Compounds and methods for treating neurological disorders

Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that modulate GCase activity. These compounds are useful, e.g., for treating a disease in which Gcase activity contributes to the disease.

Description

[0001] COMPOUNDS AND METHODS FOR TREATING NEUROLOGICAL DISORDERS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 673,119, filed on July 18, 2024, which is hereby incorporated by reference in its entirety.

[0004] FIELD

[0005] This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that modulate glucocerebrosidase (GCase) activity. These compounds are useful, e.g., for treating a disease in which Gcase activity contributes to the disease.

[0006] BACKGROUND

[0007] Glucocerebrosidase (GCase) is a lysosomal, membrane associated enzyme involved in the metabolism of glucosylceramide (GluCer) and glucosyl sphingosine (GluSph) and is encoded by the GBA1 gene. Inside the lysosomal compartment, GCase hydrolyzes the beta-glucosidic linkage of GluCer and GlySph to release glucose, which in turn regulates ceramide signaling and glycolipid metabolism.

[0008] Homozygous or compound heterozygous loss-of-function GBA1 mutations can cause Gaucher disease (GD), a rare lysosomal storage disorder characterized by accumulation of GluCer and GluSph resulting in neural toxicity. In addition, heterozygous mutations in GBA1 are one of the most common genetic risk factors for Parkinson’s disease (PD). It is estimated that anywhere between 7-12% of all patients with Parkinson’s disease carry a GBA1 gene mutation. Several studies have found reduced GCase activity in sporadic PD cases (not carrying GBA1 gene mutations), suggesting a role for GCase activity in the pathogenesis of PD via a-synuclein accumulation. Some variants of GBA1 are also known to increase the risk of dementia with Lewy bodies (DLB) — another type of neurodegenerative disease linked to abnormal accumulation a- synuclein.

[0009] Currently several treatments options for specific types of GD are available, particularly enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Unfortunately, both types of therapies are not able to reach the central nervous system and thus fail to address the neurological symptoms caused by the disease. Moreover, there is no disease-modifying treatment available for PD with GBA1 mutations (GBA-PD).

[0010] Since nigral dopamine loss observed in individuals with GBA-PD is identical to that observed in individuals with sporadic PD, patients are normally given dopaminergic therapy to alleviate motor symptomology, without addressing non-motor symptoms or other aspects influencing disease progression.

[0011] SUMMARY

[0012] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: one of Y and Z is N and the other of Y and Z is CR1;

[0013] X1is N or CRX;

[0014] X2is N or CR4;

[0015] R1is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0016] R2is C1-C6 haloalkoxy, benzyl oxy, or -NR2AR2B;

[0017] R2Aand R2Bare each independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; or R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;

[0018] R3is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, an optionally substituted 6-12 membered heteroaryl, or -NR3AR3B; each of R34and R3Bis independently selected from (i) hydrogen;

[0019] (ii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and cyano;

[0020] (iii) C1-C6 haloalkyl;

[0021] (iv) 5-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl;

[0022] (v) 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0023] (vi) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0024] Rx, R4, and R5are each independently hydrogen, C 1 -C6 alkyl, cyano, hydroxyl, or halogen; wherein when Y is CR1, Z is N, X1is CRX, and X2is CR4, then R3is not an optionally substituted

[0025] 1.5.6.7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, optionally substituted 5', 6'- dihydrospiro[cyclopropane-l,7'-pyrrolo[3,2-c]pyridin]-4'(l'H)-one, optionally substituted 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one, optionally substituted pyrrole, optionally substituted l,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, optionally substituted 3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrol-4(lH)-one, optionally substituted l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-thione, optionally substituted 1'H- spiro[cyclopropane-l,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted 1, 5,6,7- tetrahydro-4H-indol-4-one, optionally substituted 5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(lH)- one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrole-4(lH)-thione, optionally substituted

[0026] 6.7-dihydro-lH-pyrrolo[3,2-c]pyridine, optionally substituted 2,3,5, 6-tetrahydro-l'H-spiro[pyran- 4,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted l,5-dihydro-4H-pyrrolo[2,3- d]pyridazin-4-one, optionally substituted l,2-dihydro-3H-pyrrolo[l,2-c]imidazol-3-one, optionally substituted lH-pyrrolo[l,2-c]imidazole-l,3(2H)-dione, optionally substituted pyrazole, or optionally substituted 6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one.

[0027] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0028] Provided herein is a method for treating a GCase-associated disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0029] Provided herein is a method of treating a GCase-associated disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a GCase-associated disorder a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0030] In some embodiments, the GCase-associated disorder is a lysosomal storage disorder or a neurodegenerative disorder.

[0031] Other embodiments include those described in the Detailed Description and / or in the claims.

[0032] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0033] DETAILED DESCRIPTION

[0034] This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that modulate GCase function.

[0035] Formulae (I) Compounds

[0036] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: one of Y and Z is N and the other of Y and Z is CR1;

[0037] X1is N or CRX; X2is N or CR4;

[0038] R1is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0039] R2is C1-C6 haloalkoxy, benzyl oxy, or -NR2AR2B;

[0040] R2Aand R2Bare each independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; or R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;

[0041] R3is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, an optionally substituted 6-12 membered heteroaryl, or -NR3AR3B; each of R3Aand R3Bis independently selected from

[0042] (i) hydrogen;

[0043] (ii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and cyano;

[0044] (iii) C1-C6 haloalkyl;

[0045] (iv) 5-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl;

[0046] (v) 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0047] (vi) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and

[0048] Rx, R4, and R5are each independently hydrogen, C 1 -C6 alkyl, cyano, hydroxyl, or halogen; wherein when Y is CR1, Z is N, X1is CRX, and X2is CR4, then R3is not an optionally substituted l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, optionally substituted 5', 6'- dihydrospiro[cyclopropane-l,7'-pyrrolo[3,2-c]pyridin]-4l(rH)-one, optionally substituted 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one, optionally substituted pyrrole, optionally substituted l,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, optionally substituted 3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrol-4(lH)-one, optionally substituted l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-thione, optionally substituted 1'H- spiro[cyclopropane-l,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted 1,5, 6, 7- tetrahydro-4H-indol-4-one, optionally substituted 5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(lH)- one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrole-4(lH)-thione, optionally substituted 6,7-dihydro-lH-pyrrolo[3,2-c]pyridine, optionally substituted 2,3,5, 6-tetrahydro- l'H-spiro[pyran- 4,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted l,5-dihydro-4H-pyrrolo[2,3- d]pyridazin-4-one, optionally substituted l,2-dihydro-3H-pyrrolo[l,2-c]imidazol-3-one, optionally substituted lH-pyrrolo[l,2-c]imidazole-l,3(2H)-dione, optionally substituted pyrazole, or optionally substituted 6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one.

[0049] Also provided a compound of Formula (I-I): or a pharmaceutically acceptable salt thereof, wherein: one of Y and Z is N and the other of Y and Z is CR1;

[0050] R1is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0051] R2is C1-C6 haloalkoxy, benzyl oxy, or -NR2AR2B;

[0052] R2Aand R2Bare each independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; or R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; R3is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl;

[0053] X is N or CRX; and

[0054] Rx, R4, and R5are each independently hydrogen, C1-C6 alkyl, or halogen.

[0055] In some embodiments, R1is hydrogen.

[0056] In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is C1-C3 alkyl.

[0057] In some embodiments, R1is C3-C10 cycloalkyl, is In some embodiments, R1is C3-C7 cycloalkyl.

[0058] In some embodiments, Y is CR1and Z is N.

[0059] In some embodiments, Y is N and Z is CR1.

[0060] In some embodiments, R2is C1-C6 haloalkoxy. In some embodiments, R2is C1-C3 haloalkoxy.

[0061] In some embodiments, R2is benzyloxy.

[0062] In some embodiments, R2is -NR2AR2B.

[0063] In some embodiments, R2Aand R2Bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

[0064] In some embodiments, R2Aand R2Bare both hydrogen.

[0065] In some embodiments, one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 alkyl. In some embodiments, one of R2Aand R2Bis hydrogen and the other one of R2Aand

[0066] In some embodiments, one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 haloalkyl.

[0067] In some embodiments, one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxy alkyl, and C1-C6 aminoalkyl.

[0068] In some embodiments, each R2Aand R2Bis independently selected C1-C6 alkyl. In some embodiments, both of R2Aand R2Bare methyl or both of R2Aand R2Bare ethyl. In some embodiments, R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl. In some embodiments, the 4-10 membered heterocyclyl formed by R2Aand R2Btogether with the nitrogen atom to which they are attached is substituted with 1-3 substituents. In some embodiments, the 4-10 membered heterocyclyl formed by R2Aand R2Btogether with the nitrogen atom to which they are attached is unsubstituted.

[0069] In some embodiments, R3is an optionally substituted 6-12 membered aryl. In some embodiments, R3is an optionally substituted phenyl.

[0070] In some embodiments, R3is an optionally substituted 6-12 membered heterocyclyl. In some embodiments, R3is an optionally substituted 6-10 membered heterocyclyl. In some embodiments, R3is an optionally substituted 6-9 membered heterocyclyl.

[0071] In some embodiments, R3is an optionally substituted 6 membered heterocyclyl. In some embodiments, R3is unsubstituted 6-12 membered heterocyclyl.

[0072] In some embodiments, R3is an optionally substituted 6-12 membered heteroaryl. In some embodiments, R3is an optionally substituted 6-membered heteroaryl. In some embodiments, R3is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4- triazinyl, and 1,3,5-triazinyl, each of which is optionally substituted.

[0073] In some embodiments, R3is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R3is an optionally substituted 9-10 membered heteroaryl, selected from the group indicates hydrogen or an optional substituent.

[0074] In some embodiments, R3is -NR3AR3B.

[0075] In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and cyano. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C1-C6 alkyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis Cl-C3 alkyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C1-C6 haloalkyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C1-C3 haloalkyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis CF3.

[0076] In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-6 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis unsubstituted 5-6 membered heterocyclyl.

[0077] In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis unsubstituted 5-6 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl.

[0078] In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C3-C10 cycloalkyl substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis unsubstituted C3-C6 cycloalkyl.

[0079] In some embodiments, X is CRX.

[0080] In some embodiments, Rxis hydrogen.

[0081] In some embodiments, Rxis C1-C6 alkyl. In some embodiments, Rxis methyl.

[0082] In some embodiments, Rxis halogen. In some embodiments, Rxis fluoro or chloro.

[0083] In some embodiments, Rxis cyano.

[0084] In some embodiments, Rxis hydroxyl.

[0085] In some embodiments, R4is hydrogen.

[0086] In some embodiments, R4is C1-C6 alkyl. In some embodiments, R4is C1-C3 alkyl.

[0087] In some embodiments, R4is halogen. In some embodiments, R4is fluoro or chloro.

[0088] In some embodiments, R4is cyano.

[0089] In some embodiments, R4is hydroxyl.

[0090] In some embodiments, R5is hydrogen.

[0091] In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is C1-C3 alkyl.

[0092] In some embodiments, R5is halogen. In some embodiments, R5is fluoro or chloro.

[0093] In some embodiments, R5is cyano.

[0094] In some embodiments, R5is hydroxyl.

[0095] In some embodiments, X is N.

[0096] In some embodiments, X1is N.

[0097] In some embodiments, X1is CRX.

[0098] In some embodiments, X2is N.

[0099] In some embodiments, X2is CR4.

[0100] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0101] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0102] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-C): or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0103] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-D): or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0104] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-E): or a pharmaceutically acceptable salt thereof, wherein R1, R2B, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0105] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F): or a pharmaceutically acceptable salt thereof, wherein R1, R2B, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0106] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (LG): or a pharmaceutically acceptable salt thereof, wherein:

[0107] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1 -C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0108] Ring A is an optionally substituted 5-6 membered heterocyclyl, an optionally substituted 5-6 membered heteroaryl, or an optionally substituted C5-C6 cycloalkyl.

[0109] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein:

[0110] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0111] Ring A is an optionally substituted 5-6 membered heterocyclyl, an optionally substituted 5-6 membered heteroaryl, or an optionally substituted C5-C6 cycloalkyl.

[0112] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-IA): or a pharmaceutically acceptable salt thereof, wherein:

[0113] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0114] Ring A is an optionally substituted 5-6 membered heterocyclyl, an optionally substituted 5-6 membered heteroaryl, or an optionally substituted C5-C6 cycloalkyl.

[0115] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- J): or a pharmaceutically acceptable salt thereof, wherein:

[0116] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and Ring A is an optionally substituted 5-6 membered heterocyclyl, an optionally substituted 5-6 membered heteroaryl, or an optionally substituted C5-C6 cycloalkyl.

[0117] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-K): or a pharmaceutically acceptable salt thereof, wherein:

[0118] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0119] Ring B is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl.

[0120] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-L): or a pharmaceutically acceptable salt thereof, wherein:

[0121] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0122] Ring B is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl.

[0123] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-M): or a pharmaceutically acceptable salt thereof, wherein:

[0124] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5- 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0125] Ring B is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl.

[0126] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-N): or a pharmaceutically acceptable salt thereof, wherein:

[0127] R1, R2, and R4are as defined in Formula (I) or Formula (I-I); each R3Ais independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 5-

[0128] 6 membered heteroaryl, phenyl, C3-C8 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, - C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(5-6 membered heterocyclyl), and C1-C6 alkoxy; n is 0, 1, 2, or 3; and

[0129] Ring B is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl.

[0130] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula or a pharmaceutically acceptable salt thereof, wherein:

[0131] R1, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0132] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula or a pharmaceutically acceptable salt thereof, wherein:

[0133] R1, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0134] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula or a pharmaceutically acceptable salt thereof, wherein:

[0135] R1, R3, and Rxare as defined in Formula (I) or Formula (I-I). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-Q): or a pharmaceutically acceptable salt thereof, wherein:

[0136] R1, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0137] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-R): or a pharmaceutically acceptable salt thereof, wherein:

[0138] R1, R3, and R4are as defined in Formula (I) or Formula (I-I).

[0139] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-S): or a pharmaceutically acceptable salt thereof, wherein:

[0140] R1, R3, and Rxare as defined in Formula (I) or Formula (I-I).

[0141] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0142] In some embodiments, each R3Ais independently halogen or C1-C6 alkyl. In some embodiments, each R3Ais independently halogen. In some embodiments, each R3Ais independently C1-C6 alkyl. In some embodiments, each R3Ais independently fluoro or methyl. In some embodiments, each R3Ais fluoro. In some embodiments, each R3Ais methyl.

[0143] In some embodiments, at least one R3Ais cyano. In some embodiments, one R3Ais cyano.

[0144] In some embodiments, at least one R3Ais C1-C6 alkyl. In some embodiments, at least one R3Ais methyl. In some embodiments, one R3Ais C1-C6 alkyl. In some embodiments, one R3Ais methyl.

[0145] In some embodiments, at least one R3Ais C1-C6 haloalkyl. In some embodiments, at least one R3Ais C1-C3 haloalkyl. In some embodiments, one R3Ais C1-C3 haloalkyl.

[0146] In some embodiments, at least one R3Ais 5 membered heteroaryl. In some embodiments, one R3Ais 5 membered heteroaryl. In some embodiments, at least one R3Ais selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1, 2,3,4- thiatriazolyl, and 1,2,3,5-thiatriazolyl. In some embodiments, one R3Ais selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl, and 1,2,3,5-thiatriazolyl.

[0147] In some embodiments, at least one R3Ais phenyl. In some embodiments, one R3Ais phenyl.

[0148] In some embodiments, at least one R3Ais C3-C7 cycloalkyl. In some embodiments, at least one R3Ais cyclopropyl. In some embodiments, one R3Ais C3-C7 cycloalkyl.

[0149] In some embodiments, at least one R3Ais -C(O)C1-C6 alkyl. In some embodiments, at least one R3Ais acyl. In some embodiments, one R3Ais -C(O)C1-C6 alkyl. In some embodiments, one R3Ais acyl.

[0150] In some embodiments, at least one R3Ais -C(O)OC1-C6 alkyl. In some embodiments, one R3Ais -C(O)OC1-C6 alkyl.

[0151] In some embodiments, at least one R3Ais -C(O)NH(C1-C6 alkyl). In some embodiments, one R3Ais -C(O)NH(C1-C6 alkyl). In some embodiments, at least one R3Ais -C(O)N(C1-C6 alkyl)2. In some embodiments, one R3Ais -C(O)N(C1-C6 alkyl)2.

[0152] In some embodiments, at least one R3Ais -NH(5-6 membered heterocyclyl). In some embodiments, at least one R3Ais -NH(5 membered heterocyclyl). In some embodiments, at least one R3Ais -NH(6 membered heterocyclyl). In some embodiments, one R3Ais -NH(5-6 membered heterocyclyl). In some embodiments, one R3Ais -NH(5 membered heterocyclyl). In some embodiments, one R3Ais -NH(6 membered heterocyclyl).

[0153] In some embodiments, at least one R3Ais C1-C6 alkoxy. In some embodiments, one R3Ais C1-C6 alkoxy. In some embodiments, two R3Aare independently selected C1-C6 alkoxy.

[0154] Non-Limiting Exemplary Compounds

[0155] In some embodiments, the compound is selected from the group consisting of the compounds described in Table A, or a pharmaceutically acceptable salt thereof.

[0156] Table A

[0157]

[0158]

[0159]

[0160]

[0161] Additional Definitions

[0162] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0163] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0164] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0165] As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease to be treated.

[0166] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0167] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to achieve a desired beneficial result, for example, a reduction of symptoms in a subject, prolonging the life of a subject, and improving the quality of life of a subject.

[0168] The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. ; Rowe el al. , Eds. ; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, V-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, and lysine, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0169] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphinityl, phosphinyl, phosphatyl, phosphinatyl, phosphonatyl, and ureido.

[0170] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0171] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0172] The term “hydroxyl” refers to an -OH radical.

[0173] The term “sulfhydryl” refers to a -SH radical.

[0174] The term “cyano” refers to a -CN radical.

[0175] The term “azido” refers to a -N3 radical.

[0176] The term “nitro” refers to a -NO2 radical.

[0177] The term “nitroso” refers to a -N=O radical.

[0178] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Cl -CIO indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, Ao-propyl, tert-butyl, 77-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0179] The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical

[0180] (e g., -C(=O)-CH=CH2), or -C(=O)alkynyl radical (e g.,0). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens. As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.

[0181] The term “heteroalkyl” refers to an alkyl group as defined herein, wherein one or more carbon atoms in the alkyl group are replaced by a heteroatom (e.g., N, O, S, P, or Si).

[0182] The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0183] The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l. l.l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bi cyclo [3.1.1] heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0184] The term “heteroaryl,” as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-< ]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4- / >]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-£>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo|7>][l,4]dioxine, benzo[c / ][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[Z>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. Heteroaryl groups can also include oxidized atoms, such as C or S (e.g., as C=O). For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g., imidazolone (e.g., wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=0”) herein is a constituent part of the heteroaryl ring).

[0185] The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms ofN, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be oxidized (forming, e.g., a carbonyl, a lactam, or a phosphinane oxide) and one or more N or S atoms may be oxidized (forming, e.g., an N-oxide, an S-oxide, or an S,S -di oxi de), valence permitting. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, di hydropyrrolyl, di hydrofuranyl, dihydrothiophenyl, tetrahydro-2H-thiopyran 1 ,1 -dioxide, oxaphosphinanyl oxide, and azaphosphinanyl oxide. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2- azabicyclo[l .1 .0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l. l . l]pentane, 3- azabicy clo[3.1 .0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4. 1 .0]heptane, 7-azabicyclo[2.2. l]heptane, 6- azabicy clo[3.1.1 ]heptane, 7-azabi cy cl o [4.2.0] octane, 2-azabicyclo[2.2.2]octane, 3- azabicy clo[3.2. 1 ]octane, 2-oxabicyclo[ 1. 1 .0]butane, 2-oxabicyclo[2. 1.0]pentane, 2- oxabicyclo[l .1.1 ]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2. 1 . l]hexane, 3- oxabicyclo[3 ,2.0]heptane, 3-oxabicyclo[4. 1 .0]heptane, 7-oxabicyclo[2.2.1]heptane, 6- oxabicyclo[3.1.1 ]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3- oxabicyclo[3.2.1]octane. Heterocyclyl also includes spirocyclic rings (e g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7- diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3- azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2- oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7- dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3- oxaspiro[5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane.

[0186] As used herein, nonlimiting examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, and isothiazole.

[0187] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0188] The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0189] The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0190] The term “cyanoalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with cyano. The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0191] The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0192] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0193] The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy (e.g., methoxy ethyl).

[0194] The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with hydroxy.

[0195] The term “alkoxy alkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy.

[0196] The term “alkoxyamino” refers to an -O-amino radical (e.g., -OCH2CH2N(CH )2).

[0197] The term “haloalkoxy” refers to an -O-haloalkyl radical (e g., -OCF3).

[0198] The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).

[0199] The term “haloalkenoxy” refers to an -O-haloalkenyl radical.

[0200] The term “alkynoxy” refers to an -O-alkynyl radical (e g., -O-propargyl).

[0201] The term “haloalkynoxy” refers to an -O-haloalkynyl radical.

[0202] The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).

[0203] The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy).

[0204] The term “heteroaryloxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy).

[0205] The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).

[0206] The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e g., benzyl).

[0207] The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).

[0208] The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).

[0209] The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl). The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyl oxy).

[0210] The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).

[0211] The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).

[0212] A “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0213] A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen (e.g., -S(CF3) or -S(CHF2)).

[0214] A “sulfinyl” group refers to an -S(=O)R group in which R can be the same as defined with respect to sulfenyl.

[0215] A “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl.

[0216] A “sulfoximine” group refers to an -S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0217] A “sulfonimidamido” group refers to an -S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0218] An “O-carboxy” group refers to a RC(=O)O- group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0219] The terms “ester” and “C-carboxy” refer to a -C(=O)OR group in which R can be the same as defined with respect to O-carboxy. A “thiocarbonyl” group refers to a -C(=S)R group in which R can be the same as defined with respect to O-carboxy.

[0220] A “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen.

[0221] A “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0222] An “S-sulfonamido” group refers to a -S02N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0223] An “N-sulfonamido” group refers to a RSC>2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0224] An “O-carbamyl” group refers to a -OC(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0225] An “N-carbamyl” group refers to an ROC(=O)N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0226] An “O-thiocarbamyl” group refers to a -OC(=S)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0227] An “N-thiocarbamyl” group refers to an ROC(=S)N(R’) — group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “C-amido” group refers to a -C(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0228] An “N-amido” group refers to a RC(=O)N(R’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0229] The terms “ureido” or “urea” refer to an -NR(C=O)NR’R” group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0230] The term “carboxaldehyde” refers to a -C(=O)H radical.

[0231] The term “imine” or “imino” refers to a -N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0232] The term “amino” refers to a -NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is -NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl).

[0233] The term “phosphine oxide” refers to a -P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Nonlimiting examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene. In some embodiments, such as the 1,4- azaphosphinane-4-oxide of Ring B described herein, there is a phospine oxide in a ring, where R and are the points of connection of the phosphorus atom to the ring and R’ is as described above.

[0234] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, and cycloalkyl described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

[0235] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0236] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0237] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0238] Pharmaceutical Compositions

[0239] Some embodiments provide a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0240] Methods of Treatment

[0241] Provided herein are methods for modulating glucocerebrosidase (GCase) activity, encoded by the GBA1 gene. For example, provided herein are compounds that enhance GCase activity that are useful for treating diseases associated with dysregulation of a GBA1 gene, a GCase protein, or the activity of any of the same (i.e., a GCase-associated disease), such as Parkinson’s disease (e.g., a GCase-associated neurological disease).

[0242] The ability of test compounds to act as a GCase enhancer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as GCase enhancers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and / or a change in its conformation. Potency of a GCase enhancer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent GCase enhancer relative to a compound with a higher EC50 value.

[0243] Indications

[0244] Compounds disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a GCase enhancer, such as GCase-associated diseases, e.g., lysosomal storage disorder and neurological diseases.

[0245] Some embodiments provide a method of treating a subject with a GCase-asssociated disease, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof.

[0246] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof. In some embodiments, the neurological disorder is a GCase-associated neurological disorder.

[0247] Some embodiments provide a method of treating a neurological disorder in a subject that has been identified or diagnosed as having a GCase-associated neurological disorder, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof.

[0248] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising (a) determing that the subject has a GCase-associated neurological disorder, and (b) administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof.

[0249] Also provided herein are methods for treating a subject identified or diagnosed as having a GCase-associated disease that include administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a GCase-associated disease through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a GBA1 gene, a GCase protein, or activity of any of the same, in a subject or sample from the subject. In some embodiments, the test or assay is provided as a kit.

[0250] Also provided are methods for treating a neurological disease in a subject in need thereof, the method comprising: (a) detecting a GCase-associated neurological disease in the subject; and (b) administering to the subject a therapeutically effective amount of a compound disclosed herein (e g., a compound of Formula (I) or Formula (T-T)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0251] In some embodiments, the GCase-associated disease is a lysosomal storage disease.

[0252] In some embodiments, the GCase-associated disease is a sphingolipidosis.

[0253] In some embodiments, the GCase-associated disease is Parkinson’s disease (PD), Gaucher’s disease, dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Mild Cognitive Impairment (MCI), Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease, Corticobasal degeneration, Niemann-Pick disease, Progressive supranuclear palsy (PSP), Fabry disease, Krabbe disease, Metachromatic leukodystrophy, Sandhoff disease, or Tay-Sachs disease.

[0254] In some embodiments, the GCase-associated disease is PD.

[0255] In some embodiments, the GCase-associated disease is Gaucher’s disease.

[0256] In some embodiments, the GCase-associated disease is DLB.

[0257] In some embodiments, the GCase-associated disease is AD.

[0258] In some embodiments, the GCase-associated disease is ALS.

[0259] In some embodiments, the GCase-associated disease is HD.

[0260] In some embodiments, the GCase-associated disease is MCI.

[0261] In some embodiments, the GCase-associated disease is FTDP-17.

[0262] In some embodiments, the GCase-associated disease is Pick’s disease.

[0263] In some embodiments, the GCase-associated disease is Corticobasal degeneration.

[0264] In some embodiments, the GCase-associated disease is Niemann-Pick disease.

[0265] In some embodiments, the GCase-associated disease is PSP.

[0266] In some embodiments, the GCase-associated disease is Fabry disease.

[0267] In some embodiments, the GCase-associated disease is Krabbe disease.

[0268] In some embodiments, the GCase-associated disease is Metachromatic leukodystrophy.

[0269] In some embodiments, the GCase-associated disease is Sandhoff disease.

[0270] In some embodiments, the GCase-associated disease is Tay-Sachs disease.

[0271] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a dysregulation of a GBA1 gene, a GCase protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I) or Formula (T-I)), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a GBA1 gene, a GCase protein, or activity of any of the same.

[0272] Some embodiments provide a method of increasing GCase activity in a cell comprising a GCase protein, the method comprising contacting the cell with a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof.

[0273] Some embodiments provide a method of stabilizing GCase protein conformation, the method comprising contacting the GCase protein with a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof. In some embodiments, the GCase protein is misfolded prior to the contacting. In some embodiments, the GCase protein is misfolded prior to the contacting and is in its native conformation after the contacting.

[0274] Some embodiments provide a method of reducing the level of GluCer and / or GluSph in a cell comprising GluCer and / or GluSph, the method comprising contacting the cell with a compound disclosed herein (e.g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound disclosed herein (e g., a compound of Formula (I) or Formula (I-I)), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant GCase function. In some embodiments, the cell is a neural cell.

[0276] As used herein, the term “contacting” refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system. For example, “contacting” a GCase protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a GCase protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the GCase protein.

[0277] EMBODIMENTS

[0278] 1. A compound of Formula (I-I) or a pharmaceutically acceptable salt thereof, wherein: one of Y and Z is N and the other of Y and Z is CR1;

[0279] R1is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0280] R2is C1-C6 haloalkoxy, benzyl oxy, or -NR2AR2B;

[0281] R2Aand R2Bare independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; or R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;

[0282] R3is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, or an optionally substituted 6-12 membered heteroaryl;

[0283] X is N or CRX; and

[0284] Rx, R4, and R5are independently hydrogen, C1-C6 alkyl, or halogen.

[0285] 2. The compound of embodiment 1, wherein R1is C1-C6 alkyl.

[0286] 3. The compound of embodiment 1, wherein R1is C3-C10 cycloalkyl.

[0287] 4. The compound of embodiment 1, wherein R1is hydrogen.

[0288] 5. The compound of any one of embodiments 1-4, wherein Y is N and Z is CR1.

[0289] 6. The compound of any one of embodiments 1-4, wherein Y is CR1and Z is N. 7. The compound of any one of embodiments 1-6, wherein R2is C1 -C6 haloalkoxy.

[0290] 8. The compound of any one of embodiments 1-7, wherein R2is C1-C3 haloalkoxy.

[0291] 9. The compound of any one of embodiments 1-6, wherein R2is benzyloxy.

[0292] 10. The compound of any one of embodiments 1-6, wherein R2is -NR2AR2B.

[0293] 11. The compound of any one of embodiments 1-6 and 10, wherein R2Aand R2Bare independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted 1- 3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

[0294] 12. The compound of any one of embodiments 1-6 and 10-11, wherein R2Aand R2Bare both hydrogen.

[0295] 13. The compound of any one of embodiments 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 alkyl.

[0296] 14. The compound of any one of embodiments 1-6, 10-11, and 13, wherein one of R2Aand R2Bis hydrogen and the other one .

[0297] 15. The compound of any one of embodiments 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 haloalkyl.

[0298] 16. The compound of any one of embodiments 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis a 4-10 membered heterocyclyl optionally substituted 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl. 17. The compound of any one of embodiments 1-6 and 10-11, wherein each R2Aand

[0299] R2Bis independently selected C1-C6 alkyl.

[0300] 18. The compound of any one of embodiments 1-6 and 10, wherein R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

[0301] 19. The compound of any one of embodiments 1-18, wherein R3is an optionally substituted 6-12 membered aryl.

[0302] 20. The compound of any one of embodiments 1-18, wherein R3is an optionally substituted 6-12 membered heterocyclyl.

[0303] 21. The compound of any one of embodiments 1-18, wherein R3is an optionally substituted 6-12 membered heteroaryl.

[0304] 22. The compound of any one of embodiments 1-18 and 21, wherein R3is an optionally substituted 9-10 membered heteroaryl.

[0305] 23. The compound of any one of embodiments 1-18, 21, and 22, wherein R3is an optionally substituted 9-10 membered heteroaryl selected from the group consisting of wherein indicates hydrogen or an optional substituent.

[0306] 24. The compound of any one of embodiments 1-23, wherein X is CRX.

[0307] 25. The compound of any one of embodiments 1-24, wherein Rxis hydrogen. 26. The compound of any one of embodiments 1-24, wherein Rxis C1-C6 alkyl.

[0308] 27. The compound of any one of embodiments 1-24, wherein Rxis halogen.

[0309] 28. The compound of any one of embodiments 1-23, wherein X is N.

[0310] 29. The compound of any one of embodiments 1-28, wherein R4is hydrogen.

[0311] 30. The compound of any one of embodiments 1-28, wherein R4is C1-C6 alkyl.

[0312] 31. The compound of any one of embodiments 1-28, wherein R4is halogen.

[0313] 32. The compound of any one of embodiments 1-31, wherein R?is hydrogen.

[0314] 33. The compound of any one of embodiments 1-31, wherein R5is C1-C6 alkyl.

[0315] 34. The compound of any one of embodiments 1-47, wherein R5is halogen.

[0316] 35. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in Table A, or a pharmaceutically acceptable salt thereof.

[0317] 36. A pharmaceutical composition comprising a compound of any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0318] 37. A method of treating a GCase-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 36.

[0319] 38. The method of embodiment 37, wherein the GCase-associated disease is a lysosomal storage disorder or a neurodegenerative disorder. EXAMPLES

[0320] Compound Preparation

[0321] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.

[0322] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0323] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0324] The starting materials used for the synthesis were synthesized according to known literature procedures or obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like.

[0325] Normal phase chromatography and reverse phase chromatography were performed on a CombiFlash Companion automated flash chromatography system, using either RediSep® Silver (230-400 mesh, 40-63 pm irregular) or Silicycle, SiliaSep Cl 8 (230-400 mesh, 40-63 pm irregular) pre-packed silica cartridges respectively. RP flash chromatography was performed using basic modifier (C18, 0 - 100% MeCN in 0.1% aq. ammonia) except where acidic modifier (C18, 0 - 100% MeCN with 0.1% HCO2H in 0.1% aq. HCO2H) was used.

[0326] Analytical LC-MS and UPLC-MS experiments were carried out as described in the tables below.

[0327] Method A - LCMS Acidic Method NMR spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million (8 ppm). NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe™. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Standard abbreviations and acronyms as defined in Journal of Organic Chemistry’s

[0328] Author’s Guideline, and in Hans Reich's Collection. Organic Acronyms are used herein. Other abbreviations and acronyms used herein are as follows:

[0329]

[0330] General Synthetic Routes

[0331] The compounds described herein may be prepared by direct Suzuki coupling (Route A) with a boronic acid or ester (II) and a Q-functionalized moiety (I), where Q is a halogen or other moiety that enables oxidative addition to Pd, e.g., -OSO2CF3. The coupling is generally done at elevated temperatures in the presence of base and Pd catalyst.

[0332] Route A:

[0333] II 70 °C

[0334] Alternatively, the boronic acid or ester may be prepared in-situ (Route B) by reacting a Q- functionalized moiety, e g. I, wherein Q is a halogen or other moiety that enables oxidative addition to Pd, e.g., -OSO2CF3 in the presence of base, Pd catalyst, and a boronation source, e.g., B2(Neop)2 or B2Pin2to give the boronic ester, which is then coupled (typically without isolation) with a second Q’ -functionalized moety, I or II, wherein Q’ is a halogen or other moiety that enables oxidative addition to Pd, e.g., -OSO2CF3, in the presence of base and additional Pd catalyst.

[0335] Route B: B2pin2Pd(dppf)CI2 Pd(dppf)CI2CH2CI2

[0336] II 1 ,4-Dioxane Water

[0337] 60-70 °C

[0338] Example 1. Synthesis of 5-(3-benzyloxyquinoxalin-5-yl)-lW-quinolin-2-one (Compound 2) Prepared using synthetic route A: To a stirred suspension of 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-quinolin-2-one (116 mg, 0.43 mmol), K2CO3 (98 mg, 0.71 mmol), 2- benzyloxy-8-bromo-quinoxaline (132 mg, 0.36 mmol), MeCN (3 m ) and water (0.3 mL) was added Pd(dtbpf)Ch (23 mg, 0.04 mmol) and the reaction heated to 70 °C for 3h. The reaction was cooled to RT, diluted with DCM:MeOH and filtered through Celite. The filtrate was passed through a phase separator and concentrated in vacuo. The residue was purified by acidic prep HPLC to afford the title compound (28 mg, 0.073 mmol, 21% yield) as an off-white solid.

[0339] LCMS (ESI) [M+H]+m / z: calc, for C24H17N3O2: 380.1, found: 380.1.

[0340] 1HNMR (400 MHz, DMSO) 5 11.87 (s, 1H), 8.63 (s, 1H), 8.16 - 8.07 (m, 1H), 7.80 - 7.71 (m, 2H), 7.68 - 7.60 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.18 - 7.09 (m, 3H), 7.04 - 6.97 (m, 2H), 6.33 (dd, J = 9.8, 1.5 Hz, 1H), 5.11 - 4.94 (m, 2H).

[0341] Example 2. Synthesis of / V-Zc 7-butyl-8-pyrazolo[ l ,5-a]pyridin-4-yl-qiiinoxalin-2-arnine (Compound 5)

[0342] Prepared using synthetic route B: To a stirred suspension of 4-bromopyrazolo[l,5- a]pyridine (50 mg, 0.25 mmol), bis(pinacolato)diboron (97 mg, 0.38 mmol) and KO Ac (50 mg, 0.51 mmol) in 1,4-dioxane (2.5 mL) was added Pd(dppf 2Ch (19 mg, 0.025 mmol) and the reaction heated to 70 °C for 2 h. The reaction was cooled to RT, 8-bromo-A-ter / -butyl-quinoxalin-2-amine (71 mg, 0.25 mmol) and K2CO3 (70 mg, 0.51 mmol), water (0.25 mL) and Pd(dppf)C12.CH2C12 (17 mg, 0.03 mmol) were added and the reaction mixture heated to 60 °C for 3h. The reaction mixture was diluted with DCM / MeOH and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by basic prep HPLC to afford the title compound (5 mg, 0.015 mmol, 6% yield) as a brown solid.

[0343] LCMS (ESI) [M+H]+m / z: calc, for C19H19N5: 318.2, found: 318.3

[0344] 'H NMR (500 MHz, DMSO) 8 8.69 (d, J = 7.0 Hz, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.29 - 7.23 (m, 2H), 7.01 - 6.94 (m, 1H), 6.17 (s, 1H), 1.11 (s, 9H). The compound shown in Table 1 were prepared analogously to compounds 2 and 5 using the indicated route.

[0345] Table 1. Exemplary compounds, analytical data, and synthetic route Assays

[0346] Live cell GCase activity assay

[0347] Compounds are evaluated for they ability to increase GCase activation in a live cell assay reporting on enzyme activation in lysosomal compartment of an H4 Human Neurogliama cell line. Cells are seeded onto 96 well plates at 15,000 cells per well. One day latter, cells are treated with either compound or DMSO and treated with PFB-FDGlu (5-(Pentafluorobenzoylamino) Fluorecein Di-B-D-Glucopyranoside) substrate at a final concertation of 50uM and incubated overnight at 37C, 5%CO2. After incubation, cells are washed twice with PBS and lysed in lx RIPA buffer. In the endpoint mode, fluorescent signal (EX / EM: 485 / 520 nm) is measured with PheraStar reader. Data are normalized with total protein concentation. The resulting GCase cellular activity in units of AC200 (pM) and AC 150 (pM) are shown in Table 2. AC200 refers to the concentration which doubles GCase activity.

[0348] AC200 (pM) potency: A is <1.0; B <1<5; and C is 5<

[0349] AC150 (pM) potency: A is <0.5; B <0.5<3; and C is 3< Table 2. Biological activity

Claims

1. WHAT IS CLAIMED IS:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: one of Y and Z is N and the other of Y and Z is CR1;X1is N or CRX;X2is N or CR4;R1is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;R2is C1-C6 haloalkoxy, benzyl oxy, or -NR2AR2B;R2Aand R2Bare each independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl; or R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;R3is an optionally substituted 6-12 membered aryl, an optionally substituted 6-12 membered heterocyclyl, an optionally substituted 6-12 membered heteroaryl, or -NR3AR3B; each of R3Aand R3Bis independently selected from(i) hydrogen;(ii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and cyano;(iii) C1-C6 haloalkyl;(iv) 5-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 4-6 membered heterocyclyl;(v) 5-6 membered heteroaryl optionally substituted with 1 -3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; and(vi) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; andRx, R4, and R5are each independently hydrogen, C 1-C6 alkyl, cyano, hydroxyl, or halogen; wherein when Y is CR1, Z is N, X1is CRX, and X2is CR4, then R3is not an optionally substituted l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, optionally substituted 5', 6'- dihydrospiro[cyclopropane-l,7'-pyrrolo[3,2-c]pyridin]-4'(l'H)-one, optionally substituted 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one, optionally substituted pyrrole, optionally substituted l,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, optionally substituted 3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrol-4(lH)-one, optionally substituted l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-thione, optionally substituted 1'H- spiro[cyclopropane-l,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted 1, 5,6,7- tetrahydro-4H-indol-4-one, optionally substituted 5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(lH)- one, optionally substituted 5,6-dihydropyrrolo[3,4-b]pyrrole-4(lH)-thione, optionally substituted 6,7-dihydro-lH-pyrrolo[3,2-c]pyridine, optionally substituted 2,3,5, 6-tetrahydro-l'H-spiro[pyran- 4,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one, optionally substituted l,5-dihydro-4H-pyrrolo[2,3- d]pyridazin-4-one, optionally substituted l,2-dihydro-3H-pyrrolo[l,2-c]imidazol-3-one, optionally substituted lH-pyrrolo[l,2-c]imidazole-l,3(2H)-dione, optionally substituted pyrazole, or optionally substituted 6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one.

2. The compound of claim 1, wherein R1is C1-C6 alkyl.

3. The compound of claim 1, wherein R1is C3-C10 cycloalkyl.

4. The compound of claim 1, wherein R1is hydrogen.

5. The compound of any one of claims 1-4, wherein Y is N and Z is CR1.

6. The compound of any one of claims 1 -4, wherein Y is CR1and Z is N.

7. The compound of any one of claims 1-6, wherein R2is C1-C6 haloalkoxy.

8. The compound of any one of claims 1-7, wherein R2is C1-C3 haloalkoxy.

9. The compound of any one of claims 1-6, wherein R2is benzyloxy.

10. The compound of any one of claims 1-6, wherein R2is -NR2AR2B.

11. The compound of any one of claims 1-6 and 10, wherein R2Aand R2Bare independently hydrogen, C1-C6 alkyl, or a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

12. The compound of any one of claims 1-6 and 10-11, wherein R2Aand R2Bare both hydrogen.

13. The compound of any one of claims 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 alkyl.

14. The compound of any one of claims 1-6, 10-11, and 13, wherein one of R2Aand R2Bis hydrogen and the other one15. The compound of any one of claims 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis C1-C6 haloalkyl.

16. The compound of any one of claims 1-6 and 10-11, wherein one of R2Aand R2Bis hydrogen and the other one of R2Aand R2Bis a 4-10 membered heterocyclyl optionally substitutedwith 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

17. The compound of any one of claims 1-6 and 10-11, wherein each R2Aand R2Bis independently selected C1-C6 alkyl.

18. The compound of any one of claims 1-6 and 10, wherein R2Aand R2Btogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl.

19. The compound of any one of claims 1-18, wherein R3is an optionally substituted 6-12 membered aryl.

20. The compound of any one of claims 1-18, wherein R3is an optionally substituted 6-12 membered heterocyclyl.

21. The compound of any one of claims 1-18, wherein R3is an optionally substituted 6-12 membered heteroaryl.

22. The compound of any one of claims 1-18 and 21, wherein R3is an optionally substituted 9-10 membered heteroaryl.

23. The compound of any one of claims 1-18, 21, and 22, wherein R3is an optionally substituted 9-10 membered heteroaryl selected from the group consisting of24. The compound of any one of claims 1-23, wherein R3is -NR3AR3B.

25. The compound of any one of claims 1-24, wherein one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C 1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and cyano.

26. The compound of any one of claims 1 -24, wherein one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C1-C6 haloalkyl.

27. The compound of any one of claims 1-24, wherein one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 4-6 membered heterocyclyl.

28. The compound of any one of claims 1-24, wherein one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

29. The compound of any one of claims 1-24, wherein one of R3Aand R3Bis hydrogen and the other one of R3Aand R3Bis C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

30. The compound of any one of claims 1-29, wherein X is CRX.

31. The compound of any one of claims 1-29, wherein Rxis hydrogen.

32. The compound of any one of claims 1-29, wherein Rxis C1-C6 alkyl.

33. The compound of any one of claims 1-29, wherein Rxis halogen.

34. The compound of any one of claims 1-29, wherein Rxis hydroxyl.

35. The compound of any one of claims 1-29, wherein Rxis cyano.

36. The compound of any one of claims 1-29, wherein X is N.

37. The compound of any one of claims 1-36, wherein R4is hydrogen.

38. The compound of any one of claims 1-36, wherein R4is C1-C6 alkyl.

39. The compound of any one of claims 1-36, wherein R4is halogen.

40. The compound of any one of claims 1-36, wherein R4is hydroxyl.

41. The compound of any one of claims 1-36, wherein R4is cyano.

42. The compound of any one of claims 1-41, wherein R3is hydrogen.

43. The compound of any one of claims 1-41, wherein R3is C1-C6 alkyl.

44. The compound of any one of claims 1-41, wherein R5is halogen.

45. The compound of any one of claims 1-41, wherein R5is hydroxyl.

46. The compound of any one of claims 1-41, wherein R5is cyano.

47. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in Table A, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

49. A method of treating a GCase-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the GCase-associated disease is a lysosomal storage disorder or a neurodegenerative disorder.

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