Heterocyclic GPR52 modulators and methods of use thereof

Abstract

The present disclosure provides compounds that modulate GPR52 activity. These compounds may be GPR52 agonists. Also provided herein are compositions comprising the GPR52 modulating compounds, and their methods of use. The methods are useful for the treatment of neurological, neuropsychiatric, and neurodegenerative diseases or disorders.

Description

WSGR Docket No.58819-702.601 HETEROCYCLIC GPR52 MODULATORS AND METHODS OF USE THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 746,040, filed on January 16, 2025, and U.S. Provisional Application No.63 / 662,291, filed on June 20, 2024, each of which is incorporated herein by reference in their entirety. BACKGROUND

[0002] Schizophrenia is a disorder that has classically been characterized by three broad symptom domains. Positive symptoms of schizophrenia include psychomotor agitation, hallucinations, and paranoia. The dopamine hypothesis of schizophrenia posits that these positive symptoms are due to increased dopaminergic activity in the mesolimbic pathway, where the dopamine D2 receptor is most abundant. Negative symptoms of schizophrenia encompass social withdrawal, anhedonia, and blunted overall affect. Cognitive symptoms of schizophrenia are comprised of deficits in working memory, attention, and executive function. Decreased dopaminergic activity throughout the mesocortical pathway, where the dopamine D1receptor is especially important, is thought to underlie some aspects of negative and cognitive symptoms of schizophrenia.

[0003] Most clinically used treatments for schizophrenia act by antagonizing the dopamine D2receptor subtype, and hence have utility in treating positive symptoms. Dopamine D2receptors are also expressed in structures outside the mesolimbic pathway, including the nigrostriatal pathway, where they are important for mediating voluntary and involuntary movement. Further, since systemically administered D2receptor antagonists do not discriminate between these various D2receptor-expressing brain regions, long-term antipsychotic treatment is frequently associated with movement disorders. Moreover, since the hypofunctional mesocortical pathway is largely unaffected by D2antagonists, the cognitive and negative symptoms of schizophrenia are not alleviated by antipsychotic treatment.

[0004] The G-protein coupled receptor GPR52 is a constitutively active receptor that is expressed in multiple brain regions. Although an endogenous agonist for GPR52 has not been identified, activation of GPR52 is known to stimulate production of cyclic adenosine monophosphate (cAMP). Moreover, GPR52 expression is abundant in areas comprising the mesolimbic pathway, such as striatum, where it colocalizes with the Gi / o-coupled dopamine D2receptor. Expression of GPR52 in areas of the mesocortical pathway such as prefrontal cortex, has also been demonstrated, where it colocalizes with the Gs-coupled dopamine D1 receptor. A synthetic GPR52 agonist would, therefore, be expected to increase cAMP levels in both dopamine D2and D1expressing neurons. This increased cAMP production is expected to counteract hyperactive dopamine D2receptor signaling, while simultaneously augmenting the diminished dopamine D1 receptor signaling observed in schizophrenia. As such, GPR52 agonists may have utility as a treatment for schizophrenia or other diseases characterized by perturbations of dopaminergic signaling including, but not limited to Huntington’s disease, Fragile X Syndrome, Rett Syndrome, autism spectrum disorder, major depressive disorder, substance use disorder, bipolar disorder, 1WSGR Docket No.58819-702.601 Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia, attention deficit hyperactivity disorder, post-traumatic stress disorder, restless leg syndrome, and compulsive gambling disorder. SUMMARY

[0005] The present disclosure addresses a need in the art by providing compounds, compositions, and methods for modulating GPR52. The compounds, compositions, and methods herein may be useful for treating diseases associated with GPR52, such as psychotic disorders.

[0006] In one aspect, provided herein is a compound of Formula (I):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl; Ring B is phenyl or a 5- to 6- membered heteroaryl; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from 2WSGR Docket No.58819-702.601 C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and 3WSGR Docket No.58819-702.601 n is 0, 1, 2, 3, 4, or 5.

[0007] In one aspect, provided herein is a compound of Formula (II):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more 4WSGR Docket No.58819-702.601 substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5. In some embodiments, a compound of Formula (II) may be depicted as: 5WSGR Docket No.58819-702.601

[0008] In one aspect, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 6WSGR Docket No.58819-702.601 each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0009] In one aspect, provided herein is a compound of Formula (III-M-1): 7WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 8WSGR Docket No.58819-702.601 each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0010] In one aspect, provided herein is a compound of Formula (III-M-2):9WSGR Docket No.58819-702.601 or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; 10WSGR Docket No.58819-702.601 each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0011] In one aspect, provided herein is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and 11WSGR Docket No.58819-702.601 heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O;L1is bond, C1-C3alkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, -OH, cyclopropyl, and =O; 12WSGR Docket No.58819-702.601 each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5. In some embodiments, a compound of Formula (IV) may be depicted as:

[0012] In one aspect, provided herein is a compound of Formula (IV-M-1):13WSGR Docket No.58819-702.601 or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 14WSGR Docket No.58819-702.601 each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0013] In one aspect, provided herein is a compound of Formula (IV-M-2):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 15WSGR Docket No.58819-702.601 R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0014] In one aspect, provided herein is a compound of Formula (V):16WSGR Docket No.58819-702.601 or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl 17WSGR Docket No.58819-702.601 (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0015] In one aspect, provided herein is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; 18WSGR Docket No.58819-702.601 each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 19WSGR Docket No.58819-702.601L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0016] In one aspect, provided herein is a compound of Formula (VI-M-1): 20WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from 21WSGR Docket No.58819-702.601 C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0017] In one aspect, provided herein is a compound of Formula (VI-M-2):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- 22WSGR Docket No.58819-702.601 membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0018] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a 23WSGR Docket No.58819-702.601 compound, pharmaceutically acceptable salt, or isotopically enriched form, of Formula (I), (II), (III), (III- M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2). In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for injection.

[0019] In one aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering a compound, pharmaceutically acceptable salt, or isotopically enriched form, of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), to the subject. In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from schizophrenia, cognitive impairment, a panic disorder, a phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson’s disease, drug-induced Parkinson’s syndrome, extrapyramidal syndrome, Alzheimer’s Disease, Lewy Body Dementia, bipolar disorder, ADHD, Tourette’s syndrome, an extrapyramidal or movement disorder, a motor disorder, a hyperkinetic movement disorder, a psychotic disorder, catatonia, a mood disorder, a depressive disorder, an anxiety disorder, obsessive-compulsive disorder (OCD), an autism spectrum disorder, a prolactin-related disorder (e.g., hyperprolactinemia), a neurocognitive disorder, and a trauma- or stressor- related disorder (e.g., PTSD). In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from a disruptive, impulse-control, or conduct disorder, a sleep-wake disorder, a substance-related disorder, an addictive disorder, a behavioral disorder, hypofrontality, an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway, decreased activity in the striatum, cortical dysfunction, neurocognitive dysfunction, and the cognitive deficits associated with schizophrenia. In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from Parkinson’s Disease, drug induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy, progressive supranuclear palsy, and Huntington’s disease, including chorea associated with Huntington’s disease. In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from Huntington’s disease, Fragile X Syndrome, Rett Syndrome, autism spectrum disorder, major depressive disorder, substance use disorder, bipolar disorder, Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia, attention deficit hyperactivity disorder, post-traumatic stress disorder, restless leg syndrome, and compulsive gambling disorder.

[0020] In one aspect, the present disclosure relates to the use of the compound, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, of Formula (I), (II), (III), (III-M-1), (III- M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2) for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by GPR52.

[0021] In certain aspects, the present disclosure provides a kit comprising a pharmaceutical composition 24WSGR Docket No.58819-702.601 described herein and instructions for using the composition to treat a subject suffering from a disease or condition mediated by GPR52. INCORPORATION BY REFERENCE

[0022] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION

[0023] should be understood that both the general descriptions and the detailed description below are merely illustrative and descriptive and do not limit the present technology of the present application. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0024] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0025] The headings used in the present specification are for structural purposes only and must not be construed as limiting the subject matter described.

[0026] In the present specification, the use of the singular form includes the plural form unless otherwise specified. In the present specification, the use of “or (or)” means “and / or (and / or)” unless otherwise stated. Furthermore, terms such as “element” or “component” encompass both an element and a component including one unit and an element and a component including two or more subunits unless when otherwise specified.

[0027] The recitation herein of numerical ranges by endpoints is intended to include all numbers subsumed within that range (e.g., a recitation of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 4.32, and 5).

[0028] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0029] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. I. Definitions

[0030] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges 25WSGR Docket No.58819-702.601 are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0031] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0032] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0033] "Amino" refers to the –NH2radical.

[0034] "Cyano" refers to the -CN radical.

[0035] "Nitro" refers to the -NO2radical.

[0036] "Oxo" refers to the =O radical.

[0037] "Imino" refers to the =N-H radical.

[0038] "Oximo" refers to the =N-OH radical.

[0039] "Hydrazino" refers to the =N-NH2radical.

[0040] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0041] “Hydroxyamino” refers to the -NH-OH radical.

[0042] “Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0043] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 26WSGR Docket No.58819-702.601 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a C1-C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1- C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C≡CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0044] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0045] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or a C2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, 27WSGR Docket No.58819-702.601 halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0046] The term “alkenylene” or “alkenylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain in which at least one carbon-carbon double bond is present linking the rest of the molecule to a radical group. In some embodiments, the alkenylene is –CH=CH-, - CH2CH=CH-, or –CH=CHCH2-. In some embodiments, the alkenylene is –CH=CH-. In some embodiments, the alkenylene is –CH2CH=CH-. In some embodiments, the alkenylene is –CH=CHCH2-.

[0047] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8alkynyl, a C2-C7alkynyl, a C2-C6alkynyl, a C2-C5alkynyl, a C2-C4alkynyl, a C2-C3alkynyl, or a C2alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. The term “alkynylene” refers to an optionally substituted straight- chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple-bonds.

[0048] “Alkylamino” refers to a radical of the formula -N(Ra)2where Rais an alkyl radical as defined, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylamino is optionally substituted with halogen.

[0049] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally 28WSGR Docket No.58819-702.601 substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0050] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0051] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1- C6alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3,-S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0052] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for 29WSGR Docket No.58819-702.601 example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0053] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0054] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0055] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- 30WSGR Docket No.58819-702.601 ), sulfur, or combinations thereof. Examples of such heteroalkyl are, for example, –CH2-O-CH3, –CH2- N(alkyl)-CH3, –CH2-N(aryl)-CH3, -OCH2CH2OH, –OCH2CH2OCH2CH2OH, or – OCH2CH2OCH2CH2OCH2CH2OH. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0056] As used herein, a “heteroalkylene” refers to divalent heteroalkyl group. Examples of such heteroalkylene are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, - OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0057] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one hetero ring atom, e.g., a heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2- C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, 31WSGR Docket No.58819-702.601 heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0058] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring 32WSGR Docket No.58819-702.601 system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0059] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0060] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder.

[0061] In certain embodiments, “treating” includes the concepts of “alleviating,” which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. In certain embodiments, the term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0062] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that in a statistical sample, reduces the occurrences of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0063] The term "therapeutically effective amount" as used herein refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0064] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either 33WSGR Docket No.58819-702.601 “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0065] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

[0066] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). For example, “optionally substituted” or “substituted” can mean that the referenced group is optionally substituted with one or more substituents individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), - N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, - S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1- C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and - S(=O)2C1-C4alkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, - C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1- C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, - OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1- C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1- C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, 34WSGR Docket No.58819-702.601 C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, 5-6 membered heterocycloalkyl and C3- C6cycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, oxo, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)OH, - C(=O)NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, and C3-C6cycloalkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. In some embodiments, an “optionally substituted” group is unsubstituted. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1-3 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1-2 substituents.

[0067] The term “unsubstituted” means that the specified group bears no substituents.

[0068] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0069] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. Unless explicitly stated to the country, it will be understood that stereochemical markings, e.g., hash and / or wedge bonds depicting R and / or S configurations for each asymmetric center are relatively assigned and do not imply absolute configuration. In some embodiments the indicated stereochemistry is arbitrarily assigned.

[0070] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0071] As used herein, C1-Cx (or C1-x) includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl 35WSGR Docket No.58819-702.601 group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2 alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0072] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0073] It is appreciated that certain features of the disclosure, 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, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0074] Unless special definitions are given, the terminology used in relation to analytical chemistry, synthetic organic chemistry, and medical chemistry and pharmaceutical chemistry described in the present specification, as well as their procedures and techniques, are well known and commonly used in the field of the present art. Standard techniques may be used for chemical synthesis and chemical analysis. Those defined from among such techniques and procedures can be found in, for example, “K.J. Jensen, P.T. Shelton, S.L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013” and the like, and these are incorporated into the present specification by reference for all purposes. All patents, applications, published applications, and other publications, and other data referred to throughout the entire disclosure, when permitted, are incorporated into the present specification by reference.

[0075] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0076] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0077] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and 36WSGR Docket No.58819-702.601 the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0078] The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co- administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0079] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0080] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. II. GPR52 Modulators

[0081] Provided herein are compounds that modulate GPR52. In some embodiments, the compounds are GPR52 agonists. The compounds can be useful for treating GRP52 mediated diseases or disorders, such as a neurological, neuropsychiatric, or neurodegenerative disease or disorder. Described herein are pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers of said compounds.

[0082] In one aspect, provided herein is a compound of Formula (I): 37WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl; Ring B is phenyl or a 5- to 6- membered heteroaryl; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more 38WSGR Docket No.58819-702.601 substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0083] In one aspect, provided herein is a compound of Formula (I): 39WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl; Ring B is phenyl or a 5- to 6- membered heteroaryl; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more 40WSGR Docket No.58819-702.601 substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0084] In one aspect, provided herein is a compound of Formula (I): 41WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl; Ring B is phenyl or a 5- to 6- membered heteroaryl; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - 42WSGR Docket No.58819-702.601 OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0085] In one aspect, provided herein is a compound of Formula (II): 43WSGR Docket No.58819-702.601, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 44WSGR Docket No.58819-702.601 each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0086] In one aspect, provided herein is a compound of Formula (II): 45WSGR Docket No.58819-702.601, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 46WSGR Docket No.58819-702.601 each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0087] In one aspect, provided herein is a compound of Formula (II): 47WSGR Docket No.58819-702.601, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 48WSGR Docket No.58819-702.601 each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, -OH, cyclopropyl, and =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0088] In some embodiments, the compound of Formula (II) as the structure of Formula (IIa) or Formula (IIb): 49WSGR Docket No.58819-702.601, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0089] In one aspect, provided herein is a compound of Formula (III):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- 50WSGR Docket No.58819-702.601 membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or 51WSGR Docket No.58819-702.601 Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0090] In one aspect, provided herein is a compound of Formula (III):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 52WSGR Docket No.58819-702.601 each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5. 53WSGR Docket No.58819-702.601

[0091] In one aspect, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 54WSGR Docket No.58819-702.601 each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0092] In some embodiments, the compound of Formula (III) has the structure of Formula (IIIa) or Formula (IIIb):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof. 55WSGR Docket No.58819-702.601

[0093] In one aspect, provided herein is a compound of Formula (III-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more 56WSGR Docket No.58819-702.601 substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0094] In some embodiments, the compound of Formula (III-M-1) has the structure of Formula (III-M- 1a) or Formula (III-M-1b): 57WSGR Docket No.58819-702.601(III-M-1a) (III-M-1b) or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0095] In one aspect, provided herein is a compound of Formula (III-M-2):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein:each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and 58WSGR Docket No.58819-702.601 heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0096] In some embodiments, the compound of Formula (III-M-2) has the structure of Formula (III-M- 2a) or Formula (III-M-2b): 59WSGR Docket No.58819-702.601(III-M-2a) (III-M-2b)

[0097] In one aspect, provided herein is a compound of Formula (IV):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more 60WSGR Docket No.58819-702.601 substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O;L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 61WSGR Docket No.58819-702.601 each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0098] In one aspect, provided herein is a compound of Formula (IV):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached 62WSGR Docket No.58819-702.601 to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O;L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, -OH, cyclopropyl, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 63WSGR Docket No.58819-702.601 each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0099] In one aspect, provided herein is a compound of Formula (IV):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached 64WSGR Docket No.58819-702.601 to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O;L1is bond, C1-C3alkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, -OH, cyclopropyl, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; 65WSGR Docket No.58819-702.601 each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0100] In some embodiments, the compound of Formula (IV) has the structure of Formula (IVa) or Formula (IVb):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0101] In one aspect, provided herein is a compound of Formula (IV-M-1):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- 66WSGR Docket No.58819-702.601 to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or 67WSGR Docket No.58819-702.601 Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0102] In some embodiments, the compound of Formula (IV-M-1) has the structure of Formula (IV-M- 1a) or Formula (IV-M-1b):(IV-M-1a) (IV-M-1b) or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0103] In one aspect, provided herein is a compound of Formula (IV-M-2):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 68WSGR Docket No.58819-702.601 R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0104] In some embodiments, the compound of Formula (IV-M-2) has the structure of Formula (IV-M- 2a) or Formula (IV-M-2b): 69WSGR Docket No.58819-702.601(IV-M-2a) (IV-M-2b)

[0105] In one aspect, provided herein is a compound of Formula (V):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH or N; A2is CH2, NH, or O; A3is C, CH or N; and A4is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH; O, S, S(O)2, or S(O)(NH); A6is CH, CH2, N; NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH); each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and 70WSGR Docket No.58819-702.601 heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-C3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 71WSGR Docket No.58819-702.601 each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0106] In some embodiments, the compound of Formula (V) has the structure of Formula (Va) or Formula (Vb):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0107] In one aspect, provided herein is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - 72WSGR Docket No.58819-702.601 OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 73WSGR Docket No.58819-702.601L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0108] In some embodiments, the compound of Formula (VI) has the structure of Formula (VIa) or Formula (VIb): 74WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

[0109] In one aspect, provided herein is a compound of Formula (VI-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; 75WSGR Docket No.58819-702.601 wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and - OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

[0110] In some embodiments, the compound of Formula (VI-M-1) has the structure of Formula (VI-M- 1a) or Formula (VI-M-1b): 76WSGR Docket No.58819-702.601(VI-M-1a) (VI-M-1b)

[0111] In one aspect, provided herein is a compound of Formula (VI-M-2):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R3is C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; 77WSGR Docket No.58819-702.601 R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; L1is bond, C1-C3alkylene (optionally substituted with -ORb, -N(Rb)2, or -SRb), or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6-C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; and p is 0, 1, 2, 3, or 4.

[0112] In some embodiments, the compound of Formula (VI-M-2) has the structure of Formula (VI-M- 2a) or Formula (VI-M-2b):78WSGR Docket No.58819-702.601 (VI-M-2a) (VI-M-2b)

[0113] In some embodiments, for a compound of Formula (I), (III), (III-M-1), or (III-M-2), Ring H isinstances of R1. In some embodiments, for a compound of Formula (I), (III), (III-M-1), or (III-M-2), Ringoptionally substituted with p instances of R1. In some embodiments, for a compound of Formula (I) oreach of which is optionally substituted with p instances of R1. In some embodiments, Ring H is 79WSGR Docket No.58819-702.601i, , , , eo e s, g s op oa y sus ue w p saces o . so e, each of which is optionally substituted with p instances of R1. In some embodiments, Ringsubstituted with p instances of R1. In some embodiments, Ring H is80WSGR Docket No.58819-702.601 substituted with p instances of R1. In some embodiments, Ring H issubstituted with p instances of R1. In some embodiments, Ring H issubstituted with p instances of R1. In81WSGR Docket No.58819-702.60182WSGR Docket No.58819-702.601

[0114] In some embodiments of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), each R1is independently C1-C3alkyl, C1-C3heteroalkyl, -OH, C1- C3alkoxy, halogen, C1-C3haloalkyl, -S(=O)2Rb, -C(=O)NRcRd, C1-C3alkylene(phenyl), C3-C4cycloalkyl, oxetanyl, or azetidinyl, wherein the phenyl, cycloalkyl, oxetanyl, and azetidinyl are each optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, each R1is C1-C3alkyl, C1-C3heteroalkyl, -OH, C1-C3alkoxy, halogen, C1-C3haloalkyl, or -C(=O)NRcRd. In some embodiments, each R1is C1-C3alkyl, C1- C3heteroalkyl, -OH, C1-C3alkoxy, halogen, or C1-C3haloalkyl. In some embodiments, each R1is C1- C3alkyl, C1-C3heteroalkyl, halogen, C1-C3haloalkyl, -C(=O)NH2, -C(=O)NHC1-3alkyl, or -C(=O)N(C1-3alkyl)2. In some embodiments, each R1is C1-C3alkyl or C1-C3haloalkyl. In some embodiments, R1is C1- C3alkyl. In some embodiments, each R1is methyl. In some embodiments of Formula (I), (II), (III), (III- M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0115] In some embodiments of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), R1is C1-C3alkyl, C1-C3heteroalkyl, -OH, C1-C3alkoxy, halogen, C1- C3haloalkyl, -S(=O)2Rb, C1-C3alkylene(phenyl), C3-C4cycloalkyl, oxetanyl, or azetidinyl, wherein the phenyl, cycloalkyl, oxetanyl, and azetidinyl are each optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R1is C1-C3alkyl, C1-C3heteroalkyl, -OH, C1-C3alkoxy, halogen, or C1-C3haloalkyl. In some embodiments, R1is C1-C3alkyl or C1-C3haloalkyl. In some embodiments, R1is C1-C3alkyl. In some embodiments, R1is methyl. In some embodiments of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. 83WSGR Docket No.58819-702.601

[0116] In some embodiments of Formula (I), Ring A is a partially saturated 6- to 7- membered heterocycloalkyl. In some embodiments, Ring. some embodiments, Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl. In some embodiments, Ring A is a saturated 6- to 7- membered heterocycloalkyl. In some embodiments, Ring A is piperidinyl, piperazinyl, morpholino, azepanyl, or oxazepanyl. In some embodiments, Ring A is piperidinyl, piperazinyl, or, wherein t is 1 or 2, and A4is NRa, O, S, S(O)2, or S(O)(NH). In some embodiments, A4is NH, N(C1-3alkyl), O, S, S(O)2, or S(O)(NH). In some embodiments, t is 1. In some embodiments, A4is84WSGR Docket No.58819-702.601[he structure oftes the bond to L1. In some embodiments,has the structureindicates the bond to L1. In some embodiments, A1is N, A2is A2is CH2, A3is CH, A4is CH2, NH, O, S, S(O)2, or S(O)(NH), A5is CH2, and A6is CH2.. In some embodiments, A1is N, A2is A2is CH2, A3is CH, A4is O, A5is CH2, and A6is CH2. In some embodiments, A1is CH, A2is A2is CH2, A3is N, A4is CH2, A5is CH2, 85WSGR Docket No.58819-702.601some embodiments, Ring, wherein A4is CH2, NH, O, S, S(O)2, or S(O)(NH). In some embodiments, A4is NH, O, S, S(O)2, or S(O)(NH). In some embodiments, A4is O. In some86WSGR Docket No.58819-702.601. , .

[0118] In some embodiments of Formula (III), (IV), or (VI), A4is NRa, O, S, S(O)2, or S(O)(NH). In some embodiments, A4is NH, N(C1-3alkyl), or O. In some embodiments, A4is NH or N(C1-3alkyl). In some embodiments, A4is O. In some embodiments, A4is S, S(O)2, or S(O)(NH). In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments of Formula (III), (IV), or (VI),87WSGR Docket No.58819-702.601

[0119] In some embodiments of Formula (I), (II), (III), (III-M-1), (IV), (IV-M-1), (V), (VI), or (VI-M- 1), each R2is independently -CH3 or -F; or two R2groups attached to the same atom are taken together to form =O or a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments of Formula (I), (II), (III), (III-M-1), (IV), (IV-M-1), (V), (VI), or (VI-M- 1), each R2is independently -CH3; or two R2groups attached to the same atom are taken together to form =O or a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, two R2groups attached to different atoms are taken together to form a C1-C3bridge. In some embodiments, two R2groups attached to different atoms are taken together to form a C1-C2 bridge. In some embodiments, two R2groups attached to different atoms are taken together to form a C1 bridge. In some embodiments, two R2groups attached to different atoms are taken together to form a 3- to 5- membered ring. In some embodiments, two R2groups attached to different atoms are taken together to form a 3- membered ring. In some embodiments, two R2groups attached to adjacent atoms are taken together to form a cyclopropyl. In some embodiments, each R2is independently -CH3or -F; or two R288WSGR Docket No.58819-702.601 groups attached to the same atom are taken together to form =O or a cyclopropyl. In some embodiments, each R2is independently -CH3; or two R2groups attached to the same atom are taken together to form =O or a cyclopropyl. In some embodiments, m is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, m is 2 or 3. In some embodiments, m is 3.

[0120] In some embodiments, for a compound of Formula (I), Ring B is phenyl. In some embodiments, Ring B is a 5- to 6- membered heteroaryl. In some embodiments, Ring B is a 5- membered heteroaryl. In some embodiments, Ring B is a 6- membered heteroaryl. In some embodiments, Ring B is phenyl, pyrazolyl, or pyrimidinyl. In some embodiments, Ring B is pyrazolyl, or pyrimidinyl. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is pyrimidinyl. In some embodiments, for a compound of Formula (I), Ring B has the structure,. In some embodiments, for a compound of Formula (I), (II), (III), (III-M-1), (IV-M-1), (V), or (VI-M-1), n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, for a compound of Formula (I), Ring B has the structure of, ,89WSGR Docket No.58819-702.601. some embodiments for a compound of Formula (I), Ring B has the structure of. , , , , , , (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), each R3is independently C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -S-C1- C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl. In some embodiments, for a compound of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2), each R3is independently C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1- C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl. In some embodiments, each R3is C1-C3alkyl, C1- C3alkoxy, C1-C3haloalkyl, halogen, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, or cyclopropyl. In some 90WSGR Docket No.58819-702.601 embodiments, each R3is C1-C3alkyl, C1-C3haloalkyl or halogen. In some embodiments, each R3is C1- C3haloalkyl or halogen. In some embodiments, each R3is C1-fluoroalkyl or halogen. In some embodiments, each R3is C1-fluoroalkyl or -F. In some embodiments, for a compound of Formula (IV) or (VI), R3ais C1-C3alkyl, C1-C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1- C3haloalkyl, -S-C1-C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl. In some embodiments, for a compound of Formula (III-M-2), (IV), (IV-M-2), (VI), or (VI-M-2), R3ais C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl. In some embodiments, R3ais C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -O-C1- C3haloalkyl, -S-C1-C3haloalkyl, or cyclopropyl. In some embodiments, R3ais C1-C3alkyl, C1-C3haloalkyl or halogen. In some embodiments, R3ais C1-C3haloalkyl or halogen. In some embodiments, R3ais C1- fluoroalkyl or halogen. In some embodiments, R3ais C1-fluoroalkyl or -F.

[0121] In some embodiments, for a compound of Formula (I), (II), or (V), L1is bond, C1-C3alkylene, C1- C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or - SRb), C1-C3haloalkyl, halogen, -CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, for a compound of Formula (I), (II), or (V), L1is a bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, or -O-, wherein each alkylene and heteroalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, for a compound of Formula (I), (II), or (V), L1is a bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, or -O-, wherein each alkylene and heteroalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is bond, C1-C3alkylene, or C1-C3heteroalkylene, wherein each alkylene and heteroalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, - CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkyl substituted with -ORb, C1-C3alkyl substituted with -N(Rb)2, C1-C3alkyl substituted with -SRb, C1-C3haloalkyl, halogen, -CN, -OH, and - C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents 91WSGR Docket No.58819-702.601 independently selected from C1-C3alkyl, C1-C3alkyl substituted with -OH, C1-C3alkyl substituted with - OMe,C1-C3alkyl substituted with -NH2, C1-C3alkyl substituted with -NHMe, C1-C3alkyl substituted with - N(Me)2, C1-C3alkyl substituted with -SH, C1-C3alkyl substituted with -SMe, C1-C3haloalkyl, halogen, - CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-alkylene optionally substituted with 1 or 2 substituents independently selected from -CH3, and -F; or L1is C1-alkylene optionally substituted with two substitutions attached to the same atom taken together to form cyclopropyl or =O. In some embodiments, L1is C1-alkylene. In some embodiments of Formula (I), (II), or (V), L1is C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, halogen, -OH, and =O. In some embodiments, Z is azetidinylene, cyclopropylene, or cyclobutylene, each of which is optionally substituted with 1 or 2 substituents independently selected from -CH3, -F, and =O.

[0122] In some embodiments, for a compound of Formula (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (VI), (VI-M-1), or (VI-M-2), L1is C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1- C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, for a compound of Formula (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (VI), (VI-M-1), or (VI-M-2), L1is C1-C3alkylene, C1-C3heteroalkylene, or C3- C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene, C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, -CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkyl substituted with -ORb, C1-C3alkyl substituted with -N(Rb)2, C1-C3alkyl substituted with -SRb, C1-C3haloalkyl, halogen, -CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkyl substituted with -OH, C1-C3alkyl 92WSGR Docket No.58819-702.601 substituted with -OMe,C1-C3alkyl substituted with -NH2, C1-C3alkyl substituted with -NHMe, C1-C3alkyl substituted with -N(Me)2, C1-C3alkyl substituted with -SH, C1-C3alkyl substituted with -SMe, C1- C3haloalkyl, halogen, -CN, -OH, and -C(=O)NH2; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-C3alkylene, optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. In some embodiments, L1is C1-alkylene optionally substituted with 1 or 2 substituents independently selected from -CH3 and -F; or L1is C1-alkylene optionally substituted with two substitutions attached to the same atom taken together to form cyclopropyl or =O. In some embodiments, L1is C1-alkylene.

[0123] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds.

[0124] In some embodiments, a compound of the present disclosure, for example, a compound of a compound of Formula (I), (II), (III), (III-M-1), (III-M-2), (IV), (IV-M-1), (IV-M-2), (V), (VI), (VI-M-1), or (VI-M-2) is selected Table 1. Table 193WSGR Docket No.58819-702.60194WSGR Docket No.58819-702.60195WSGR Docket No.58819-702.60196WSGR Docket No.58819-702.60197WSGR Docket No.58819-702.60198WSGR Docket No.58819-702.60199WSGR Docket No.58819-702.601100WSGR Docket No.58819-702.601101WSGR Docket No.58819-702.601102WSGR Docket No.58819-702.601103WSGR Docket No.58819-702.601104WSGR Docket No.58819-702.601105WSGR Docket No.58819-702.601106WSGR Docket No.58819-702.601107WSGR Docket No.58819-702.601108WSGR Docket No.58819-702.601109WSGR Docket No.58819-702.601110WSGR Docket No.58819-702.601111WSGR Docket No.58819-702.601112WSGR Docket No.58819-702.601113WSGR Docket No.58819-702.601114WSGR Docket No.58819-702.601115WSGR Docket No.58819-702.601

[0125] Compounds in Table 1 may have stereocenters. Compounds containing hash and / or wedge bonds are not intended to denote absolute stereochemical configuration. Instead, it will be understood that hash and / or wedge bonds present in compounds of Table 1 may be arbitrarily assigned and used to depict relative stereochemistry between two or more isomers.

[0126] In some embodiments, exemplary compounds may include, but are not limited to, a compound or salt thereof selected from Table 2. Table 2Pharmaceutically acceptable salts

[0127] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. As used herein, a “pharmaceutically acceptable salt” refers to any salt of a compound that is useful for therapeutic purposes of a subject.

[0128] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0129] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, 116WSGR Docket No.58819-702.601 hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0130] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0131] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0132] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0133] In some embodiments, the compounds described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0134] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some 117WSGR Docket No.58819-702.601 embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of compounds of the present disclosure and / or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like. Pharmaceutical Compositions

[0135] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) and a pharmaceutically acceptable excipient or carrier.

[0136] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent.

[0137] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0138] In certain embodiments, a composition of a compound or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the composition is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the composition is administered topically. 118WSGR Docket No.58819-702.601

[0139] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising 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. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

[0140] Provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds or salts described are administered as pharmaceutical compositions in which the compound or salt is mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of active ingredients set forth in the combination therapies section below and throughout this disclosure.

[0141] A pharmaceutical composition, as used herein, refers to a mixture of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. A compound or salt of as described herein may be used singly or in combination with one or more additional therapeutic agents.

[0142] In one embodiment, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein a compound or salt a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or 119WSGR Docket No.58819-702.601 (VI)) is formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0143] In another embodiment, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for oral administration. A compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) may be formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compound is formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0144] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0145] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0146] In certain embodiments, a therapeutically effective amount of a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0147] In other embodiments, a therapeutically effective amount of a compound or salt of a compound 120WSGR Docket No.58819-702.601 disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, a compound or salt a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, a suspension of a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In certain embodiments, the active agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0148] In still other embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is administered topically. The compound or salt thereof may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0149] In yet other embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for transdermal administration. Transdermal formulations may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compound or salt thereof is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compound or salt thereof. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to 121WSGR Docket No.58819-702.601 increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound or salt thereof optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0150] In other embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of the compound or salt thereof are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound or salt thereof and a suitable powder base such as lactose or starch.

[0151] In still other embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0152] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising 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. Any pharmaceutically acceptable techniques, carriers, and excipients may be optionally used as suitable. Pharmaceutical compositions comprising a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0153] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)), sometimes referred to herein as an active agent or ingredient. The active ingredient may be in free-acid or free-base form, or in a pharmaceutically acceptable salt form. Additionally, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) may be in unsolvated or solvated forms with pharmaceutically acceptable 122WSGR Docket No.58819-702.601 solvents such as water and ethanol. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0154] Methods for the preparation of compositions comprising a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising the compound or salt thereof. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions of the compound or salt thereof include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0155] In some embodiments, a pharmaceutical composition comprising a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0156] In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0157] Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound described herein. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0158] Pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of 123WSGR Docket No.58819-702.601 the composition in an acceptable range.

[0159] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0160] Pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0161] Pharmaceutical compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0162] Pharmaceutical compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0163] In certain embodiments, aqueous suspension compositions are packaged in single-dose non- reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0164] In certain embodiments, delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials may be used herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0165] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0166] For use in the therapeutic applications described herein, kits and articles of manufacture are also 124WSGR Docket No.58819-702.601 provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0167] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes a compound or salt of a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)), optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0168] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. 125WSGR Docket No.58819-702.601 III. METHOD OF TREATMENT

[0169] The present disclosure provides a method of treating a disease or disorder modulated by GPR52 comprising administering to a subject a compound disclosed herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)). The present disclosure also provides the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a disease or disorder modulated by GPR52. Also described is the use of a compound disclosed herein for use in the treatment of a disease or disorder modulated by GPR52. In some embodiments, the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder.

[0170] In some embodiments, the methods comprise administering to a subject a therapeutically effective amount of a compound described herein, or a thereof, or isotopically enriched form thereof, or solvate thereof. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, or isotopically enriched form thereof, or solvate thereof is administered in a pharmaceutical composition. In some embodiments, the subject has a neurological, neuropsychiatric, or neurodegenerative disease or disorder. In some embodiments, the disease or disorder is selected from schizophrenia, cognitive impairment, a panic disorder, a phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson’s disease, drug-induced Parkinson’s syndrome, extrapyramidal syndrome, Alzheimer’s Disease, Lewy Body Dementia, bipolar disorder, ADHD, Tourette’s syndrome, an extrapyramidal or movement disorder, a motor disorder, a hyperkinetic movement disorder, a psychotic disorder, catatonia, a mood disorder, a depressive disorder, an anxiety disorder, obsessive-compulsive disorder (OCD), an autism spectrum disorder, a prolactin- related disorder (e.g., hyperprolactinemia), a neurocognitive disorder, a trauma- or stressor- related disorder (e.g., PTSD), a disruptive, impulse-control, or conduct disorder, a sleep-wake disorder, a substance-related disorder, an addictive disorder, a behavioral disorder, hypofrontality, an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway, decreased activity in the striatum, cortical dysfunction, neurocognitive dysfunction, the cognitive deficits associated with schizophrenia, Parkinson’s Disease, drug induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy, progressive supranuclear palsy, and Huntington’s disease, including chorea associated with Huntington’s disease.

[0171] In some embodiments, provided herein is a method for treatment a neurological, neuropsychiatric, or neurodegenerative disease or disorder provided, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or isotopically enriched form thereof, or solvate thereof, or a pharmaceutical composition comprising the compound described herein, or the pharmaceutically acceptable salt thereof, or isotopically enriched form thereof, or solvate thereof, to a subject in need thereof. In other embodiments, the neurological, neuropsychiatric, or neurodegenerative disease or disorder is selected from schizophrenia, cognitive impairment, a panic disorder, a phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson’s disease, drug-induced 126WSGR Docket No.58819-702.601 Parkinson’s syndrome, extrapyramidal syndrome, Alzheimer’s Disease, Lewy Body Dementia, bipolar disorder, ADHD, Tourette’s syndrome, an extrapyramidal or movement disorder, a motor disorder, a hyperkinetic movement disorder, a psychotic disorder, catatonia, a mood disorder, a depressive disorder, an anxiety disorder, obsessive-compulsive disorder (OCD), an autism spectrum disorder, a prolactin- related disorder (e.g., hyperprolactinemia), a neurocognitive disorder, and a trauma- or stressor- related disorder (e.g., PTSD). In other embodiments, the neurological, neuropsychiatric, or neurodegenerative disease or disorder selected is from a disruptive, impulse-control, or conduct disorder, a sleep-wake disorder, a substance-related disorder, an addictive disorder, a behavioral disorder, hypofrontality, an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway, decreased activity in the striatum, cortical dysfunction, neurocognitive dysfunction, and the cognitive deficits associated with schizophrenia. In other embodiments, the neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from Parkinson’s Disease, drug induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy, progressive supranuclear palsy, and Huntington’s disease, including chorea associated with Huntington’s disease. In some embodiments, the neurological, neuropsychiatric, or neurodegenerative disease or disorder is selected from Huntington’s disease, Fragile X Syndrome, Rett Syndrome, autism spectrum disorder, major depressive disorder, substance use disorder, bipolar disorder, Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia, attention deficit hyperactivity disorder, post-traumatic stress disorder, restless leg syndrome, and compulsive gambling disorder. In some embodiments, the disease or disorder is a psychosis or a psychotic disease or disorder, a mood disorder, or a sleep-wake disorder. In some embodiments, the disease or disorder is a psychosis or a psychotic disease or disorder. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is a sleep-wake disorder. In some embodiments, the disease or disorder is insomnia or narcolepsy.

[0172] The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways (e.g., pathways other than the GPR52 pathway), or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or salt of a compound described herein. In one aspect, such therapy includes the combination of one or more compounds of the disclosure and a second therapeutic agent to provide a synergistic or additive therapeutic effect. In some embodiments, the second therapeutic agent is an antidepressant, an antipsychotic, a tranquilizer, or a mood stabilizer. In some embodiments, the second therapeutic agent is an antidepressant. In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor, a serotonin-noradrenaline reuptake inhibitor, a noradrenaline and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonists and reuptake inhibitor, or a monoamine oxidase inhibitor. In some embodiments, the second therapeutic agent is an antipsychotic. In some embodiments, the antipsychotic is a typical antipsychotic or an atypical antipsychotic. In some embodiments, the second therapeutic agent is a tranquilizer. In some embodiments, the tranquilizer is a benzodiazepine, a barbiturate, or a non-benzodiazepine. In some embodiments, the second therapeutic agent is a mood 127WSGR Docket No.58819-702.601 stabilizer. In some embodiments, the mood stabilizer is lithium or an anticonvulsant.

[0173] The compounds described herein can be used in combination with other agents depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any additional therapeutic agent can be formulated together in the same dosage form and / or administered simultaneously. Alternatively, a compound of the disclosure and an additional agent can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by an additional agent, or vice versa. When administered separately, a compound of the disclosure and an additional agent are administered a few minutes apart, or a few hours apart, or a few days apart.

[0174] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims.

[0175] The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way. EXAMPLES

[0176] Example 1: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-2H-pyridin-5- yl]-1-methyl-benzimidazole (Compound 1-3)

[0177] Step 1：tert-butyl 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate A mixture of 6-bromo-1-methyl-1H-benzo[d]imidazole (1 g, 4.74 mmol, 1 eq), tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.20 g, 7.11 mmol, 1.5 eq), Pd(dppf)Cl2.CH2Cl2 (386.92 mg, 473.80 μmol, 0.1 eq), K2CO3 (1.96 g, 14.21 mmol, 3 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N23 times, and then the mixture was stirred at 90 °C for 1 hour under a N2 atmosphere. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (30 mL). The organic phase was separated, washed with brine (20 mL × 3) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (acetonitrile in water from 0 to 23%, 0.225% FA) and lyophilized to give tert-butyl 5-(1- 128WSGR Docket No.58819-702.601 methyl-1H-benzo[d]imidazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.00 mmol, 63.31% yield, 94% purity) as a brown oil. 1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1H), 7.79 (s, 1H), 7.40 (s, 2H), 6.26 (s, 1H), 4.36 (s, 2H), 3.92 (s, 3H), 3.59 (t, J = 5.2 Hz, 2H), 2.37 (s, 2H), 1.52 (s, 9H). LCMS [ESI, M+1]: 314.2.

[0178] Step 2：1-methyl-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazole To a solution of tert-butyl 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-3,6-dihydropyridine-1(2H)- carboxylate (900 mg, 2.87 mmol, 1 eq) in DCM (18 mL) was added TFA (13.82 g, 121.16 mmol, 9.00 mL, 42.19 eq). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was basified by adding 5 mL of TEA until the pH reached about 7. The reaction mixture was concentrated under the reduced pressure to give the product, which was used in the next step without further purification.1-methyl-6- (1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazole (1 g, crude, TFA adduct) as a dark oil.

[0179] Step 3：6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl- 1H-benzo[d]imidazole To a mixture of 1-methyl-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazole (340.74 mg, 1.04 mmol, 1 eq, TFA adduct) in THF (2 mL) was added dropwise HOAc (1.05 g, 17.47 mmol, 1 mL, 16.78 eq) and 3-fluoro-5-(trifluoromethyl)benzaldehyde (200 mg, 1.04 mmol, 1 eq) at 25 °C over 10 minutes. After addition, NaBH(OAc)3(110.32 mg, 520.53 μmol, 0.5 eq) was added. The resulting mixture was stirred at 25 °C for 20 minutes. The reaction mixture was concentrated under the reduced pressure to give a residue. The crude residue was purified by reversed-phase HPLC (1% - 25% ACN in water (0.225% FA), 10 minutes) and lyophilized to give 6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)-1,2,5,6- tetrahydropyridin-3-yl)-1-methyl-1H-benzo[d]imidazole (33.09 mg, 81.58 μmol, 7.84% yield, 96% purity).1H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.63 - 7.51 (m, 5H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 6.22 (s, 1H), 3.82 (s, 3H), 3.80 (s, 2H), 3.44 (s, 2H), 2.59 - 2.55 (m, 2H), 2.30 (d, J = 2.0 Hz, 2H). LCMS [ESI, M+1]: 390.2.

[0180] Example 2: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-1-methyl- benzimidazole (Compound 1-4)

[0181] To a mixture of 6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1- methyl-1H-benzo[d]imidazole (20 mg, 51.36 μmol, 1 eq) in MeOH (5 mL) and was added 10% Pd / C (10.00 mg, 9.40 μmol,) at N2. The mixture was degassed and purged with H23 times, and then the mixture was stirred at 25 °C for 12 h under H2atmosphere (30 psi). The reaction mixture was filtered through celite and concentrated under the reduced pressure to give the a residue. The crude product was 129WSGR Docket No.58819-702.601 purified by reversed-phase HPLC (50% - 80% ACN in water (10 mM NH4HCO3), 10 minutes) and lyophilized to give 6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-3-yl)-1-methyl-1H- benzo[d]imidazole (2.83 mg, 7.16 μmol, 13.94% yield, 99% purity). 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (s, 1H), 7.58 - 7.46 (m, 4H), 7.42 (s, 1H), 7.09 (dd, J = 8.4, 1.6 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 2H), 2.92 (s, 1H), 2.89 - 2.79 (m, 2H), 2.17 (t, J = 11.2 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.88 (d, J = 11.6 Hz, 1H), 1.79 - 1.71 (m, 1H), 1.69 - 1.60 (m, 1H), 1.59 - 1.48 (m, 1H). LCMS [ESI, M+1]: 392.2.

[0182] Example 3: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-1-methyl- benzimidazole, enantiomer A (Compound 1-7)

[0183] Racemic 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-1-methyl-benzimidazole was separated by SFC (column: Daicel Chiralcel OJ (250mm*30mm,10um); mobile phase: [CO2-i- PrOH(0.1%NH3H2O)];B%:15%, isocratic elution mode) and concentrated under reduced pressure to give 6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-3-yl)-1-methyl -1H-benzo[d] imidazole enantiomer A (21.93 mg, 55.47 μmol, 10.80% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 1.2 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 3.10 - 2.98 (m, 2H), 2.94 (d, J = 11.2 Hz, 1H), 2.20 (t, J = 11.2 Hz, 1H), 2.12 (m, J = 10.8, 4.4 Hz, 1H), 2.05 - 1.99 (m, 1H), 1.82 (d, J = 4.0 Hz, 2H), 1.63 - 1.51 (m, 1H). LCMS [ESI, M+1]: 392.2. Analytical SFC RT = 1.035 minutes.

[0184] Example 4: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-1-methyl- benzimidazole, enantiomer B (Compound 1-8)

[0185] Racemic 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-1-methyl-benzimidazole was separated by SFC (condition: column: Daicel Chiralcel OJ (250mm*30mm,10um); mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:15%, isocratic elution mode) and concentrated under the reduced 130WSGR Docket No.58819-702.601 pressure to give 6-(1-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-3-yl)-1-methyl-1H- benzo[d]imidazole enantiomer B (13.8 mg, 34.91 μmol, 6.80% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 1.2 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 3.10 - 2.98 (m, 2H), 2.94 (d, J = 10.8 Hz, 1H), 2.20 (t, J = 11.2 Hz, 1H), 2.16 - 2.08 (m, 1H), 2.05 - 1.99 (m, 1H), 1.86 - 1.76 (m, 2H), 1.64 - 1.52 (m, 1H). LCMS [ESI, M+1]: 392.2. Analytical SFC RT = 1.114 minutes.

[0186] The synthetic steps used to prepare examples 1 – 4 comprise general method A. The following compounds were prepared according to general method A:131WSGR Docket No.58819-702.601132WSGR Docket No.58819-702.601133WSGR Docket No.58819-702.601

[0187] Example 13: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2,5-dihydropyrrol-3-yl]-1- methyl-benzimidazole (Compound 2-1)134WSGR Docket No.58819-702.601

[0188] Compound 2-1 was prepared according to method A.1H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.26 (s, 2H), 6.21 (s, 1H), 4.02 (s, 4H), 3.84 (s, 3H), 3.82 (s, 2H). LCMS [ESI, M+1]: 376.2. MS: ES+m / z 376.2 [M+H]+

[0189] Example 14: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-1-methyl- benzimidazole (Compound 2-2)

[0190] Compound 2-2 was prepared according to general method A.1H NMR (400 MHz, CDCl3) δ = 7.85 (s, 1H), 7.73 (s, 1H), 7.47 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 6.0 Hz, 2H), 3.90 - 3.81 (m, 3H), 3.78 (s, 1H), 3.74 - 3.68 (m, 1H), 3.59 - 3.50 (m, 1H), 3.01 (t, J = 8.8 Hz, 1H), 2.90 - 2.73 (m, 2H), 2.68 (dd, J = 9.2, 7.2 Hz, 1H), 2.50 - 2.37 (m, 1H), 2.00 (dd, J = 12.8, 8.4 Hz, 1H). LCMS [ESI, M+1]: 378.2.

[0191] Example 15: 6-[1-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-1-methyl- benzimidazole, enantiomer A (Compound 1-30)

[0192] Step 1: tert-butyl 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine-4-carboxylate To a mixture of 6-bromo-1-methyl-1H-benzo[d]imidazole(0.1 g, 473 μmol, 1 eq) in DMSO (2 mL) was added 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (164 mg, 710 μmol, 1.5 eq), [Ir(dF(Me)ppy)2(dtbbpy)]PF6(2.37 mg, 4.74 μmol, 0.01 eq) , dtbbpy (6.36 mg, 23.7 μmol, 0.05 eq), phthalimide (69.7 mg, 473 μmol, 1 eq), NiBr2∙3H2O (6.46 mg, 23.7 μmol, 0.05 eq) and TMG (81.86 mg, 710.70 μmol, 89.36 μL, 1.5 eq). The mixture was stirred at 25 °C under blue LED irradiation for 72 hours. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with water (20 mL), brine (20 mL) and then dried over with anhydrous Na2SO4. The solvent was removed under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, methanol / dichloromethane 1:10 as eluent) to give tert- butyl 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine-4-carboxylate (150 mg, 0.472 mmol, 99% yield) as a white solid.

[0193] Step 2: 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine 135WSGR Docket No.58819-702.601 To a mixture of tert-butyl 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine-4-carboxylate(100 mg, 315 μmol, 1 eq) in DCM (6 mL) was added TFA (179 mg, 1.58 mmol, 5 eq). The mixture was then stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2-(1-methyl- 1H-benzo[d]imidazol-6-yl)morpholine (68 mg, 0.312 mmol, 99% yield) as a yellow oil, which was used in the next step without further purification.

[0194] Step 3: 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine To a solution of 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine (68 mg, 312 μmol, 1 eq) in DCM (20 mL) was added 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (120 mg, 469 μmol, 1.5 eq) and DIPEA (404 mg, 3.13 mmol, 10 eq). And then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (water / ACN gradient (formic acid, 0.1%)) to give 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1- methyl-1H-benzo[d]imidazol-6-yl)morpholine (90 mg, 0.229 mmol, 73% yield).

[0195] Step 4: 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine, enantiomer A Racemic 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine(80 mg, 203 μmol, 1 eq) was purified by SFC (column: Daicel Chiralpak AS (250mm*30mm,10um);mobile phase: [CO2 / i-PrOH(0.1%NH3H2O), 25%]; isocratic elution mode) to give 4-(3-fluoro-5- (trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine, enantiomer A (15.52 mg, 18% yield, 98% purity).1H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.78 - 7.70 (m, 1H), 7.50 - 7.40 (m, 2H), 7.37 - 7.29 (m, 1H), 7.27 - 7.20 (m, 2H), 4.79 - 4.69 (m, 1H), 4.14 - 4.05 (m, 1H), 3.95 - 3.87 (m, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.98 - 2.90 (m, 1H), 2.80 - 2.73 (m, 1H), 2.42 - 2.33 (m, 1H), 2.27 - 2.18 (m, 1H); LCMS [ESI, M+1]: 394.4. Analytical SFC RT: 1.204 minutes.

[0196] Example 16: 4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-(3-methylbenzimidazol-5- yl)morpholine, enantiomer B (Compound 1-31)

[0197] Racemic 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine(80 mg, 203 μmol, 1 eq) was purified by SFC (column: Daicel Chiralpak AS(250mm*30mm,10um);mobile phase: [CO2 / i-PrOH(0.1%NH3H2O), 25%], isocratic elution mode ) to give 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine, enantiomer B (15.05 mg, 18% yield, 98% purity,). 136WSGR Docket No.58819-702.6011H NMR (400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.78 - 7.70 (m, 1H), 7.50 - 7.40 (m, 2H), 7.37 - 7.29 (m, 1H), 7.27 - 7.20 (m, 2H), 4.79 - 4.69 (m, 1H), 4.14 - 4.05 (m, 1H), 3.95 - 3.87 (m, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.98 - 2.90 (m, 1H), 2.80 - 2.73 (m, 1H), 2.42 - 2.33 (m, 1H), 2.27 - 2.18 (m, 1H); LCMS [ESI, M+1]: 394.4. Analytical SFC RT = 1.384 minutes.

[0198] Example 17: 6-[3-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-piperidyl]-1-methyl- benzimidazole (Compound 1-6)

[0199] Step 1：tert-butyl 5-(3-fluoro-5-(trifluoromethyl) benzyl)-3,6-dihydropyridine -1(2H) - carboxylate A mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (3 g, 9.70 mmol, 1 eq), 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (2.49 g, 9.70 mmol, 1 eq), Pd(dppf)Cl2·CH2Cl2(792.32 mg, 970.22 μmol, 0.1 eq), K2CO3(4.02 g, 29.11 mmol, 3 eq) in dioxane (30 mL) and H2O (3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 90 °C for 2 hours under N2atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a residue. The crude product was purified by silica gel column chromatography(ethyl acetate in petroleum ether from 0 to 15%) and lyophilized to give tert- butyl 5-(3-fluoro-5-(trifluoromethyl)benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (3 g, 6.68 mmol, 68.84% yield, 80% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.24 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 5.60 (s, 1H), 3.76 - 3.68 (m, 2H), 3.45 (t, J = 5.6 Hz, 2H), 3.35 (s, 2H), 2.16 (s, 2H), 1.44 (s, 9H).

[0200] Step 2：tert-butyl 3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate A mixture of tert-butyl 5-(3-fluoro-5-(trifluoromethyl)benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 1.11 mmol, 1 eq) in MeOH (20 mL) and was added 10% Pd / C (200 mg, 187.93 μmol) under a gentle stream of nitrogen. The mixture was degassed and purged with H23 times, and then the mixture was stirred at 25 °C for 12hoursunder a H2 atmosphere (30 psi). The reaction mixture was filtered, and the filtrate was concentrated under the reduced pressure to give the product. The crude product was purified by silica gel column chromatography (ethyl acetate in petroleum ether from 0 to 23%) to give tert-butyl 3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (120 mg, 315.46 μmol, 28.34% yield, 95% purity) as a colorless oil.1H NMR (400 MHz, CDCl3): δ = 7.21 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H), 3.96 - 3.84 (m, 2H), 2.88 - 2.77 (m, 1H), 2.67 - 2.50 (m, 3H), 1.79 - 1.71 (m, 2H), 1.68 - 1.62 (m, 1H), 1.43 (s, 10H), 1.22 - 1.11 (m, 1H). LCMS: ES+m / z 393.2 [M+H]+137WSGR Docket No.58819-702.601

[0201] Step 3：3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine To a mixture of tert-butyl 3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (110 mg, 304.39 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 44.23 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between DCM (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine (10 mL × 3) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine (60 mg, 229.66 μmol, 75.45% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6): δ = 7.46 (d, J = 8.8 Hz, 1H), 7.42 - 7.33 (m, 2H), 2.87 - 2.64 (m, 2H), 2.63 - 2.51 (m, 2H), 2.37 (m, J = 2.7, 11.5 Hz, 1H), 2.15 (dd, J = 12.0, 10.0 Hz, 1H), 1.71 - 1.55 (m, 2H), 1.55 - 1.44 (m, 1H), 1.39 - 1.08 (m, 2H), 1.07 - 1.00 (m, 1H).

[0202] Step 4：6-(3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-1-yl)-1-methyl-1H- benzo[d]imidazole A mixture of 3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine (50 mg, 191.38 μmol, 1 eq), 6-bromo-1- methyl-1H-benzo[d]imidazole (60.59 mg, 287.07 μmol, 1.5 eq), Cs2CO3(187.07 mg, 574.15 μmol, 3 eq), Pd-PePPSI (9.31 mg, 9.57 μmol, 0.05 eq) in dioxane (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 1 hour under a N2atmosphere. The reaction mixture was concentrated under the reduced pressure to give the a residue. The crude product was purified by reversed-phase HPLC (24% - 54% ACN in water (0.225% FA), 10 minutes) and lyophilized to give 6-(3- (3-fluoro-5(trifluoromethyl)benzyl)piperidin-1-yl)-1-methyl-1H-benzo[d]imidazole (3.77 mg, 9.44 μmol, 4.93% yield, 98% purity).1H NMR (400 MHz, CDCl3) δ = 7.88 (s, 1H), 7.62 (s, 1H), 7.29 - 7.27 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 3.81 (s, 3H), 3.60 - 3.45 (m, 2H), 2.85 - 2.76 (m, 1H), 2.76 - 2.63 (m, 2H), 2.56 (t, J = 10.8 Hz, 1H), 2.11 (m, J = 10.0, 7.2 Hz, 2H), 1.81 - 1.74 (m, 1H), 1.39 - 1.09 (m, 2H). LCMS [ESI, M+1]: 392.2.

[0203] Example 18: 6-[3-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-piperidyl]-1-methyl- benzimidazole, enantiomer A (Compound 1-9)

[0204] Racemic 6-(3-(3-fluoro-5-(trifluoromethyl) benzyl) piperidin-1-yl)-1-methyl-1H - benzo[d]imidazole (180 mg) was separated by SFC (column: Daicel Chiralpak AS (250mm*30mm,10um); mobile phase: [A:CO2, B: EtOH (0.1%NH3H2O), 30%], isocratic elution mode) and concentrated under reduced pressure to give 6-(3-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-1- yl)-1-methyl-1H-benzo[d]imidazole, enantiomer A (56.07 mg, 141.82 μmol, 30.84% yield, 99% purity). 138WSGR Docket No.58819-702.6011H NMR (400 MHz, CDCl3) δ = 7.80 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.28 - 7.27 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 6.99 (dd, J = 9.2, 2.0 Hz, 1H), 6.83 (s, 1H), 3.78 (s, 3H), 3.57 (d, J = 12.0 Hz, 1H), 3.53 - 3.46 (m, 1H), 2.81 (dt, J = 11.6, 2.8 Hz, 1H), 2.77 - 2.71 (m, 1H), 2.70 - 2.64 (m, 1H), 2.61 - 2.53 (m, 1H), 2.16 - 2.09 (m, 1H), 1.88 - 1.79 (m, 3H), 1.24 - 1.14 (m, 1H). LCMS [ESI, M+1]: 392.1. Analytical SFC RT: 0.926 minutes.

[0205] Example 19: 6-[3-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-piperidyl]-1-methyl- benzimidazole, enantiomer B (Compound 1-10)

[0206] Racemic 6-(3-(3-fluoro-5-(trifluoromethyl) benzyl) piperidin-1-yl)-1-methyl-1H - benzo[d]imidazole (180 mg) was separated by SFC (column: Daicel Chiralpak AS (250mm*30mm,10um); mobile phase: [CO2 / EtOH (0.1%NH3H2O), 30%]; isocratic elution mode) and concentrated under the reduced pressure to give 6-(3-(3-fluoro-5-(trifluo-romethyl)benzyl)piperidin-1- yl)-1-methyl-1H-benzo[d]imidazole, enantiomer B (52.83 mg, 133.63 μmol, 29.06% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.80 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.28 - 7.27 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 6.99 (dd, J = 9.2, 2.0 Hz, 1H), 6.83 (s, 1H), 3.78 (s, 3H), 3.57 (d, J = 12.0 Hz, 1H), 3.53 - 3.46 (m, 1H), 2.81 (dt, J = 11.6, 2.8 Hz, 1H), 2.77 - 2.71 (m, 1H), 2.70 - 2.64 (m, 1H), 2.61 - 2.53 (m, 1H), 2.16 - 2.09 (m, 1H), 1.88 - 1.79 (m, 3H), 1.24 - 1.14 (m, 1H). LCMS [ESI, M+1]: 392.1. Analytical SFC RT: 1.465 minutes.

[0207] Example 20: 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine, enantiomer A (Compound 1-23)

[0208] Step 1：tert-butyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)morpholine-4-carboxylate To a mixture of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (1.00 g, 4.11 mmol, 1 eq), tert-butyl 2- (bromomethyl)morpholine-4-carboxylate (1.72 g, 6.17 mmol, 1.5 eq), dibromonickel;1,2- dimethoxyethane (127.00 mg, 411.5 μmol, 0.1 eq) , 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (110.50 mg, 411.5 μmol, 0.1 eq) and Zn (2.15 g, 32.9 mmol, 8 eq) in THF (80 mL) and 1,3- 139WSGR Docket No.58819-702.601 dimethylhexahydropyrimidin-2-one (6.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under the reduced pressure to give the product. The crude product was purified by silica gel column chromatography (EtOAc in PE from 10 to 30%) and concentrated under the reduced pressure to give tert- butyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)morpholine-4-carboxylate (400 mg, crude) as yellow solid.

[0209] Step 2：2-(3-fluoro-5-(trifluoromethyl)benzyl)morpholine To a mixture of tert-butyl 2-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]morpholine-4-carboxylate (400 mg, 1.10 mmol, 1 eq), TFA (1.26 g, 11.01 mmol, 817.76 μL, 10 eq) in DCM (3 mL) and then the mixture was stirred at 25 °C for 0.1 h. The reaction mixture was concentrated under the reduced pressure to give 2-(3-fluoro-5-(trifluoromethyl)benzyl)morpholine (260 mg, crude).

[0210] Step 3：4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-(3-methylbenzimidazol-5- yl)morpholine, enantiomer A A mixture of 2-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]morpholine (200 mg, 759.79 μmol, 1 eq) , 6- bromo-1-methyl-benzimidazole (160.36 mg, 759.79 μmol, 1 eq), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (73.91 mg, 75.98 μmol, 0.1 eq), Cs2CO3(990.22 mg, 3.04 mmol, 4 eq) in dioxane (30 mL) was degassed and purged with N23 times, and then the mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. The crude product was purified by reversed-phase HPLC (eluent: 47% - 77% ACN in water (10 mM NH4HCO3), 12 min) and lyophilized to give a residue, which was further separated by SFC (column: Daicel Chiralcel OJ(250mm*30mm,10um); mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%: 30%, isocratic elution mode) and concentrated under reduced pressure to give 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1- methyl-1H-benzo[d]imidazol-6-yl)morpholine, enantiomer A (28.9 mg, 71.26 μmol, 28.32% yield, 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.54 (d, J = 5.2 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.97 - 6.89 (m, 1H), 4.01 - 3.83 (m, 2H), 3.77 (s, 3H), 3.70 - 3.57 (m, 2H), 3.49 (d, J = 11.6 Hz, 1H), 3.10 - 2.97 (m, 1H), 2.96 - 2.86 (m, 1H), 2.82 - 2.66 (m, 1H), 2.60 - 2.53 (m, 1H). LCMS [ESI, M+1]: 394.1. Analytical SFC RT: 1.318 minutes.

[0211] Example 21: 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine, enantiomer B (Compound 1-24)

[0212] Racemic 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine was separated by SFC (column: Daicel Chiralcel OJ(250mm*30mm,10um); mobile phase: 140WSGR Docket No.58819-702.601 [CO2-i-PrOH(0.1%NH3H2O)]; B%:30%, isocratic elution mode) and concentrated under the reduced pressure to give 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine, enantiomer B (28.7 mg, 71.50 μmol, 28.41% yield, 98% purity).1H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.54 (br d, J = 5.2 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.98 - 6.90 (m, 1H), 4.02 - 3.84 (m, 2H), 3.77 (s, 3H), 3.71 - 3.57 (m, 2H), 3.49 (d, J = 11.6 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.96 - 2.85 (m, 1H), 2.81 - 2.67 (m, 1H), 2.58 - 2.53 (m, 1H). LCMS [ESI, M+1]: 394.1. Analytical SFC RT: 1.510 minutes

[0213] Example 22: 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one, enantiomer A (Compound 1-60)

[0214] Step 1：tert-butyl 2-(1-oxoisoindolin-5-yl)morpholine-4-carboxylate A mixture of 5-bromoisoindolin-1-one (5 g, 1 eq), 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (8.2 g, 1.5 eq), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (6.1 g, 1.5 eq), bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (0.53 g, 0.02 eq), 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;dichloronickel (0.47 g, 0.05 eq) and isoindoline-1,3-dione, (3.469 g, 1 eq) was dissolved in DMSO (100 mL) and pumped at a rate of 0.554 mL / min through a flow reactor (FEP Coils, 3.175 mm ID, 50 mL total volume). The reactor coil was maintained at 50 °C, and exposed to a 450 nm, 400W LED light source. The residence time was 90 min. The crude product mixture was collected, diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL×3), and washed with brine (50 mL×5). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel column chromatography (MeOH in DCM from 0 to 15%) and concentrated under reduced pressure to give tert-butyl 2-(1- oxoisoindolin-5-yl) morpholine-4-carboxylate (3.3 g, 10.37 mmol, 66% yield) as an off-white solid. LCMS [ESI, M+1]: 319.2.

[0215] Step 2：5-(morpholin-2-yl)isoindolin-1-one To a solution of tert-butyl 2-(1-oxoisoindolin-5-yl)morpholine-4-carboxylate (500 mg, 1.57 mmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 8.57 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The product 5- morpholin-2-ylisoindolin-1-one (500 mg, crude) was obtained as a yellow oil and was used into the next step without further purification. 141WSGR Docket No.58819-702.601

[0216] Step 3：5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one To a solution of 5-(morpholin-2-yl)isoindolin-1-one (500 mg, 2.29 mmol, 1 eq) in DCM (5 mL) was added DIEA (888.26 mg, 6.87 mmol, 1.20 mL, 3 eq) and 1-(bromomethyl)-3-fluoro-5- (trifluoromethyl)benzene (529.94 mg, 2.06 mmol, 0.9 eq) .The mixture was stirred at 25 °C for 2 hours . The reaction was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (acetonitrile in water from 48 to 62%) and lyophilized to give 5-(4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (680 mg, 1.72 mmol, 74.93% yield, 99.55% purity) as a white solid. LCMS [ESI, M+1]: 395.1.

[0217] Step 4: 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one, enantiomer A Racemic 5-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]morpholin-2-yl]isoindolin-1-one (600 mg, 1.52 mmol, 1 eq) was resolved by chiral SFC (column: Phenomenex cellulose-2 (250mm*30mm,10um); mobile phase: [CO2-MeOH (0.1%NH3H2O)]; 40% B, isocratic elution mode) to give 5-[-4-[[3-fluoro-5- (trifluoromethyl)phenyl]methyl]morpholin-2-yl]isoindolin-1-one (352.0 mg, 890.22 μmol, 58.51% yield, 99.736% purity).1H NMR (400 MHz,CDCl3) δ = 7.83 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.48 - 7.39 (m, 2H), 7.32 (d, J = 9.2 Hz, 1H), 7.24 ( d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 4.70 (dd, J = 10.0, 2.0 Hz, 1H), 4.45 (s, 2H), 4.07 (dd, J = 11.6, 2.0 Hz, 1H), 3.88 (dt, J = 11.6, 2.4 Hz, 1H), 3.59 (s, 2H), 2.91 (d, J = 11.6 Hz, 1H), 2.75 (d, J = 11.2 Hz, 1H), 2.35 (dt, J = 11.6, 3.2 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: 394.9.

[0218] Example 23: 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one, enantiomer B (Compound 1-61)

[0219] Racemic 5-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]morpholin-2-yl]isoindolin-1-one (600 mg, 1.52 mmol, 1 eq) was resolved by chiral SFC (column: Phenomenex cellulose-2 (250mm*30mm,10um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; 40% B, isocratic elution mode) to give 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one, enantiomer B.1H NMR (400 MHz, CDCl3 ) δ = 7.83 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.48 - 7.40 (m, 2H), 7.32 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.70 (dd, J = 10.0, 2.0 Hz, 1H), 4.45 (s, 2H), 4.06 (dd, J = 11.6, 2.0 Hz, 1H), 3.88 (dt, J = 11.6, 2.4 Hz, 1H), 3.59 (s, 2H), 2.91 (d, J = 11.6 Hz, 1H), 2.75 (d, J = 11.2 Hz, 1H), 2.35 (dt, J = 11.6, 3.2 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: 394.9. 142WSGR Docket No.58819-702.601 Analytical SFC retention time: 2.190 min

[0220] Example 24: 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4-dihydroisoquinolin- 1(2H)-one, enantiomer A (Compound 1-99)

[0221] Step 1：6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4-dihydroisoquinolin- 1(2H)-one A mixture of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (0.2 g, 1 eq), 4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholine-2-carboxylic acid (0.408 g, 1.5 eq), BTMG (0.227 g, 1.5 eq), [Ir(dF(Me)ppy)2(dtbbpy)]PF6(0.02 g, 0.02 eq), NiCl2•dtbbpy (0.018 g, 0.05 eq) and phthalimide (0.13 g, 1 eq) was dissolved in DMSO (6 mL). This solution was pumped at a rate of 0.554 mL / min through a flow reactor (FEP Coils, 3.175 mm diameter, 50 mL total volume). The reactor coil was maintained at 50 °C, and exposed to a 450 nm, 400W LED light source. The residence time was 90 min. The reaction mixture was collected after running 120 mins. The reaction mixture was partitioned between EtOAc (20 mL× 3) and H2O (20 mL). The organic phase was collected, washed with brine (20 mL × 6), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (15% - 45% ACN in water (0.225% formic acid), 10 min gradient). The collected fractions were combined. Most of the organic volatiles were removed under reduced pressure. The resulting suspension was then lyophilized to give 6-(4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholin-2-yl) -3,4-dihydroisoquinolin-1(2H)-one (40 mg, 97.95 μmol, 10.00% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.03 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.26 - 7.21 (m, 2H), 6.46 - 6.02 (m, 1H), 4.62 (d, J = 8.8 Hz, 1H), 4.05 (dd, J = 11.6, 1.6 Hz, 1H), 3.86 (dt, J = 11.6, 2.0 Hz, 1H), 3.60 - 3.53 (m, 4H), 3.00 (t, J = 6.8 Hz, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 11.6 Hz, 1H), 2.34 (dt, J = 11.6, 3.2 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H).

[0222] Step 2: 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4-dihydroisoquinolin- 1(2H)-one, enantiomer A Racemic 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4-dihydroisoquinolin- 1(2H)-one (80 mg, 195.89 μmol, 1 eq). was separated by chiral SFC (column: Daicel Chiralpak AD (250mm*30mm,10um); mobile phase: [CO2-MeOH(0.1%NH3H2O)]; 25% B, isocratic elution mode) and concentrated under reduced pressure to give 6-(4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholin-2-yl)- 3,4-dihydroisoquinolin-1(2H)-one, enantiomer A (20.2 mg, 48.47 μmol, 24.74% yield, 98% purity).1H NMR (400 MHz, CDCl3) δ = 8.04 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.26 - 7.21 143WSGR Docket No.58819-702.601 (m, 2H), 5.98 (s, 1H), 4.62 (dd, J = 10.4, 2.4 Hz, 1H), 4.05 (dd, J = 11.6, 2.0 Hz, 1H), 3.86 (dt, J = 11.6, 2.4 Hz, 1H), 3.59 - 3.53 (m, 4H), 3.00 (t, J = 6.8 Hz, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 11.6 Hz, 1H), 2.34 (dt, J = 11.6, 3.6 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: = 409.1 Analytical SFC retention time: 1.197 min

[0223] Example 25: 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4- dihydroisoquinolin-1(2H)-one, enantiomer B (Compound 1-100)

[0224] Racemic 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)-3,4-dihydroisoquinolin- 1(2H)-one (80 mg, 195.89 μmol, 1 eq). was separated by chiral SFC (column: Daicel Chiralpak AD (250mm*30mm,10um); mobile phase: [CO2-MeOH(0.1%NH3H2O)]; 25% B, isocratic elution mode) and concentrated under reduced pressure to give 6-(4-(3-fluoro-5-(trifluoromethyl)benzyl) morpholin-2-yl)- 3,4-dihydroisoquinolin-1(2H)-one, enantiomer B (21.7 mg, 52.07 μmol, 26.58% yield, 98% purity).1H NMR (400 MHz, CDCl3) δ = 8.03 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.26 - 7.21 (m, 2H), 6.09 (s, 1H), 4.62 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 11.6 Hz, 1H), 3.86 (t, J = 11.6 Hz, 1H), 3.59 - 3.53 (m, 4H), 3.00 (t, J = 6.4 Hz, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 11.6 Hz, 1H), 2.34 (t, J = 11.6 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: = 409.1 Analytical SFC retention time: 1.297 min

[0225] Example 26: 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide

[0226] Step 1：4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide A mixture of 4-bromobenzamide (0.09 g, 1 eq), 4-(3-fluoro-5-(trifluoromethyl)benzyl) morpholine-2- carboxylic acid (0.207 g, 1.5 eq), BTMG (0.116 g, 1.5 eq), [Ir(dF(Me)ppy)2(dtbbpy)]PF6(0.01 g, 0.02 eq), NiCl2•dtbbpy (0.009 g, 0.05 eq), and phthalimide (0.066 g, 1 eq) was dissolved in DMSO (2.7 mL). This solution was pumped at a rate of 0.554 mL / min through a flow reactor (FEP Coils, 3.175 mm diameter, 50 mL total volume). The reactor coil was maintained at 50 °C, and exposed to a 450 nm, 144WSGR Docket No.58819-702.601 400W LED light source. The reaction mixture was partitioned between EtOAc (20 mL×3) and H2O (20 mL). The organic phase was collected, washed with brine (20 mL×6) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (ethyl acetate in petroleum ether, gradient from 0 to 42%). The collected fractions were combined. Most of the organic volatiles were removed under reduced pressure to give 4- (4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide (25.4 mg, 66.43 μmol, 12.70% yield, 100% purity).1H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.4 Hz, 2H), 7.47 - 7.41 (m, 3H), 7.32 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 6.15 - 5.82 (m, 1H), 5.57 (s, 1H), 4.66 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.93 - 3.81 (m, 1H), 3.59 (s, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 10.4 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.14 (t, J = 10.4 Hz, 1H). LCMS [ESI, M+1]: = 383.0.

[0227] Example 27: 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide, enantiomer A (Compound 1-88)

[0228] 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide (20 mg, 52.31 μmol, 1 eq). was separated by chiral SFC(column: Daicel Chiralpak IG (250mm*30mm,10um); mobile phase: [CO2- MeOH(0.1%NH3•H2O)]; 32% B, isocratic elution mode) and concentrated under reduced pressure to give 4-(4-(3-fluoro-5-(trifluoromethyl) benzyl)morpholin-2-yl)benzamide, enantiomer A (7.2 mg, 18.64 μmol, 35.64% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.4 Hz, 2H), 7.47 - 7.39 (m, 3H), 7.32 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.18 - 5.41 (m, 2H), 4.65 (dd, J = 10.4, 2.4 Hz, 1H), 4.10 - 4.02 (m, 1H), 3.86 (dt, J = 11.6, 2.4 Hz, 1H), 3.58 (s, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.77 - 2.70 (m, 1H), 2.34 (dt, J = 11.6, 3.6 Hz, 1H), 2.14 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: = 383.1. Analytical SFC retention time: 1.394 min

[0229] Example 28: 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide, enantiomer B (Compound 1-89) 145WSGR Docket No.58819-702.601

[0230] 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide (20 mg, 52.31 μmol, 1 eq). was separated by chiral SFC (column: Daicel Chiralpak IG (250mm*30mm,10um); mobile phase: [CO2- MeOH(0.1%NH3•H2O)]; 32% B, isocratic elution mode) and concentrated under reduced pressure to give 4-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)benzamide, enantiomer B (8.1 mg, 20.97 μmol, 40.10% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.4 Hz, 2H), 7.47 - 7.40 (m, 3H), 7.32 (d, J = 9.6 Hz, 1H), 7.23 (s, 1H), 6.15 - 5.39 (m, 2H), 4.65 (dd, J = 10.4, 2.4 Hz, 1H), 4.06 (dd, J = 11.6, 2.0 Hz, 1H), 3.86 (dt, J = 11.6, 2.4 Hz, 1H), 3.62 - 3.55 (m, 2H), 2.89 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 11.2 Hz, 1H), 2.34 (dt, J = 11.6, 3.6 Hz, 1H), 2.14 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1]: = 383.1. Analytical SFC retention time: 1.525 min

[0231] Example 29: (S)-5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (Compound 1-61) and (R)-5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (Compound 1-60)

[0232] Step 1: Tert-butyl 2-(1-oxoisoindolin-5-yl)morpholine-4-carboxylate 146WSGR Docket No.58819-702.601To a solution of 5-bromoisoindolin-1-one (8.00 g, 37.7 mmol, 1.0 eq) and 4-tert- butoxycarbonylmorpholine-2-carboxylic acid (13.1 g, 56.6 mmol, 1.5 eq) in DMSO (160 mL) was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dichloronickel (751 mg, 1.89 mmol, 0.05 eq), bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+) 4-tert-butyl-2-(4-tert-butyl- 2-pyridyl)pyridine hexafluorophosphate (847 mg, 755 μmol, 0.02 eq), phthalimide (5.55 g, 37.7 mmol, 1.0 eq) and BTMG (9.69 g, 56.6 mmol, 1.5 eq). The reaction was degassed and purged with N2three times. The solution was pumped at 0.554 mL / min through flow reactor 1 [FEP, Coils reactor, 3.175 (1 / 8’’) mm, 49.853 mL, 50 °C]. The residence time of flow reactor 1 was 90 min. A 450 nm, 400 W light was turned on. The reaction mixture was collected after running for 6.3 h. On completion, the reaction mixture was diluted with H2O (90 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (80 mL × 5), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Hexane / EtOAc =10 / 1 to 1 / 10) to give tert-butyl 2-(1-oxoisoindolin-5-yl)morpholine-4-carboxylate (3.00 g, 8.86 mmol, 23% yield, 94% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.54 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.53 (dd, J = 2.4, 10.4 Hz, 1H), 4.36 (s, 2H), 4.02 - 3.76 (m, 3H), 3.58 (dt, J = 2.8, 11.6 Hz, 1H), 3.10 - 2.90 (m, 1H), 2.88 - 2.66 (m, 1H), 1.42 (s, 9H). LCMS [ESI, M+1] = 319.1.

[0233] Step 2: 5-(morpholin-2-yl)isoindolin-1-oneTo a solution of tert-butyl 2-(1-oxoisoindolin-5-yl)morpholine-4-carboxylate (3.00 g, 9.42 mmol, 1.0 eq) in DCM (20 mL) was added TFA (9.98 g, 87.5 mmol, 9.3 eq). The mixture was stirred at 25 °C for 4 h. On completion, the reaction was concentrated under reduced pressure to give 5-(morpholin-2- yl)isoindolin-1-one (3.00 g, 9.03 mmol, 96% yield, TFA salt) as a yellow oil. LCMS [ESI, M+1] = 219.2.

[0234] Step 3: 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one 147WSGR Docket No.58819-702.601To a solution of 5-morpholin-2-ylisoindolin-1-one (2.90 g, 8.73 mmol, 1.0 eq, TFA) in THF (58.0 mL) was added TEA to adjust the pH value to 7 and the reaction was stirred at 25 °C for 10 min. Then 3- fluoro-5-(trifluoromethyl)benzaldehyde (2.52 g, 13.1 mmol, 1.5 eq) and AcOH (524 mg, 8.73 mmol, 1.0 eq) was added and stirred at 25 °C for 0.5 h. Then NaBH(OAc)3(3.70 g, 17.5 mmol, 2.0 eq) was added and stirred at 25 °C for 12 h. On completion, the reaction was diluted with H2O (60 mL) and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (60 mL × 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Hexane / EtOAc =10 / 1 to 1 / 10) to give 5-(4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholin- 2-yl)isoindolin-1-one (2.20 g, 5.39 mmol, 62% yield, 97% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.48 - 7.41 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 6.77 (s, 1H), 4.70 (dd, J = 2.0, 10.0 Hz, 1H), 4.45 (s, 2H), 4.07 (dd, J = 2.0, 11.6 Hz, 1H), 3.88 (dt, J = 2.4, 11.6 Hz, 1H), 3.59 (s, 2H), 2.91 (d, J = 11.6 Hz, 1H), 2.76 (d, J = 10.8 Hz, 1H), 2.35 (dt, J = 3.2, 11.6 Hz, 1H), 2.16 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1] = 395.0.

[0235] Step 4: (S)-5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (R)-5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-oneCompound 5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (2.20 g, 5.39 mmol, 97% purity) was separated by SFC {condition: column: Chiral-Cellulose-2-30-Phenomenex- Cellulose-2 (250 mm * 30 mm, 10 um; mobile phase: [CO2-MeOH (0.1% NH3•H2O)]; B%: 35%, isocratic elution mode} to give (S)-5-(4-(3-fluoro-5-(trifluoromethyl)benzyl)morpholin- 2-yl)isoindolin-1-one (969 mg, 2.41 mmol, 43% yield, 98% purity) and (R)-5-(4-(3-fluoro-5- (trifluoromethyl)benzyl)morpholin-2-yl)isoindolin-1-one (982 mg, 2.49 mmol, 45% yield, 100% purity). 148WSGR Docket No.58819-702.6011H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 4.71 (dd, J = 2.0, 10.0 Hz, 1H), 4.45 (s, 2H), 4.13 - 4.02 (m, 1H), 3.89 (dt, J = 2.4, 11.6 Hz, 1H), 3.60 (s, 2H), 2.92 (d, J = 11.6 Hz, 1H), 2.76 (d, J = 11.6 Hz, 1H), 2.36 (dt, J = 3.6, 11.6 Hz, 1H), 2.16 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1] = 395.1.1H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.48 - 7.39 (m, 2H), 7.32 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 4.70 (dd, J = 2.0, 10.0 Hz, 1H), 4.45 (s, 2H), 4.07 (dd, J = 2.0, 11.6 Hz, 1H), 3.88 (dt, J = 2.4, 11.6 Hz, 1H), 3.59 (s, 2H), 2.91 (d, J = 11.6 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.35 (dt, J = 3.2, 11.6 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H). LCMS [ESI, M+1] = 395.1.

[0236] Example 30: 5-[4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholin-2-yl]isoindolin-1- one (Compound 1-101)

[0237] Step 1: 4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylateTo a solution of methyl morpholine-2-carboxylate (553 mg, 3.05 mmol, 1.0 eq, HCl) in DCM (12 mL) was added TEA (339 mg, 3.35 mmol, 1.1 eq) and 3-fluoro-5-(trifluoromethyl)benzenesulfonyl chloride (720 mg, 2.74 mmol, 0.90 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition of H2O (15 mL) at 25 °C, then diluted with H2O (15 mL) and extracted with DCM (30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 4-[3-fluoro-5- (trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylate (1.05 g, 2.80 mmol, 92% yield, 99% purity) as a colorless solid. 149WSGR Docket No.58819-702.6011H NMR (400 MHz, DMSO-d6) δ = 8.19 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 4.40 (dd, J = 3.2, 7.6 Hz, 1H), 3.92 (td, J = 4.0, 12.0 Hz, 1H), 3.68 (s, 3H), 3.67 - 3.60 (m, 1H), 3.45 (dd, J = 2.8, 12.0 Hz, 1H), 3.28 - 3.20 (m, 1H), 2.99 (dd, J = 8.0, 12.0 Hz, 1H), 2.84 (ddd, J = 3.2, 8.4, 11.6 Hz, 1H). LCMS [ESI, M+23] = 394.1.

[0238] Step 2: 4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylic acidTo a solution of methyl 4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylate (500 mg, 1.35 mmol, 1 eq) in THF (3 mL) and H2O (3 mL) was added LiOH•H2O (113 mg, 2.69 mmol, 2.0 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with aqueous HCl (2 N, 4 mL) to adjust the pH value to 6 and extracted with DCM / MeOH = 1 / 10 (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 4-[3-fluoro-5- (trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylic acid (330 mg, 924 μmol, 68% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 3.97 - 3.86 (m, 2H), 3.60 - 3.49 (m, 2H), 3.33 (d, J = 12.0 Hz, 1H), 2.64 - 2.52 (m, 2H). LCMS [ESI, M+1] = 358.0.

[0239] Step 3: 5-[4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholin-2-yl]isoindolin-1-oneThe solution of 4-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylmorpholine-2-carboxylic acid (330 mg, 924 μmol, 1.5 eq), 5-bromoisoindolin-1-one (131 mg, 616 μmol, 1.0 eq), NiCl2•dtbbpy (12.3 mg, 30.8 μmol, 0.05 eq), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (158 mg, 924 μmol, 1.5 eq), isoindoline-1,3- dione (90.6 mg, 616 μmol, 1.0 eq) and [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (13.8 mg, 12.3 μmol, 0.02 eq) in DMSO (6 mL) was pumped at 0.554 mL / min through flow reactor 1 [FEP, Coils reactor, 3.175 (1 / 8’’) mm, 49.853 mL, 50 °C]. The residence time of flow reactor 1 was 90 min. A 450 nm, 400 W light was turned on. The reaction mixture was collected after running for 1.5 h. On completion, the reaction mixture was quenched by addition of H2O (80 mL) at 25 °C, and then diluted with H2O (20 mL) 150WSGR Docket No.58819-702.601 and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Neutral condition) to give 5-[4-[3-fluoro-5- (trifluoromethyl)phenyl]sulfonylmorpholin-2-yl]isoindolin-1-one (8.70 mg, 18.8 μmol, 3% yield, 96% purity).1H NMR (400 MHz, CDCl3) δ = 7.80 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J = 8.0, 17.6 Hz, 2H), 7.44 - 7.35 (m, 2H), 6.17 (s, 1H), 4.66 (dd, J = 2.4, 10.0 Hz, 1H), 4.37 (s, 2H), 4.09 (dd, J = 2.8, 12.0 Hz, 1H), 3.88 - 3.75 (m, 2H), 3.66 (d, J = 11.6 Hz, 1H), 2.57 (dt, J = 3.4, 11.6 Hz, 1H), 2.31 - 2.22 (m, 1H).LCMS [ESI, M+1] = 445.0.

[0240] Example 31: 4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine (Compound 1-102)A mixture of 2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine (100 mg, 460 μmol, 1.0 eq), 1-bromo- 3-fluoro-5-(trifluoromethyl)benzene (111 mg, 460 μmol, 1.0 eq), RuPhos-Pd-G3 (38.5 mg, 46.0 μmol, 0.10 eq) and Cs2CO3 (449 mg, 1.38 mmol, 3.0 eq) in dioxane (5.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. On completion, the mixture was extracted with EtOAc (20 mL × 3), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC {column: CD24-WePure Biotech XPT C18150*25*7 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 40%-70% B over 10.0 min} to give 4-(3-fluoro-5- (trifluoromethyl)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine (67.5 mg, 176 μmol, 38% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.92 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.83 - 6.72 (m, 2H), 4.82 (dd, J = 2.4, 10.4 Hz, 1H), 4.27 (dd, J = 2.4, 11.6 Hz, 1H), 4.00 (dt, J = 2.8, 11.6 Hz, 1H), 3.88 (s, 3H), 3.72 (d, J = 12.0 Hz, 1H), 3.58 (d, J = 12.0 Hz, 1H), 3.09 (dt, J = 3.6, 12.0 Hz, 1H), 2.89 (dd, J = 10.8, 12.0 Hz, 1H). LCMS [ESI, M+1] = 380.4.

[0241] Example 32: (R)-4-(3-cyclopropyl-5-fluorobenzyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine (Compound 1-103) 151WSGR Docket No.58819-702.601

[0242] Step 1: 3-cyclopropyl-5-fluorobenzaldehydeA mixture of 3-bromo-5-fluorobenzaldehyde (500 mg, 2.46 mmol, 1.0 eq), cyclopropylboronic acid (254 mg, 2.96 mmol, 1.2 eq), Pd(dppf)Cl2(180 mg, 246 μmol, 0.10 eq), K2CO3(1.02 g, 7.39 mmol, 3.0 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2three times, and then the mixture was stirred at 90 °C for 12 h under N2atmosphere. On completion, the mixture was quenched with H2O (20 mL) and extracted with EtOAc (25 mL × 3), the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Hexane / EtOAc = 7 / 1 to 5 / 1) to give 3-cyclopropyl-5-fluorobenzaldehyde (240 mg, 1.32 mmol, 53% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.94 (d, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.36 - 7.31 (m, 1H), 7.05 - 7.00 (m, 1H), 2.03 - 1.93 (m, 1H), 1.11 - 1.05 (m, 2H), 0.81 - 0.74 (m, 2H)

[0243] Step 2: (R)-4-(3-cyclopropyl-5-fluorobenzyl)-2-(1-methyl-1H-benzo[d]imidazol-6- yl)morpholine 152WSGR Docket No.58819-702.601To a solution of (R)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine (100 mg, 394 μmol, 1.0 eq, HCl) and 3-cyclopropyl-5-fluorobenzaldehyde (65.0 mg, 394 μmol, 1.0 eq) in MeOH (1.5 mL) was added TEA (39.88 mg, 394 μmol, 54.8 μL, 1.0 eq), AcOH (2.37 mg, 39.4 μmol, 2.26 μL, 0.10 eq) and NaBH3CN (74.30 mg, 1.18 mmol, 3.0 eq). Then the mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was quenched by addition of H2O (0.5 ml) and filtered. The crude product was purified by prep-HPLC {Column: CD07-Daisogel SP-100-8-ODS-PK 150*25*10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 38%-68% B over 13.0 min} and lyophilized to give (R)-4-(3-cyclopropyl-5-fluorobenzyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)morpholine (25.8 mg, 69.9 μmol, 18% yield, 99% purity).1H NMR (400 MHz, CDCl3) δ = 7.86 (br s, 1H), 7.75 (br d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.61 (br d, J = 10.0 Hz, 1H), 4.79 - 4.70 (m, 1H), 4.11 - 4.04 (m, 1H), 3.94 - 3.87 (m, 1H), 3.85 (s, 3H), 3.50 (s, 2H), 2.97 (br d, J = 11.2 Hz, 1H), 2.78 (br d, J = 11.2 Hz, 1H), 2.37 - 2.28 (m...

Claims

WSGR Docket No.58819-702.601 CLAIMS We claim:

1. A compound of Formula (I):Ring A is a saturated or partially saturated 6- to 7- membered heterocycloalkyl; Ring B is phenyl or a 5- to 6- membered heteroaryl; each R1is independently C1-C3alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, - S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, 4- to 10- membered heterocycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), C1-C3alkylene(4- to 10- membered heterocycloalkyl), C1-C3alkylene(C6-C10aryl), or C1-C3alkylene(5- to 10- membered heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R2is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3- C6cycloalkyl, and C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; or two R2groups attached 287WSGR Docket No.58819-702.601 to the same atom are taken together to form =O, =NH, or a C3-C6cycloalkyl; or two R2groups attached to different atoms are taken together to form a C1-C3bridge or a 3- to 5- membered ring; wherein the C1-C3bridge or the 3- to 5- membered ring is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each R3is independently C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, - NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, - OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, - C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, and C1-C3alkylene(C3- C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3- C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z- C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl (optionally substituted with -ORb, -N(Rb)2, or -SRb), C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; Z is 3- to 4- membered heterocycloalkylene or C3-C4cycloalkylene, each of which is optionally substituted with one or more substituents independently selected from C1-C3alkyl, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C6-C10aryl, C1-C3alkylene(C6- C10aryl), C3-C6cycloalkyl, C1-C3alkylene(C3-C6cycloalkyl), 5- to 10- membered heteroaryl, C1- C3alkylene(5- to 10- membered heteroaryl), 4- to 6- membered heterocycloalkyl, or C1- C3alkylene(4- to 6- membered heterocycloalkyl), wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rcand Rdis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; p is 0, 1, 2, 3, or 4; 288WSGR Docket No.58819-702.601 m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound has the structure of Formula (III):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: A4is NRa, O, S, S(O)2, or S(O)(NH); t is 1 or 2; and L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O.

3. The compound of claim 2, wherein the compound has the structure of Formula (III-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

4. The compound of claim 3, wherein the compound has the structure of Formula (III-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: 289WSGR Docket No.58819-702.601 R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, - S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O., , , , , soptionally substituted with p instances of R1.is optionallysubstituted with p instances of R1.290WSGR Docket No.58819-702.60110. The compound of claim of any one of claims 1-4, wherein Ring H isoptionally substituted with p instances of R1.

11. The compound of any one of claims 1 or 6-10, wherein Ring A is a partially saturated 6- to 7- membered heterocycloalkyl.

12. The compound of claim 11, wherein Ring.

13. The compound of any one of claims 1 or 6-10, wherein Ring A is a saturated 6- to 7- membered heterocycloalkyl.

14. The compound of claim 13, wherein Ring A is piperidinyl, piperazinyl, morpholino, azepanyl, or oxazepanyl.

15. The compound of claim 13 or 14, wherein Ring.

16. The compound of any one of claims 13-15, wherein Ring.

17. The compound of any one of claims 13-15, wherein Ring. . The compound of any one of claims 13-15, wherein Ring. 291WSGR Docket No.58819-702.601 19. The compound of claim 13, wherein Ring, O, S, S(O)2, or S(O)(NH).

20. The compound of claim 13, wherein Ring,. 292WSGR Docket No.58819-702.60124. The compound of claim 13, wherein Ring A is.

25. The compound of any one of claims 1 or 5-24, wherein Ring B is a 5- to 6- membered heteroaryl.

26. The compound of any one of claims 1 or 5-24, wherein Ring B is phenyl.

27. The compound of any one of claims 1 or 5-24, wherein Ring B is phenyl, pyrazolyl, or pyrimidinyl.

28. The compound of claim 1, wherein the compound has the structure of Formula (II):, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH, or N; A2is CH2, NH, or O; A3is C, CH, or N; and A4is CH, CH2, N, NH, O, S, S(O)2, or S(O)(NH); 293WSGR Docket No.58819-702.601 A5is CH2, NH, O, S, S(O)2, or S(O)(NH); and A6is CH, CH2, N, NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH).

29. The compound of claim 1, wherein the compound has the structure of Formula (V):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: each is independently a single or double bond; A1is C, CH, or N; A2is CH2, NH, or O; A3is C, CH, or N; and A4is CH, CH2, N, NH, O, S, S(O)2, or S(O)(NH); A5is CH2, NH, O, S, S(O)2, or S(O)(NH); and A6is CH, CH2, N, NH, O, S, S(O)2, or S(O)(NH); provided that one or two of A1, A2, A3, A4, A5, and A6is N or NH, and when two of A1, A2, A3, A4, A5, and A6are N or NH, then none of A2, A4, A5, or A6are O, S, S(O)2, or S(O)(NH).

30. The compound of claim 1, wherein the compound has the structure of Formula (IV-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: 294WSGR Docket No.58819-702.601 L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O.

31. The compound of claim 1, wherein the compound has the structure of Formula (VI-M-1):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: L1is bond, C1-C3alkylene, C1-C3heteroalkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O.

32. The compound of any one of claims 1-3, 5-19, or 25-31, wherein each R2is independently -CH3 or -F; or two R2groups attached to the same atom are taken together to form =O or a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

33. The compound of any one of claims 1-3, 5-19, or 25-31, wherein each R2is independently -CH3; or two R2groups attached to the same atom are taken together to form =O or a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

34. The compound of any one of claims 1-19 or 25-33, wherein m is 0 or 1.

35. The compound of any one of claims 1-19 or 25-33, wherein m is 0.

36. The compound of any one of claims 1-35, wherein n is 0, 1, 2, or 3.

37. The compound of any one of claims 1-35, wherein n is 1, 2, or 3.

38. The compound of any one of claims 1-35, wherein n is 1 or 2.

39. The compound of claim 1, wherein the compound has the structure of Formula (IV): 295WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, - S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; t is 1 or 2; A4is NRa, O, S(O)2, or S(O)(NH); , or. L1is bond, C1-C3alkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O.

40. The compound of claim 1, wherein the compound has the structure of Formula (VI): 296WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof, wherein: R3ais C1-C6alkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Rb, - S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C3-C6cycloalkyl, or C1-C3alkylene(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; t is 1 or 2; A4is NRa, O, S(O)2, or S(O)(NH);. L1is bond, C1-C3alkylene, or C3-C4cycloalkylene, wherein each alkylene and cycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O. 297WSGR Docket No.58819-702.60144. The compound of claim 39, wherein the compound has the structure of Formula (IV-M-2): 298WSGR Docket No.58819-702.601or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

45. The compound of claim 40, wherein the compound has the structure of Formula (VI-M-2):or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

46. The compound of any one of claims 1-45, wherein each R1is independently C1-C3alkyl, C1- C3heteroalkyl, -OH, C1-C3alkoxy, halogen, C1-C3haloalkyl, -S(=O)2Rb, -C(=O)NRcRd, C1- C3alkylene(phenyl), C3-C4cycloalkyl, oxetanyl, or azetidinyl, wherein the phenyl, cycloalkyl, oxetanyl, and azetidinyl are each optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O 47. The compound of any one of claims 1-45, wherein each R1is C1-C3alkyl, C1-C3heteroalkyl, -OH, C1-C3alkoxy, halogen, C1-C3haloalkyl, -S(=O)2Rb, C1-C3alkylene(phenyl), C3-C4cycloalkyl, oxetanyl, or azetidinyl, wherein the phenyl, cycloalkyl, oxetanyl, and azetidinyl are each optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

48. The compound of any one of claims 1-45, wherein R1is C1-C3alkyl, C1-C3haloalkyl, -OH, C1- C3alkoxy, halogen, or C1-C3haloalkyl.

49. The compound of any one of claims 1-45, wherein each R1is C1-C3alkyl, C1-C3heteroalkyl, halogen, C1-C3haloalkyl, -C(=O)NH2, -C(=O)NHC1-3alkyl, or -C(=O)N(C1-3alkyl)250. The compound of any one of claims 1-45, wherein R1is C1-C3alkyl or C1-C3haloalkyl.

51. The compound of any one of claims 1-50, wherein p is 0, 1, or 2. 299WSGR Docket No.58819-702.601 52. The compound of any one of claims 1-51, wherein each R3is independently C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -S-C1- C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl.

53. The compound of any one of claims 1-51, wherein each R3is independently C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -SF5, - S(=O)2CF3, or cyclopropyl.

54. The compound of any one of claims 1-51, wherein each R3is independently C1-C3haloalkyl or halogen.

55. The compound of any one of claims 4-10 or 39-54, wherein R3ais C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -S-C1- C3haloalkyl, -SF5, -S(=O)2CF3, or cyclopropyl 56. The compound of any one of claims 4-10 or 39-54, wherein R3ais C1-C3alkyl, C1- C3hydroxyalkyl, C1-C3alkoxy, C1-C3haloalkyl, halogen, -CN, -OH, -O-C1-C3haloalkyl, -SF5, - S(=O)2CF3, or cyclopropyl.

57. The compound of any one of claims 4-10 or 39-54, wherein R3ais C1-C3haloalkyl or halogen.

58. The compound of any one of claims 1, 5-29, 32-38, or 46-57, wherein L1is bond, C1-C3alkylene, C1-C3heteroalkylene, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-3alkyl)-, -O-, C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O; 59. The compound of any one of claims 1-57, wherein L1is bond, C1-C3alkylene, or C1- C3heteroalkylene, wherein each alkylene and heteroalkylene is optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O.

60. The compound of any one of claims 1-57, wherein L1is C1-C3alkylene optionally substituted with one or more substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, halogen, and -OH; or two substitutions attached to the same atom are taken together to form cyclopropyl or =O .

61. The compound of any one of claims 1-57, wherein L1is C1-alkylene optionally substituted with 1 or 2 substituents independently selected from -CH3 and -F; or L1is C1-alkylene optionally substituted with two substitutions attached to the same atom taken together to form cyclopropyl or =O.

62. The compound of any one of claims 1-57, wherein L1is C1-alkylene.

63. The compound of any one of claims 1, 5-29, 32-38, or 46-57, wherein L1is C3-C4cycloalkylene, 3- to 4- membered heterocycloalkylene, -O-Z-, -Z-O-, C1-C3alkylene-Z-, or -Z-C1-C3alkylene, wherein each alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene is optionally 300WSGR Docket No.58819-702.601 substituted with one or more substituents independently selected from C1-C3alkyl, halogen, -OH, and =O.

64. The compound of claim 63, wherein Z is azetidinylene, cyclopropylene, or cyclobutylene, each of which is optionally substituted with 1 or 2 substituents independently selected from -CH3, -F, and =O.301WSGR Docket No.58819-702.601302WSGR Docket No.58819-702.601303WSGR Docket No.58819-702.601, 304WSGR Docket No.58819-702.601305WSGR Docket No.58819-702.601306WSGR Docket No.58819-702.601307WSGR Docket No.58819-702.601308WSGR Docket No.58819-702.601enriched forms thereof.

66. A compound selected frompharmaceutically acceptable salts and isotopically enriched forms thereof.

67. The compound of claim 1, wherein the compound is selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, or an isotopically enriched form thereof.

68. The compound of claim 1, wherein the compound is selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotopically enriched form thereof.

69. A pharmaceutical composition comprising the compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, or isotopically enriched form thereof.

70. The pharmaceutical composition of claim 69, further comprising a pharmaceutically acceptable excipient.

71. A method of treating a disease or disorder in a subject in need thereof, comprising administering the compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, or isotopically enriched form thereof, to the subject.

72. The method of claim 71, wherein the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder. 309WSGR Docket No.58819-702.601 73. The method of claim 71 or 72, wherein the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from schizophrenia, cognitive impairment, a panic disorder, a phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson’s disease, drug-induced Parkinson’s syndrome, extrapyramidal syndrome, Alzheimer’s Disease, Lewy Body Dementia, bipolar disorder, ADHD, Tourette’s syndrome, an extrapyramidal or movement disorder, a motor disorder, a hyperkinetic movement disorder, a psychotic disorder, catatonia, a mood disorder, a depressive disorder, an anxiety disorder, obsessive-compulsive disorder (OCD), an autism spectrum disorder, a prolactin-related disorder (e.g., hyperprolactinemia), a neurocognitive disorder, and a trauma- or stressor- related disorder (e.g., PTSD).

74. The method of claim 71 or 72, wherein the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from a disruptive, impulse- control, or conduct disorder, a sleep-wake disorder, a substance-related disorder, an addictive disorder, a behavioral disorder, hypofrontality, an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway, decreased activity in the striatum, cortical dysfunction, neurocognitive dysfunction, and the cognitive deficits associated with schizophrenia.

75. The method of claim 71 or 72, wherein the disease or disorder is a neurological, neuropsychiatric, or neurodegenerative disease or disorder selected from Parkinson’s Disease, drug induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy, progressive supranuclear palsy, and Huntington’s disease, including chorea associated with Huntington’s disease.

76. The method of claim 71, wherein the disease or disorder is a psychosis or a psychotic disease or disorder, a mood disorder, or a sleep-wake disorder.

77. The method of claim 76, wherein the psychosis is schizophrenia.

78. The method of claim 76, wherein the mood disorder is anxiety.

79. The method of claim 76, wherein the sleep-wake disorder is insomnia or narcolepsy. 310

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