.6 Hz, 1H), 6.58 - 6.54 (m, 1H), 6.43 - 6.26 (m, 1H), 6.29 - 6.16 (m, 1H), 5.74 (br d, J= 10.3 Hz, 1H), 5.01 (m, 1H), 4.67 (br d, J= 8.9 Hz, 4H), 4.54 (m, 1H), 2.58 (s, 3H), 2.37 (s, 3H).19F NMR (376 MHz, CHLOROFORM-d): δ - 68.5 (s, IF). LCMS ES-MS m / z = 491 [M]+.Example 57 : l-(3-(3-Chloro-2-methylphenyl)-3-((l-methyl-lH-indazol-6-yl)amino)azetidin- l-yl)prop-2-en-l-one (Compound 57)lnt-1 57a 57b Compound 57

[0336] Preparation of tert-butyl 3-(3-chloro-2-methylphenyl)-3-((l-methyl-lH-indazol-6- yl)amino)azetidine-l -carboxylate (57a): To a stirred solution of tert-butyl 3-amino-3-(3-chloro- 2-methylphenyl)azetidine-l -carboxylate (Int-1) (42 mg, 0.14 mmol, 1 eq.) in 1,4-dioxane (1.3 mL) were added 6-bromo-l-methyl-lH-indazole (30 mg, 0.14 mmol, 1 eq.), Xphos (3.4 mg, 0.007 mmol, 0.5 eq.), Pd2(dba)s (6.5 mg, 0.007 mmol, 0.05 eq.) and Z-B...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I’):Formula (F); or a pharmaceutically acceptable salt thereof, wherein: each Y is C(R3a)2; each Z is C(R3b)2;R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R3ais independently selected from hydrogen and C1-6alkyl; each R3bis independently selected from hydrogen and C1-6alkyl; each R4is independently selected from halogen, oxo, -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, -CFL-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-10aryl, -CFL-C1-10aryl, C1- 9heteroaryl, and -CFL-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CFL-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-10aryl, -CFL-C1-10aryl, 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, C1-10aryl,WSGR Docket No. 52234-724.601C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, C1-9heteroaryl, and -CH2-C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- ealkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl;WSGR Docket No. 52234-724.601 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- ealkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl; n is 1 or 2; and p is 1, 2, or 3.

2. A compound of Formula (I):Formula (I); or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups;R2is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, phenyl fused with C2- 9heterocycloalkyl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, phenyl fused with C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups;R3is selected from -C(O)C(R6)=C(R7)(R8), -C(O)C=C(R7), -S(O)2C(R6)=C(R7)(R8), - S(O)2C=C(R7), and -C(O)CH2F; each R4is independently selected from halogen, oxo, -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, -WSGR Docket No. 52234-724.601N(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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R4are combined to form a C3-5cycloalkyl ring; each R5is independently selected from halogen, oxo, -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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, -CH2-C1-10aryl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring;R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and - C(O)N(R10)(R11);R7and R8are independently selected from hydrogen, halogen, -CN, -OR10, - C(O)N(R10)(R11), -N(R12)C(O)R13, C1-6alkyl, C1-6haloalkyl, C2.6heteroalkyl, C2. 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - N(R12)C(O)R13;WSGR Docket No. 52234-724.601R9is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- ealkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, 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 C1-C3alkyl, C3-C6 cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; 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- ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1- ealkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- ealkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl; n is 1 or 2; and p is 1, 2, or 3.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, having the structure of Formula (la):WSGR Docket No. 52234-724.6014. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, having the structure of Formula (lb):Formula (lb).

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

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl optionally substituted with 1-5 R4groups.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11).

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen, unsubstituted C1-6alkyl, and C1-6haloalkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen and unsubstituted C1-6alkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1-3 R4groups and each R4is independently selected from halogen.WSGR Docket No. 52234-724.60111. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl, wherein phenyl fused with C2-9heterocycloalkyl and C1-9heteroaryl are optionally substituted with 1-5 R5groups.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl optionally substituted with 1-5 R5groups.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1- ealkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2- C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, -OR10, C1-6alkyl, C1-6haloalkyl, -CH2-C3- ecycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, -CH2-C3- ecycloalkyl, and -CH2-C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3-5cycloalkyl ring.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3- ecycloalkyl, C2-9heterocycloalkyl, and -OR10; or two R5are combined to form a C3- scycloalkyl ring.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo, unsubstituted C1-6alkyl, and C 1 -6haloalky 1; or two R5are combined to form a C3-5cycloalkyl ring.WSGR Docket No. 52234-724.60117. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from oxo and unsubstituted C1-6alkyl.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:

19. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, -CN, -OR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, -N(R10)(R11), and - C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl fused with C2-9heterocycloalkyl substituted with 1-5 R5groups and each R5is independently selected from halogen, oxo, C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)N(R10)(R11); or two R5are combined to form a C3-5cycloalkyl ring.

22. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:WSGR Docket No. 52234-724.60123. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R2is C1-9heteroaryl optionally substituted with 1-5 R5groups.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R2is C1- 9heteroaryl optionally substituted with 1-5 R5groups and each R5is independently selected from halogen, -CN, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -S(O)2R13, -S(O)2N(R10)(R11)-, C1-6alkyl, C1-6haloalkyl, C3- ecycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, 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, C i -6haloalky 1, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11).

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R2is C1- 9heteroaryl substituted with 1-5 R5groups and each R5is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with one, two, or three groups selected from C3-6cycloalkyl, C2-9heterocycloalkyl, and -OR10.

26. The compound of any one of claims 23-25, or a pharmaceutically acceptable salt thereof, wherein R2is C1-9heteroaryl substituted with 1-3 R5groups and each R5is independently selected from unsubstituted C1-6alkyl.

27. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R2is unsubstituted C1-9heteroaryl.

28. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R2is independently selected from:

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R3is selected from30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R3is -C(O)C(R6)=C(R7)(R8).

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R6is selected from hydrogen and halogen.WSGR Docket No. 52234-724.60132. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R7and R8are independently selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11).

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen and R8are independently selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three groups selected from C2-9heterocycloalkyl, - OR10, and -N(R10)(R11).

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen and R8is unsubstituted C1-6alkyl.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen and R8is hydrogen.

37. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R3is -C(O)C=C(R7).

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R7is unsubstituted C1-6alkyl.

39. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof,.0 erein R3is selected from. wh40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

41. A compound, or a pharmaceutically acceptable salt thereof, selected from:WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.60142. A compound, or a pharmaceutically acceptable salt thereof, selected from:WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.601WSGR Docket No. 52234-724.60143. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.

44. A method of inhibiting SARM1 comprising contacting the SARM1 with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.WSGR Docket No. 52234-724.60145. A method of inhibiting axonal degeneration in a patient in need thereof comprising administering to the patient an inhibiting amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.

46. The method of claim 45, wherein the axonal degeneration is caused by abnormal reduction or depletion of NAD+ in the axons.

47. A method of treating or preventing 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 1-42, or a pharmaceutically acceptable salt thereof.

48. The method of claim 47 wherein the neurological disorder is a neurodegenerative disease.

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