CN119907800A

CN119907800A - Hexahydro-2H-pyrido[2,1-a]isoquinoline VMAT2 inhibitors and methods of use thereof

Info

Publication number: CN119907800A
Application number: CN202380067647.3A
Authority: CN
Inventors: 拜伦·A·布恩; 尼古拉斯·帕加诺; 尼科尔·哈里奥特; 顾洁予; 薛一斌
Original assignee: Neurocrine Biosciences Inc
Current assignee: Neurocrine Biosciences Inc
Priority date: 2022-09-21
Filing date: 2023-09-20
Publication date: 2025-04-29
Also published as: CL2025000826A1; TW202421131A; MX2025003264A; IL319670A; CR20250139A; EP4590676A1; CO2025004869A2; DOP2025000071A; CA3267926A1; WO2024064178A1; JP2025531352A; PE20251750A1; KR20250083502A; AU2023347329A1

Abstract

The present disclosure relates, inter alia, to certain compounds, compositions, and pharmaceutical compositions thereof that modulate the activity of transporter-vesicle monoamine transporter-2 (VMAT 2), and to methods for treating transporter-vesicle monoamine transporter-2 mediated disorders such as neurological or psychiatric diseases or disorders including, but not limited to, hyperkinesia (e.g., tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea (such as chorea associated with huntington's disease), dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors. The disclosure also relates to synthetic methods and intermediates for preparing the compounds.

Description

Hexahydro-2H-pyrido [2,1-a ] isoquinoline VMAT2 inhibitors and methods of use thereof

Technical Field

The present disclosure relates, inter alia, to certain compounds, compositions, and pharmaceutical compositions thereof that modulate the activity of transporter-vesicle monoamine transporter-2 (VMAT 2), and to methods for treating transporter-vesicle monoamine transporter-2 mediated disorders such as neurological or psychiatric diseases or disorders including, but not limited to, hyperkinesia (e.g., tardive dyskinesia, tourette's syndrome, huntington's disease, tics, ataxia, chorea (such as chorea associated with Huntington's disease), dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors.

Description of the Related Art

Disorders of the dopaminergic system are an integral part of several Central Nervous System (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinesias, and conditions such as schizophrenia and mood disorders. Transporton protein vesicle monoamine transporter-2 (VMAT 2) plays an important role in presynaptic dopamine release and regulates monoamine uptake from the cytoplasm to the synaptic vesicles for storage and release.

For decades, (±) -tetrabenazine ((±) -TBZ) has been used as a medicament. (+ -.) -TBZ is reported to be a potent reversible inhibitor of VMAT2 uptake of catecholamines (IC ₅₀ = 3.2 nM) (see, e.g., scherman et al, proc. Natl. Acad. Sci. USA, (1983) 80:584-8) and is currently used to treat a variety of hyperactivity disorders. Inhibition of VMAT2 by (+ -) -TBZ results in consumption of brain monoamine in vivo (see, e.g., pettibone et al, eur. J. Pharmacol. (1984) 102:431-6). (+ -.) -TBZ also inhibits presynaptic and postsynaptic dopamine receptors in rat brain (see, e.g., login et al, (1982) Ann. Neurology 12:257-62; reches et al, J. Pharmacol. Exp. Ther. (1983) 225:515-521). After oral administration to humans, (±) -TBZ exhibits extensive first pass metabolism, with little or no (±) -TBZ observed in the systemic circulation. Thus, it is believed that the pharmacological activity of (+ -) -TBZ is mediated primarily by the active metabolite. (±) -TBZ has two chiral centers and is a racemic mixture of two stereoisomers. It has been determined that (±) -TBZ is rapidly and widely metabolized in vivo by carbonyl reductase to four metabolic stereoisomers of 3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (also known as Dihydrotetrabenazine (DHTBZ)). The inhibition constants of these four metabolites for VMAT2 have been reported in example 7, such as WO 2008/058261. As shown, only two of the four DHTBZ isomers ([ + ] -alpha-DHTBZ and [ + ] -beta-DHTBZ) showed significant efficacy as VMAT2 inhibitors.

(±) -TBZ metabolite	pK_i	K_i
			[+]-α-DHTBZ(2R,3R,11bR)	8.7±0.2(n=6)	1.9nM
[+]-β-DHTBZ(2S,3R,11bR)	7.9±0.1(n=5)	13nM
			[-]-α-DHTBZ(2S,3S,11bS)	6.7±0.1(n=3)	202nM
[-]-β-DHTBZ(2R,3S,11bS)	6.1±0.1(n=4)	714nM

In patients administered (+ -) -TBZ, [ - ] - α -DHTBZ (2S, 3S,11 bS-DHTBZ) and [ + ] - β -DHTBZ (2S, 3R,11 bR-DHTBZ) are the most abundant DHTBZ isomers, while [ - ] - β -DHTBZ (2R, 3S,11 bS-DHTBZ) and [ + ] - α -DHTBZ (2R, 3R,11 bR-DHTBZ) are present as minor metabolites. The [ + ] -alpha-DHTBZ (2R, 3R,11 bR-DHTBZ) isomer is determined to be present in the smallest amount of all four isomers. Thus, [ + ] - β -DHTBZ (2S, 3R,11 bR-DHTBZ) appears to be the major DHTBZ isomer contributing to the pharmacological activity of (+ -) -TBZ. After formation, the half-life of [ (+ ] - β -DHTBZ (2S, 3R,11 bR-DHTBZ) is relatively short (about 5 hours), which requires a sub-optimal (TID) dosing regimen for (+ -) -TBZ.

(±) -TBZ has a narrow therapeutic window and its clinical use requires careful dose titration. Side effects associated with (+ -) -TBZ and/or its metabolites include mental retardation malignant syndrome, somnolence, fatigue, stress, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia and parkinson's disease. In general, the probability of observing side effects is a function of the plasma concentration achieved from a given dosing regimen. Given equal dosing intervals, compounds with longer half-lives (t _1/2) and lower clearance will have lower peak-to-valley fluctuations in plasma exposure. These longer half-life compounds may exhibit improved tolerability by maintaining the drug concentration at the level required for efficacy but below the level that may cause side effects.

A basic and effective strategy to improve drug half-life is to reduce clearance. The term clearance describes the process by which a drug is eliminated from the body or from a single organ, defined as the volume of fluid per unit time that the drug is cleared from the body. Clearance is a fundamental pharmacokinetic parameter and is typically measured in drug research and development, as this parameter affects drug properties, such as half-life, and ultimately the dosing regimen. Benefits of small plasma-concentration fluctuations seen in compounds with low clearance when optimizing the compound and dose selection include potentially reduced steady state peak concentrations, increased trough concentrations, and the prospect of improved drug compliance due to potentially improved risk-benefit characteristics.

Despite advances in the art, there remains a need in the art for improved VMAT2 inhibitors, including compounds, compositions, and methods related thereto. The identification of long half-life/low clearance VMAT2 small molecule inhibitors is advantageous for drug development, particularly when developed for long term administration. In certain disease populations where patient compliance and tablet burden are persistent challenges, reducing dosing frequency is highly desirable and provides increased patient benefit.

The present disclosure meets these benefits, such as improved in vitro VMAT2 efficacy or improved pharmacokinetics or both, as well as other needs, as will be apparent with reference to the following disclosure.

Disclosure of Invention

One aspect of the present disclosure encompasses, inter alia, compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl, C ₅-C₁₁ -spirocycloalkyl, cubic alkyl-C ₁-C₄ -alkylene, and 4-8 membered heterobicycloyl-C ₁-C₄ -alkylene;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy and C ₂-C₄ -dialkylamino.

Also provided herein are pharmaceutical products selected from the group consisting of pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound as described herein or a pharmaceutically acceptable salt thereof.

Also provided herein are pharmaceutical products selected from the group consisting of pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Also provided herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Also provided herein are methods for preparing a pharmaceutical composition comprising the step of mixing a compound as described herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

Also provided herein are methods of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein.

Also provided herein are methods of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder in a subject in need thereof, comprising administering to said subject a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein said VMAT2 disease or disorder is selected from ataxia or spinal muscular atrophy, chorea, congenital malformations, deformations or abnormalities, dementia, oral, salivary gland or jaw diseases, dyskinesia, dystonia, endocrine, nutritional or metabolic diseases, epilepsy, habit or impulse disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative diseases of the basal ganglia, extrapyramidal and movement disorders, neurological or psychiatric diseases or disorders, neurological or movement dysfunction, parkinson's/parkinsonism, childhood behavioral and childhood disorders, pervasive developmental disorders, and substance abuse or dependency disorders.

Also provided herein are methods of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as described herein, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein.

Also provided herein are methods of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as described herein, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-related tremor ataxia syndrome, autism spectrum disorders, rate syndrome, and chorea-acanthocytosis.

Also provided herein are methods of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as described herein, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the neurological or psychiatric disease or disorder is hyperkinesia.

Also provided herein are methods of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea associated with huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors.

Also provided herein are methods of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the hyperkinesia is tardive dyskinesia.

Also provided herein are methods of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the hyperkinesia is huntington's disease.

Also provided herein are methods of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the hyperkinesia is chorea associated with huntington's disease.

Also provided herein are methods of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as described herein, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the methods comprise using the compounds, salts, products, or compositions in adjuvant therapy.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a vesicle monoamine transporter-2 (VMAT 2) disease or disorder.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a vesicle monoamine transporter-2 (VMAT 2) disease or disorder selected from ataxia or spinal muscular atrophy, chorea, congenital malformations, deformations or abnormalities, dementia, oral, salivary gland or jaw diseases, movement disorders, dystonia, endocrine, nutritional or metabolic diseases, epilepsy, habitual or impulsive disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative disorders of the basal ganglia, extrapyramidal and movement disorders, neurological or psychiatric diseases or disorders, neurological or movement dysfunction, parkinson's/parkinsonism, childhood onset behavioral and mood disorders, extensive developmental disorders, and substance abuse or dependency disorders.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder.

Also provided herein is a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or the use of a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinesias, schizophrenia, schizoaffective disorders, mood disorders, treatment of refractory obsessive compulsive disorder, neurological disorders associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X related ataxia syndrome, autism spectrum disorders, rate syndrome and chorea-acanthocytosis.

Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of hyperkinesia.

Also provided herein is a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or the use of a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of hyperkinesia, wherein the hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea associated with huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of tardive dyskinesia.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of huntington's disease.

Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of chorea associated with huntington's disease.

Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical product as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the treatment comprises using the compound, salt, product, or composition in adjuvant therapy.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating the human or animal body by therapy.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder selected from ataxia or spinal muscular atrophy, chorea, congenital malformations, deformities or abnormalities, dementia, oral, salivary gland or jaw diseases, movement disorders, dystonia, endocrine, nutritional or metabolic diseases, epilepsy, habitual or impulsive disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative diseases of the basal ganglia, extrapyramidal and movement disorders, neurological or psychiatric diseases or disorders, neurological or movement dysfunction, parkinson's/parkinsonism, childhood onset behavioural and emotional disorders, pervasive developmental disorders, and substance abuse or dependency disorders.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a neurological or psychiatric disease or disorder.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-related tremor-ataxia syndrome, autism spectrum disorders, lett's syndrome and chorea-acanthocytosis.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating hyperkinesia.

Also provided herein are compounds as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating hyperkinesia, wherein the hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea associated with huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremor.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating tardive dyskinesia.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating huntington's disease.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating chorea associated with huntington's disease.

Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a neurological or psychiatric disease or disorder selected from the group consisting of schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the method for treatment comprises using the compound, salt, product, or composition in adjuvant therapy.

These and other aspects of the invention disclosed herein will be described in more detail as this patent disclosure proceeds.

Drawings

FIG. 1A shows a general synthetic scheme for preparing certain compounds of formula (Ia) and intermediates related thereto, wherein R ¹ is methyl. In this representative example, R ¹ is methyl and is incorporated into compounds 2-3.

FIG. 1B shows a general synthetic scheme for preparing certain compounds of formula (Ia) and intermediates related thereto, wherein R ¹ is methyl. In this representative example, compounds (i.e., compound 15, compound 76, compound 77, and compound 78) were isolated by Supercritical Fluid Chromatography (SFC) as described in example 1.

FIG. 2A shows a general synthetic scheme for the preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22) using the resolution steps of intermediate (. + -.) -1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one (compound 2-17) and (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.) -2-19) with (2S, 3S) -2, 3-bis (4-methylbenzyloxy) butanedioic acid (DPTTA) to provide (2R, 11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.)) to provide (2R, 11 b) -9- (tert-butoxy) -3-methoxy-propan-1-2-one, and (compound).

FIG. 2B shows a general synthetic scheme for the preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22) using the intermediates 1- (tert-butoxy) propan-2-one (compound 2-25) and 3- (tert-butoxy) -4- (dimethylamino) butan-2-one (compound 2-26) to give (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (+ -) -2-18) which is subsequently reduced to give (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinol-2-one (compound 19). The resolution step using compound (±) -2-19 with (2 s,3 s) -2, 3-bis (4-methylbenzyloxy) succinic acid (DPTTA) to afford (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21) which is then deprotected to afford compound 2-22.

FIG. 3 shows a general synthetic scheme for the preparation of compounds of formula (Ia) using 3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol and a different alkylating agent, wherein R ¹ has the same meaning as described herein, LG ¹ is a leaving group and R ^3a may be H or C ₁-C₄ -alkyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, C ₁-C₄ -alkoxy and C ₂-C₄ -dialkylamino. It is understood that LG ¹ can be a variety of leaving groups, such as those described herein and those known in the art.

FIG. 4 shows a general synthetic scheme for the preparation of a compound of formula (Ie) wherein R ¹ has the same meaning as described herein, LG ¹ is a leaving group and R ^3a may be H or C ₁-C₄ -alkyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, C ₁-C₄ -alkoxy and C ₂-C₄ -dialkylamino using (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22) and a different alkylating agent. It is understood that LG ¹ can be a variety of leaving groups, such as those described herein and those known in the art.

FIG. 5 shows in vivo pharmacology of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 18 and (2R, 3R,11 bR) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 22 in Sprague Dawley rats in the open field low motion model described in example 15.

Detailed Description

Definition of the definition

For clarity and consistency, the following definitions will be used in this patent document.

As used herein, "about" means ± 20% of the value, and more specifically includes values of ± 10%, ± 5%, ± 2%, and ± 1% of the value.

The terms "adjuvant therapy," "co-therapy," "combination therapy," and "combination therapy" as used herein refer to the treatment of a patient in need thereof by administering a compound (as described herein) in combination with one or more drugs, wherein administration is by any suitable means, such as simultaneously, sequentially, separately, or in a single pharmaceutical formulation.

The terms "Administration (ADMINISTERING)" and "administration" as used herein refer to providing a subject with a compound described herein or other therapy in a form that can be introduced into the subject in a therapeutically useful form and in a therapeutically useful amount, including, but not limited to, oral dosage forms such as tablets, capsules, syrups, suspensions, and the like, injectable dosage forms such as Intravenous (IV), intramuscular (IM), subcutaneous (SC), and the like, transdermal dosage forms including creams, gels, powders and patches, buccal dosage forms, inhalation powders, sprays, suspensions, and the like, and rectal dosage forms such as suppositories.

The health care practitioner may provide the compound described herein directly to the individual in the form of a sample, or may provide the compound indirectly to the individual by providing an oral or written prescription for the compound. Furthermore, for example, an individual may obtain a compound by himself without the involvement of a health care practitioner. When a compound is administered to an individual, the body is somehow transformed by the compound. When a compound as described herein is provided in combination with one or more other agents, "administration" and "administration" are understood to include the compound and at least one other agent is administered at the same time or at a different time. When the combined agents are administered simultaneously, they may be administered together in a single composition, or they may be administered separately. The preferred method of administration may vary depending on various factors, such as the composition of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

The term "composition" refers to a compound or crystalline form thereof, including but not limited to salts, solvates and hydrates of the compounds described herein, in combination with at least one additional component, such as a composition obtained/prepared during synthesis, pre-formulation, in-process testing (e.g., TLC, HPLC, NMR samples), etc.

The term "compound" as used herein refers to all stereoisomers, geometric isomers, tautomers and isotopic variations of the structures described herein. The term also means a compound described herein prepared in any manner, e.g., synthetically, by biological processes (e.g., metabolic or enzymatic transformations), or combinations thereof. All compounds and pharmaceutically acceptable salts thereof can be found (e.g., hydrates and solvates) or can be isolated, along with other materials such as water and solvents. When in the solid state, the compounds described herein and salts thereof may exist in various forms and may, for example, be presented as co-crystals or solvates (including hydrates). The compounds may be in any solid state form, such as polymorphs or solvates, and thus reference to a compound and salts thereof in this specification is to be understood as encompassing any solid state form of the compound unless explicitly indicated otherwise. In some embodiments, a compound described herein, or a salt thereof, is substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial isolation may include, for example, a composition enriched in the compounds described herein. Substantial isolation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein or a salt thereof.

The term "solvate" as used herein refers to a compound as described herein or a pharmaceutically acceptable salt thereof that includes a stoichiometric or non-stoichiometric amount of a solvent that binds by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

The term "hydrate" as used herein refers to a compound as described herein or a pharmaceutically acceptable salt thereof that further includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

The terms "in need of treatment" and "in need of treatment" are used interchangeably as referring to treatment and refer to the judgment made by a caregiver (e.g., physician, nurse, practitioner, etc. in the case of humans) that an individual or animal in the case of animals (including non-human mammals) is in need of treatment or will benefit from treatment. In addition to including knowledge that an individual or animal is ill or will be ill due to a disease, condition, or disorder that can be treated by the compounds described herein, such judgment is made based on a variety of factors that are within the expertise of the care giver. Thus, the compounds described herein may be used in a protective or prophylactic manner, or the compounds described herein may be used to alleviate, inhibit or mitigate a disease, condition or disorder.

The term "individual" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In the context of a clinical trial or screening or activity trial, an individual may be a healthy volunteer or healthy participant without a potential VMAT 2-mediated disorder or condition, or a volunteer or participant who has received a diagnosis of a disorder or condition for which medical treatment is indicated as judged by a healthcare professional. In situations outside of clinical trials, individuals who have received diagnosis of a disorder or condition under the care of a healthcare professional are often described as individuals.

The term "pediatric subject" refers to a subject under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (first month of birth to life), infants (1 month to two years), children (2 years to 12 years), and teenagers (12 years to 21 years (up to but excluding the twenty-second birthday)), see, for example, berhman et al, textbook of Pediatrics, 15 th edition Philadelphia: W.B. Saunders Company,1996; rudolph et al, rudolph' S PEDIATRICS, 21 st New York: mcGraw-Hill,2002, and Avery et al, PEDIATRIC MEDICINE, 2 nd edition Baltimore: williams & Wilkins;1994.

The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutical composition" refers to a particular composition comprising at least one active ingredient, including but not limited to salts, solvates and hydrates of the compounds described herein, whereby a particular effective outcome of the composition in a mammal (e.g., without limitation, a human) can be studied. Those of ordinary skill in the art will understand and appreciate techniques suitable for determining whether an active ingredient has a desired effective result based on the needs of the skilled artisan.

The terms "prevention", "prevention" and "prophylaxis" refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder. For example, the terms "prevention", "prevention" and "prevention" may refer to administration of therapy to an individual who may ultimately exhibit at least one symptom of a disorder, but not yet so, on a prophylactic or preventative basis. Such individuals may be identified based on risk factors known to be associated with subsequent occurrence of the disease, such as the presence of biomarkers. Alternatively, the prophylactic treatment may be administered as a prophylactic measure without the need to pre-identify risk factors. Delaying the onset of at least one occurrence and/or symptom of a disorder may also be considered to be prevention or control. In some embodiments, the subject may be a pediatric subject.

The terms "treatment", "treatment" and "treatment" refer to the medical management of a disease, disorder or condition in an individual (e.g., an individual) (see, e.g., stedman' sMedical Dictionary). Generally, the appropriate dosage and treatment regimen provides an amount of VMAT2 inhibitor sufficient to provide a therapeutic benefit. Therapeutic benefits for individuals administered VMAT2 inhibitor compounds described herein include, for example, improved clinical outcome, wherein the goal is to prevent or slow down or delay (lessen) an undesired physiological change associated with a disease, or prevent or slow down or delay (lessen) the amplification or severity of such a disease. The effectiveness of one or more VMAT2 inhibitors may include beneficial or desired clinical results including, but not limited to, reducing, alleviating, or alleviating symptoms caused by or associated with the treated disease, reducing the incidence of symptoms, improving quality of life, prolonging the non-pathological state (i.e., reducing the likelihood or propensity that an individual will present with symptoms based on the disease diagnosis made), alleviating the extent of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, ameliorating or alleviating the disease state, and alleviating (whether partially or wholly detectable or undetectable), and/or overall survival. In some embodiments, the subject may be a pediatric subject.

The term "therapeutically effective amount" refers to an amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a subject, researcher, veterinarian, medical doctor, or other clinician or care provider, which may include one or more of the following:

(1) Prevention of a disorder, e.g., prevention of a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who has not experienced or exhibited the associated pathology or symptom;

(2) Inhibiting a disorder, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the associated pathology or symptom (i.e., arresting further development of the pathology and/or symptom), and

(3) Alleviation of a disorder, e.g., alleviation of a disease, a condition, or a disorder of an individual experiencing or exhibiting the associated pathology or symptom (i.e., reversal of pathology and/or symptom).

The term "contacting" refers to the aggregation of the indicated moieties in an in vitro system or in an in vivo system. For example, "contacting" a VMAT2 protein with a compound provided herein includes administering a compound provided herein (or a pharmaceutically acceptable salt thereof) to an individual (such as a human) having a VMAT2 protein, and for example, introducing a compound provided herein into a sample comprising a cell preparation or purified preparation comprising a VMAT2 protein.

Chemical groups

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. Where there are multiple definitions of terms herein, those defined in this section control unless otherwise indicated.

The term "a-member" preceding the name of a group (where "a" is an integer) refers to the number of atoms in the group. For example, oxetanyl contains 4 atoms and is a 4 membered heterocyclyl, 2-oxaspiro [3.3] heptyl is an example of a 7 membered spiroheterocyclyl, and piperidinyl is an example of a 6 membered heterocyclyl ring. Similarly, the term "a-b member" preceding a group name (where "a" and "b" are integers) refers to the inclusive range of atoms in the group. For example, a "3-7 membered heterocyclyl" group refers to all "heterocyclyl" groups having 3 to 7 atoms (i.e., 3, 4, 5, 6, and 7 atoms), wherein "heterocyclyl" is defined herein, and a "4-5 membered heterocyclyl" refers to all "heterocyclyl" groups having 4 to 5 atoms (i.e., 4 and 5 atoms). If "a" and "b" are not specified for a group, the broadest scope described in these definitions is assumed.

For a compound as described herein, or a pharmaceutically acceptable salt thereof, in which a variable occurs more than once, each variable may be a different moiety independently selected from the groups defining the variable. For example, when describing a structure having two R groups, for example, that are both present on the same compound, the two R groups may represent different moieties independently selected from the groups defined for R, or the two R groups may be the same.

Whenever a group is described as "substituted," the group may be substituted with one or more of the specified substituents. Also, when a group is described as "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the specified substituents. It is understood that substitution at a given atom is limited by valence. Furthermore, it is understood that "optionally substituted" means that the group is unsubstituted or substituted.

The term "C _a-C_b" (where "a" and "b" are integers) preceding the name of a group refers to the inclusive range of carbon atoms in the group. For example, "C ₁-C₄ -alkyl" refers to the alkyl groups having 1 to 4 carbons (i.e., 1,2, 3, and 4 carbons), such as methyl (CH ₃ -), ethyl (CH ₃CH₂ -), n-propyl (CH ₃CH₂CH₂ -), isopropyl ((CH ₃)₂ CH-), n-butyl (CH ₃CH₂CH₂CH₂ -), isobutyl ((CH ₃)₂CHCH₂ -), sec-butyl (CH ₃CH₂CH(CH₃) -), and tert-butyl ((CH ₃)₃ C-)) if "a" and "b" are not specified for the groups, then the broadest scope described in these definitions is assumed.

In addition to the foregoing, as used in the specification and claims, the following terms have the indicated meanings unless otherwise indicated.

The terms "C ₁-C₄ -alkylene" and "C ₂-C₄ -alkylene" refer to straight or branched chain saturated aliphatic divalent radicals having a defined number of carbons (1 to 4 carbon atoms or 2 to 4 carbon atoms), respectively. Some embodiments contain 1 to 2 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 carbon atom. Some embodiments contain 2 to 3 carbons. Some embodiments contain 2 carbon atoms. Examples include, but are not limited to, methylene (i.e., -CH ₂ -); ethylene (i.e., -CH ₂CH₂ -and-CH (CH ₃) -); n-propylene, i-propylene, n-butylene, s-butylene, i-butylene and t-butylene. When one or more substituents are present on an "alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, an "alkylene" may be substituted or unsubstituted.

The term "C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene" refers to a group consisting of a "C ₁-C₄ -alkyl" group bonded to an oxygen atom, and the oxygen atom is bonded to a "C ₂-C₄ alkylene" group, where "C ₁-C₄ -alkyl" and "C ₂-C₄ alkylene" have the same definitions as described herein. examples include, but are not limited to, 1-methoxyethyl (i.e., CH ₃-O-CH(CH₃) -), 2-methoxyethyl (i.e., CH ₃-O-CH₂CH₂ -), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, and 3-isopropoxypropyl. In some embodiments, "C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene" refers to a group selected from the group consisting of 2-methoxyethyl (i.e., CH ₃-O-CH₂CH₂ -), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl and 3-isopropoxypropyl. When one or more substituents are present on a "C ₁-C₄ alkyl-O-C ₂-C₄ alkylene" the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene" group may be substituted or unsubstituted.

The term "alkoxy" refers to a group comprising an "alkyl" group directly attached to an oxygen atom, wherein "alkyl" has the same definition as seen herein. Some embodiments contain 1 to 4 carbons (i.e., "C ₁-C₄ -alkoxy"). Some embodiments contain 1 to 3 carbons (i.e., "C ₁-C₃ -alkoxy"). Some embodiments contain 1 or 2 carbons. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "alkyl" refers to a straight or branched hydrocarbon radical that is fully saturated. In some embodiments, the alkyl group may have 1 to 6 carbons (i.e., "C ₁-C₆ -alkyl"). Some embodiments are 1 to 5 carbons (i.e., "C ₁-C₅ -alkyl"), some embodiments are 1 to 4 carbons (i.e., "C ₁-C₄ -alkyl"), some embodiments are 1 to 3 carbons (i.e., "C ₁-C₃ -alkyl"), and some embodiments are 1 or 2 carbons. By way of example only, "C ₁-C₄ -alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [ i.e., -CH (CH ₃)CH₂CH₂CH₃), 2-methylbutyl [ i.e., -CH ₂CH(CH₃)CH₂CH₃ ], and n-hexyl.

The term "alkylsulfonyl" refers to a group consisting of a sulfur bond of an "alkyl" group with a sulfone group of the formula-S (=o) ₂ -, wherein "alkyl" has the same definition as described herein. The "alkylsulfonyl" group may have from 1 to 4 carbon atoms (i.e., "C ₁-C₄ -alkylsulfonyl"). Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl and tert-butylsulfonyl.

The term "amino" refers to the group-NH ₂.

The term "bicycloalkyl" refers to a group comprising two fused or bridged cycloalkyl rings. In some embodiments, a "bicycloalkyl" group contains 4 to 8 ring carbon atoms. In some embodiments, a "bicycloalkyl" group contains 5 to 8 ring carbon atoms. In some embodiments, a "bicycloalkyl" group contains 5 to 7 ring carbon atoms. In some embodiments, a "bicycloalkyl" group contains 5 or 6 ring carbon atoms. Examples include, but are not limited to, bicyclo [1.1.0] butyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] heptyl, and bicyclo [3.2.1] octyl. When one or more substituents are present on a "bicycloalkyl" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "bicycloalkyl" group may be substituted or unsubstituted.

The term "C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene" refers to a group consisting of "C ₄-C₈ -bicycloalkyl" bonded to "C ₁-C₄ -alkylene", wherein "C ₄-C₈ -bicycloalkyl" and "C ₁-C₄ -alkylene" have the same definitions as described herein. Examples include, but are not limited to, (bicyclo [1.1.0] butan-1-yl) methyl (i.e., (bicyclo [1.1.0] butan-1-yl) CH ₂ -), (bicyclo [1.1.1] pentan-1-yl) methyl (i.e., (bicyclo [1.1.1] pentan-1-yl) CH ₂ -), (bicyclo [2.2.1] hexan-1-yl) methyl, (bicyclo [2.2.1] heptan-1-yl) methyl, and (bicyclo [2.2.2] octan-1-yl) methyl. When one or more substituents are present on a "C ₄-C₈ bicycloalkyl-C ₁-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene" group may be substituted or unsubstituted.

The term "4-8 membered heterobicyclic group" refers to a group comprising two fused or bridged rings, said rings comprising a carbon atom and at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen, and when more than one heteroatom is present in the ring, the heteroatoms may be the same or different. In some embodiments, a "4-8 membered heterobicycloyl" is a group selected from the group consisting of 2-oxabicyclo [2.1.1] hex-1-yl and 2-oxabicyclo [2.1.1] hex-4-yl. When one or more substituents are present on a "4-8 membered heterobicyclic" group, the substituents may be bonded at any available ring atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "4-8 membered heterobicyclic" group may be substituted or unsubstituted.

The term "carbonyl" refers to the group-C (=o) -.

The term "cubanyl" refers to a group having the structure:

The term "cubanyl-C ₁-C₄ -alkylene" refers to a group consisting of "cubanyl" bonded to "C ₁-C₄ -alkylene", wherein "cubanyl" and "C ₁-C₄ -alkylene" have the same definition as described herein. Examples include, but are not limited to, (cubanyl) methyl. When one or more substituents are present on a "cubanyl-C ₁-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "cubanyl-C ₁-C₄ -alkylene" group may be substituted or unsubstituted.

The term "cyano" refers to the group-CN.

The term "cyano-C ₁-C₄ -alkylene" refers to a group consisting of "cyano" bonded to "C ₁-C₄ -alkylene", where "cyano" and "C ₁-C₄ -alkylene" have the same definition as described herein. Examples include, but are not limited to, cyanomethyl (i.e., -CH ₂ CN), 2-cyanoethyl, 1-cyanoethyl (i.e., -CH (CH ₃) -CN) and 3-cyanopropyl.

The term "cycloalkenyl" refers to a non-aromatic monocyclic hydrocarbon ring system containing at least one double bond in the ring. The "cycloalkenyl" group may contain 4 to 7 atoms in the ring (i.e., "C ₄-C₇ -cycloalkenyl"). Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. In some embodiments, the "cycloalkenyl" is selected from the group consisting of cyclobut-1-en-1-yl, cyclobut-2-en-1-yl, cyclopent-1-en-1-yl, cyclopent-2-en-1-yl, and cyclopent-3-en-1-yl. When one or more substituents are present on a "cycloalkenyl" the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "cycloalkenyl" group may be substituted or unsubstituted.

The term "cycloalkyl" refers to a single ring system of all carbons that are fully saturated. In some embodiments, cycloalkyl is a single ring containing 3 to 7 carbon atoms (i.e., "C ₃-C₇ -cycloalkyl"). Some embodiments contain 3 to 6 carbons (i.e., "C ₃-C₆ -cycloalkyl"). Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When one or more substituents are present on a "cycloalkyl" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "cycloalkyl" group may be substituted or unsubstituted.

The term "C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene" refers to a group consisting of "C ₃-C₇ -cycloalkyl" bonded to "C ₁-C₄ -alkylene", wherein "C ₃-C₇ -cycloalkyl" and "C ₁-C₄ -alkylene" have the same definitions as described herein. Examples include, but are not limited to, cyclopropylmethyl (cyclopropyl-CH ₂ -), cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl (cyclopropyl-CH ₂CH₂ -), 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclopropylethyl (cyclopropyl-CH (CH ₃) -), 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 1-cycloheptylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 4-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclohexylbutyl and 4-cycloheptylbutyl. When one or more substituents are present on a "C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene" group may be substituted or unsubstituted.

The term "C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene" refers to a group consisting of "C ₃-C₇ -cycloalkyl" bonded to an oxygen atom, and the oxygen atom is bonded to "C ₂-C₄ -alkylene", where "C ₃-C₇ -cycloalkyl" and "C ₂-C₄ -alkylene" have the same definitions as described herein. Examples include, but are not limited to, 2-cyclopropyloxyethyl (i.e., cyclopropyl-O-CH ₂CH₂ -), 2-cyclobutoxyethyl, 2-cyclopentyloxyethyl, 2-cyclohexyloxyethyl, 2-cycloheptyloxyethyl, 1-cyclopropyloxyethyl (i.e., cyclopropyl-O-CH (CH ₃) -), 1-cyclobutoxyethyl, 1-cyclopentyloxyethyl, 1-cyclohexyloxyethyl, 1-cycloheptyloxyethyl, 3-cyclopropoxypropyl, 3-cyclobutoxypropyl, 3-cyclopentoxypropyl, 3-cyclohexyloxypropyl and 3-cycloheptoxypropyl. It is understood that the chemical group "(cyclopropyl) methyl-d ₂" refers to a group in which the deuterium atom is bonded to the methylene carbon (i.e. cyclopropyl-CD ₂ -), see for example compound 99. When one or more substituents are present on a "C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene" group may be substituted or unsubstituted.

The term "dialkylamino" refers to an amino (-NH ₂) group in which the nitrogen is substituted with two "alkyl groups". The two alkyl groups may be the same or different. The term "alkyl" has the same definition as described herein. The "dialkylamino" group can have 2 to 4 carbon atoms (i.e., "C ₂-C₄ -dialkylamino") provided that the total number of carbon atoms between the two alkyl groups is not more than 4. Examples include dimethylamino (i.e., -N (Me) ₂), ethyl (methyl) amino (i.e., -N (Me) (Et)), diethylamino (i.e., -N (Et) ₂), and methyl (propyl) amino (i.e., -N (Me) (propyl)).

The term "haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogen atoms of the alkyl group have been replaced with halogen atoms. In some embodiments, the haloalkyl may have 1 to 6 carbons (i.e., "C ₁-C₆ -haloalkyl"). The halo C ₁-C₆ alkyl may be fully substituted, in which case it may be represented by formula C _nL_2n+1, wherein L is halogen and "n" is 1,2, 3, 4, 5 or 6. When more than one halogen is present, they may be the same or different and are selected from fluorine, chlorine, bromine and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons (i.e., "C ₁-C₅ -haloalkyl"). In some embodiments, haloalkyl contains 1 to 4 carbons (i.e., "C ₁-C₄ -haloalkyl"). In some embodiments, haloalkyl contains 1 to 3 carbons (i.e., "C ₁-C₃ -haloalkyl"). In some embodiments, the haloalkyl contains 1 or 2 carbons. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-trifluoroethyl, pentafluoroethyl and 4, 4-trifluorobutyl.

The term "halogen" or "halo" refers to a fluoro, chloro, bromo or iodo group. In some embodiments, the halogen or halo is fluoro, chloro or bromo. In some embodiments, the halogen or halo is fluoro or chloro. In some embodiments, the halogen or halo is fluoro.

The term "heterocyclyl" refers to a non-aromatic monocyclic system containing carbon atoms and at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen, and when more than one heteroatom is present in the ring, the heteroatoms may be the same or different. In some embodiments, "3-7 membered heterocyclyl" refers to a ring system containing 3 to 7 ring atoms, at least one of which is a heteroatom. In some embodiments, "4-5 membered heterocyclyl" refers to a ring system containing 4 or 5 ring atoms, at least one of which is a heteroatom. In some embodiments, "4-7 membered heterocyclyl" refers to a ring system containing 4 to 7 ring atoms, at least one of which is a heteroatom. In some embodiments, "3-6 membered heterocyclyl" refers to a ring system containing 3 to 6 ring atoms, at least one of which is a heteroatom. In some embodiments, "4-6 membered heterocyclyl" refers to a ring system containing 4 to 6 ring atoms, at least one of which is a heteroatom. In some embodiments, one or both heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, the heterocyclic group may include a carbonyl (c=o) group adjacent to the heteroatom, i.e., substituted with oxo on a carbon adjacent to the heteroatom, where the substituted ring system is a lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate. Examples include, but are not limited to, aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothiopyranyl. When one or more substituents are present on a "heterocyclyl" group, the substituents may be bonded at any available carbon atom and/or heteroatom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "heterocyclyl" group may be substituted or unsubstituted.

The term "4-8 membered heterobicycloyl-C ₁-C₄ -alkylene" refers to a group consisting of "4-8 membered heterobicycloyl" bonded to "C ₁-C₄ -alkylene", wherein "4-8 membered heterobicycloyl" and "C ₁-C₄ -alkylene" have the same definitions as described herein. In some embodiments, the "4-8 membered heterobicyclo-C ₁-C₄ -alkylene" is a group selected from (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl. When one or more substituents are present on a "4-8 membered heterobicycloyl-C ₁-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "4-8 membered heterobicyclo-C ₁-C₄ -alkylene" group may be substituted or unsubstituted.

The term "3-7 membered heterocyclyl-C ₁-C₄ -alkylene" refers to a group consisting of "3-7 membered heterocyclyl" bonded to "C ₁-C₄ -alkylene", wherein "3-7 membered heterocyclyl" and "C ₁-C₄ -alkylene" have the same definition as described herein. Examples include, but are not limited to, aziridin-1-ylmethyl (i.e., (aziridin-1-yl) CH ₂ -), aziridin-2-ylmethyl, azetidin-2-ylmethyl (i.e., (azetidin-2-yl) CH ₂ -), azetidin-3-ylmethyl (i.e., (azetidin-3-yl) CH ₂ -), azetidin-2-ylmethyl, Piperidinylmethyl, morpholinyl, oxetan-3-ylmethyl (i.e. (oxetan-3-yl) CH ₂ -), oxetan-2-ylmethyl (i.e. (oxetan-2-yl)) CH ₂ -), 2-oxetan-3-ylethyl (i.e. (oxetan-3-yl) CH ₂CH₂ -), 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl) CH ₂CH₂ -), imidazolidinylmethyl, piperazin-1-ylmethyl, piperazin-2-ylmethyl, pyrrolidin-3-ylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, and tetrahydrothiopyranylmethyl. In some embodiments, a "3-7 membered heterocyclyl-C ₁-C₄ -alkylene" is a group selected from the group consisting of oxetan-3-ylmethyl (i.e., (oxetan-3-yl) CH ₂ -), oxetan-2-ylmethyl (i.e., (oxetan-2-yl) CH ₂ -), and, 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl) CH ₂CH₂ -) and 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl) CH ₂CH₂ -). When one or more substituents are present on a "3-7 membered heterocyclyl-C ₁-C₄ -alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "3-7 membered heterocyclyl-C ₁-C₄ -alkylene" group may be substituted or unsubstituted.

The term "spirocycloalkyl" refers to all carbon bicyclic ring systems that are not aromatic, wherein the two rings are joined together by a single common ring carbon. In some embodiments, "C ₅-C₁₁ -spirocycloalkyl" refers to a spirocyclic system containing 5 to 11 ring carbons. In some embodiments, "C ₅-C₈ -spirocycloalkyl" refers to a spirocyclic system containing 5 to 8 ring carbons. In some embodiments, "C ₅-C₇ -spirocycloalkyl" refers to a spirocyclic system containing 5 to 7 ring carbons. In some embodiments, "C ₇ -spirocycloalkyl" refers to a spirocyclic system containing 7 ring carbons (i.e., spiro [3.3] heptyl and spiro [2.4] heptane). Examples include, but are not limited to, spiro [2.2] pentyl, spiro [2.3] hexyl, spiro [3.3] heptyl, spiro [2.4] heptyl, spiro [2.5] octyl, spiro [3.4] octyl, spiro [2.6] nonyl, spiro [3.5] nonyl, spiro [4.4] nonyl, spiro [2.7] decyl, spiro [3.6] decyl, and spiro [4.5] decyl. When one or more substituents are present on a "spirocycloalkyl" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "spirocycloalkyl" group may be substituted or unsubstituted.

The term "spiroheterocyclyl" refers to a bicyclic system containing a carbon atom and at least one heteroatom, wherein the two rings are joined together by a single common ring carbon. In some embodiments, "5-11 membered spiroheterocyclyl" refers to a spiro ring system containing 5 to 11 ring atoms. In some embodiments, "5-8 membered spiroheterocyclyl" refers to a spiro ring system containing 5 to 8 ring atoms. In some embodiments, "5-7 membered spiroheterocyclyl" refers to a spiro ring system containing 5 to 7 ring atoms. Examples include, but are not limited to, azaspiro [2.2] pentyl, azaspiro [2.3] hexyl, oxaspiro [3.3] heptyl, azaspiro [3.4] octyl, azaspiro [3.5] nonyl, and oxaspiro [3.5] non-9-yl. When one or more substituents are present on a "spiroheterocyclyl" group, the substituents may be bonded at any available carbon atom and/or heteroatom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, the "spiroheterocyclyl" group may be substituted or unsubstituted.

The term "hydroxy" refers to the group-OH.

As used herein, "excipient" refers to a substance added to a composition to provide the composition with, but not limited to, volume, consistency, stability, binding capacity, lubricity, disintegration capacity, and the like. "diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, diluents may be used to increase the volume of an effective drug whose mass is too small for manufacture and/or administration. It may also be a liquid for dissolution of a drug for administration by injection, ingestion or inhalation. Pharmaceutically acceptable excipients are physiologically and pharmaceutically suitable non-toxic and inactive materials or ingredients that do not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, properties, AND SAFETY, 5 th edition, 2006 and Remington: THE SCIENCE AND PRACTICE of Pharmacy (Gennaro, 21 st edition Mack Pub.Co., easton, pa.). Preservatives, stabilizers, dyes, buffers and the like may be provided in the pharmaceutical compositions. The compounds as disclosed and described herein may be further formulated in an appropriate manner and according to accepted practices (e.g., those disclosed in Remington, supra) by those skilled in the art.

As used herein, "dose" or "dose (dosage)" refers to a measured amount of a drug substance that is administered to an individual at one time. In certain embodiments wherein the drug substance is not a free base or a free acid, the amount is equivalent to the molar amount of the corresponding amount of the free base or the free acid.

As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic moiety, which is biologically or otherwise suitable for use in a pharmaceutical product. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by the presence of acidic or basic moieties (e.g., amino and/or carboxyl groups or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with an inorganic acid and an organic acid. Pharmaceutically acceptable base addition salts can be formed by combining compounds having an acidic moiety with inorganic and organic bases.

The compounds described herein may have one or more stereocenters. Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. It will be appreciated that in any of the compounds described herein having one or more chiral centers, each center may independently be in the (R) -configuration or the (S) -configuration, or mixtures thereof, if absolute stereochemistry is not explicitly indicated. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. The preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by resolution of the racemic mixture or by use of enantiomerically pure or enriched starting materials or by stereoselective or stereospecific synthesis. Stereochemical definitions may be obtained in E.L.Eliel,S.H.Wilen&L.N.Mander,Stereochemistry of Organic Compounds,John Wiley&Sons,Inc.,New York,NY,1994, which is incorporated herein by reference in its entirety. In some embodiments, when a compound described herein is chiral or otherwise includes one or more stereocenters, the compound can be prepared with an enantiomeric excess or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%.

Resolution of the racemic mixture of the compounds can be carried out by any of a variety of methods known in the art. An exemplary method includes fractional recrystallization using chiral resolution of an organic acid with a racemic compound containing a basic group. Other chiral resolving agents suitable for use in the fractional crystallization process include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycine alcohol, norephedrine, ephedrine, N-methyl ephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using chiral resolving bases can be used with racemic compounds containing basic groups.

Resolution of the racemic mixture may also be carried out by elution on a chiral column. Suitable eluting solvent compositions can be determined by those skilled in the art.

In some embodiments, compounds described herein can be prepared having an enantiomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or at least about 99.9%, or an enantiomeric excess within a range defined by any of the foregoing numbers. In some embodiments, compounds described herein can be prepared having an enantiomeric excess of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or at least 99.9% or an enantiomeric excess within a range defined by any of the foregoing numbers.

In some embodiments, compounds described herein can be prepared having a diastereomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or at least about 99.9%, or a diastereomeric excess within a range defined by any of the foregoing numbers. In some embodiments, compounds described herein can be prepared having a diastereomeric excess of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or at least 99.9%, or a diastereomeric excess within a range defined by any of the foregoing numbers.

Furthermore, it is to be understood that when a compound described herein contains one or more double bonds (e.g., c= C, C =n, etc.) or has other centers of geometric asymmetry, and unless otherwise indicated, it is to be understood that the compound includes both Z and E geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds as described herein may be separated into mixtures of isomers or isolated isomeric forms.

The compounds described herein also include tautomeric forms. Tautomeric forms result from the exchange of single bonds with adjacent double bonds and concomitant proton migration. Tautomeric forms include proton transfer tautomers, which are in isomerically protonated states of the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imide pairs, lactam-lactam pairs, enamine-imine pairs, and cyclic forms in which protons may occupy two or more positions of the heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole, and 4H-1,2, 4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms may be in equilibrium or spatially locked into one form by appropriate substitution.

The compounds described herein and pharmaceutically acceptable salts thereof may be present, for example, in the form of hydrates or solvates with other substances, such as water and solvents. The compounds described herein and salts thereof, when in the solid state, may exist in various forms and may be, for example, in the form of solvates (including hydrates). The compounds may be in any solid state form, such as crystalline, amorphous, solvated forms, etc., and references to compounds and salts thereof in the specification are to be understood as encompassing any solid state form of the compounds unless explicitly stated otherwise.

The compounds described herein may be used in neutral form, such as the free acid or free base form. Alternatively, the compounds may be used in the form of pharmaceutically acceptable salts, such as pharmaceutically acceptable acid or base addition salts.

In some embodiments, a compound described herein, or a salt thereof, is substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, a composition enriched in the compounds described herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein or a salt thereof.

Isotope element

The compounds disclosed and described herein allow and encompass, independently, atoms at each position of the compound to have 1) a proportional amount of isotopic distribution of the chemical elements that is typically found in nature, or 2) a different proportional amount of isotopic distribution than is typically found in nature, unless the context clearly dictates otherwise. A particular chemical element has an atomic number defined by the number of protons within the atomic core. Each atomic number determines a particular chemical element, rather than an isotope, and the atoms of a given element may have a wide range of sub-numbers therein. The number of both protons and neutrons in the nucleus is the mass number of atoms, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of chemical elements different from the proportional amounts of isotopes normally present in nature are commonly referred to as isotopically labeled. Each chemical element as represented in the structure of the compound may include any isotopic distribution of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be an isotopic distribution of hydrogen, including, but not limited to, protium (¹ H) and deuterium (² H) in proportion to and in amounts different from those typically present in nature. Thus, unless the context clearly dictates otherwise, reference to a compound herein encompasses all potential isotopic distributions of each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those of skill in the art, any of the compounds as disclosed and described herein may include a radioisotope. Thus, also contemplated is the use of a compound as disclosed and described herein, wherein one or more atoms have an isotopic distribution that is different from the amounts typically present in nature, such as having a greater proportion of ² H or ³ H, or a greater proportion of ¹¹C、¹³ C or ¹⁴ C than is present in nature. Isotopes of hydrogen include, as general examples, but are not limited to, protium (¹ H), deuterium (² H), and tritium (³ H). Isotopes of carbon include carbon-11 (11C), carbon-12 (12C), carbon-13 (¹³ C), and carbon-14 (¹⁴ C). Isotopes of nitrogen include nitrogen-13 (¹³ N), nitrogen-14 (¹⁴ N) and nitrogen-15 (¹⁵ N). Isotopes of oxygen include oxygen-14 (¹⁴ O), oxygen-15 (¹⁵ O), oxygen-16 (¹⁶ O), oxygen-17 (¹⁷ O), and oxygen-18 (¹⁸ O). Isotopes of fluorine include fluorine-17 (¹⁷ F), fluorine-18 (¹⁸ F), and fluorine-19 (¹⁹ F). Isotopes of phosphorus include phosphorus-31 (³¹ P), phosphorus-32 (³² P), phosphorus-33 (³³ P), phosphorus-34 (³⁴ P), Phosphorus-35 (³⁵ P) and phosphorus-36 (³⁶ P). Isotopes of sulfur include sulfur-32 (³² S), sulfur-33 (³³ S), sulfur-34 (³⁴ S), sulfur-35 (³⁵ S), Sulfur-36 (³⁶ S) and sulfur-38 (³⁸ S). Isotopes of chlorine include chlorine-35 (³⁵ Cl), chlorine-36 (³⁶ Cl), and chlorine-37 (³⁷ Cl). Isotopes of bromine include bromine-75 (⁷⁵ Br), bromine-76 (⁷⁶ Br), bromine-77 (⁷⁷ Br), bromine-79 (⁷⁹ Br), bromine-81 (⁸¹ Br) and bromine-82 (⁸² Br). Isotopes of iodine include iodine-123 (¹²³ I), iodine-124 (¹²⁴ I), iodine-125 (¹²⁵ I), iodine-131 (¹³¹ I) and iodine-135 (¹³⁵ I). in some embodiments, the atoms at each position of the compound have a distribution of isotopes of the proportional amounts typically found in nature of each chemical element. In some embodiments, an atom in one position of a compound has a different isotopic distribution of chemical elements than the proportional amounts typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of chemical elements typically found in nature). In some embodiments, the atoms in at least two positions of the compound independently have a different isotopic distribution of the chemical element than the proportional amount typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of the chemical element typically found in nature). In some embodiments, the atoms in at least three positions of the compound independently have a different isotopic distribution of the chemical element than the proportional amount typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of the chemical element typically found in nature). In some embodiments, the atoms in at least four positions of the compound independently have a different isotopic distribution of the chemical element than the proportional amount typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of the chemical element typically found in nature). In some embodiments, the atoms in at least five positions of the compound independently have a different isotopic distribution of the chemical element than the proportional amount typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of the chemical element typically found in nature). in some embodiments, the atoms in at least six positions of the compound independently have a different isotopic distribution of the chemical element than the proportional amount typically found in nature (the remaining atoms have a proportional amount of isotopic distribution of the chemical element typically found in nature).

Certain compounds, such as compounds incorporating radioisotopes such as ³ H and ¹⁴ C, may also be used in drug or substrate tissue distribution assays. Tritium (³ H) and carbon-14 (¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Compounds having a larger proportional amount of isotopes than typically present in nature, such as deuterium (² H), may afford certain therapeutic advantages due to greater metabolic stability such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds can generally be prepared by carrying out procedures conventionally practiced in the chemical arts. Methods of measuring such isotope perturbation or enrichment are readily available, such as mass spectrometry, and for isotopes that are radioisotopes, additional methods may be available, such as a radioactive detector used in conjunction with HPLC or GC.

As used herein, "isotopic variation" means a compound containing an unnatural proportion of an isotope at one or more of the atoms comprising such compound. In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of one or more isotopes, including, but not limited to, protium (¹ H), deuterium (² H), tritium (³ H), carbon-11 (¹¹ C), Carbon-12 (¹² C), carbon-13 (¹³ C), carbon-14 (¹⁴ C), nitrogen-13 (¹³ N), Nitrogen-14 (¹⁴ N), nitrogen-15 (¹⁵ N), oxygen-14 (¹⁴ O), oxygen-15 (¹⁵ O), Oxygen-16 (¹⁶ O), oxygen-17 (¹⁷ O), oxygen-18 (¹⁸ O), fluorine-17 (¹⁷ F), Fluoro-18 (¹⁸ F), phosphorus-31 (³¹ P), phosphorus-32 (³² P), phosphorus-33 (³³ P), Sulfur-32 (³² S), sulfur-33 (³³ S), sulfur-34 (³⁴ S), sulfur-35 (³⁵ S), Sulfur-36 (³⁶ S), chlorine-35 (³⁵ Cl), chlorine-36 (³⁶ Cl), chlorine-37 (³⁷ Cl), Bromine-79 (⁷⁹ Br), bromine-81 (⁸¹ Br), iodine-123 (¹²³ I), iodine-125 (¹²⁵ I), Iodine-127 (¹²⁷ I), iodine-129 (¹²⁹ I) and iodine-131 (¹³¹ I). in certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of one or more isotopes, including but not limited to protium (¹ H), deuterium (² H), carbon-12 (¹² C), carbon-13 (¹³ C), and combinations thereof, Nitrogen-14 (¹⁴ N), nitrogen-15 (¹⁵ N), oxygen-16 (¹⁶ O), oxygen-17 (¹⁷ O) and oxygen-18 (¹⁸ O). in certain embodiments, an "isotopic variant" of a compound is in an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound described herein contains a non-natural proportion of one or more isotopes, including but not limited to tritium (³ H), carbon-11 (¹¹ C), carbon-14 (¹⁴ C), nitrogen-13 (¹³ N), oxygen-14 (¹⁴ O) and oxygen-15 (¹⁵ O). It is to be understood that in a compound as provided herein, any hydrogen may include ² H as the primary isotopic form, or any carbon may include ¹³ C as the primary isotopic form, or any nitrogen may include ¹⁵ N as the primary isotopic form, as examples, and any oxygen may include ¹⁸ O as the primary isotopic form, as examples. in certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of deuterium (² H).

With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D", it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is about 0.015%. In certain embodiments, the positions designated as having deuterium typically have a minimum isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. Similarly, with respect to the compounds provided herein, when any atomic position is designated as a particular isotope, it is understood that the abundance of the particular isotope at that position is significantly greater than the natural abundance of that isotope. In certain embodiments, the positions designated as having a particular isotope typically have a minimum isotopic enrichment factor of at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 99.5% incorporation of the isotope at each designated position.

Synthetic methods for incorporating radioisotopes into organic compounds are suitable for use with the compounds described herein and are well known in the art. These synthetic methods, for example, incorporate active levels of tritium into target molecules as follows:

A. catalytic reduction with tritium gas this process generally produces a highly specific active product and requires halogenated or unsaturated precursors.

B. reduction with sodium borohydride [ ³ H ] this process is quite inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

C. The reduction with lithium aluminum hydride [ ³ H ] provided a product at nearly theoretical specific activity. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

D. Tritium gas exposure labeling, which involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

E. N-methylation Using methyl iodide [ ³ H ] this method is commonly used to prepare O-methyl or N-methyl (³ H) products by treating the appropriate precursor with high specific activity methyl iodide (³ H). This method generally allows higher specific activities, for example about 70-90Ci/mmol.

The synthetic method for incorporating ¹²⁵ I at the level of activity into a target molecule includes:

A. Sha Demai mol (Sandmeyer) and the like, which converts an aryl or heteroaryl amine to a diazonium salt, such as diazonium tetrafluoroborate, and then converts to a ¹²⁵ I labeled compound using Na ¹²⁵ I. Representative methods are reported by Zhu, G-d, and colleagues in j.org.chem.,2002,67,943-948.

B. Ortho ¹²⁵ iodination of phenol this method allows for the incorporation of ¹²⁵ I in ortho-position to phenol as reported by Collier, t.l. and colleagues in j.labelled compact. Radiopharm, 1999,42, S264-S266.

C. Aryl and heteroaryl bromides are exchanged with ¹²⁵ I, the process is typically a two-step process. The first step is to convert the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using, for example, a Pd catalytic reactant [ Pd (Ph ₃P)₄ ] or by aryl or heteroaryl lithium in the presence of a trialkyltin halide or hexaalkylditin [ e.g., (CH ₃)₃SnSn(CH₃)₃) ].

Radiolabeled forms of the compounds described herein can be used in screening assays to identify/evaluate compounds. In general, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of radiolabeled forms of the compounds disclosed herein to VMAT 2. The ability of a test compound to compete with the radiolabeled form of the compounds described herein for binding to VMAT2 correlates with its binding affinity.

Compounds of formula (I)

or a pharmaceutically acceptable salt thereof,

Wherein:

Another aspect of the present disclosure encompasses, inter alia, compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl and C ₅-C₁₁ -spirocycloalkyl;

In some embodiments, the R ¹ group is optionally substituted with one, two, three, four, five, six, seven, or eight substituents. In some embodiments, the R ¹ group is optionally substituted with one, two, three, four, five, six, or seven substituents. In some embodiments, the R ¹ group is optionally substituted with one, two, three, four, five, or six substituents. In some embodiments, the R ¹ group is optionally substituted with one, two, three, four, or five substituents. In some embodiments, the R ¹ group is optionally substituted with one, two, three, or four substituents. In some embodiments, the R ¹ group is optionally substituted with one, two, or three substituents. In some embodiments, the R ¹ group is optionally substituted with one or two substituents. In some embodiments, the R ¹ group is optionally substituted with one substituent. In some embodiments, the R ¹ group is unsubstituted.

In some embodiments, the R ¹ group is substituted with one, two, three, four, five, six, seven, or eight substituents. In some embodiments, the R ¹ group is substituted with one, two, three, four, five, six, or seven substituents. In some embodiments, the R ¹ group is substituted with one, two, three, four, five, or six substituents. In some embodiments, the R ¹ group is substituted with one, two, three, four, or five substituents. In some embodiments, the R ¹ group is substituted with one, two, three, or four substituents. In some embodiments, the R ¹ group is substituted with one, two, or three substituents. In some embodiments, the R ¹ group is substituted with one or two substituents. In some embodiments, the R ¹ group is substituted with one substituent.

Some embodiments provide compounds of formula (Ic):

Or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described above and below herein. It is understood that the stereochemistry of the compound of formula (Ic) includes both the 2s,3r,11br isomer and the 2r,3r,11br isomer.

Some embodiments provide compounds of formula (Ie):

or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described above and below herein. The stereochemistry of the compound of formula (Ie) is the 2r,3r,11br isomer.

Some embodiments provide compounds of formula (Ig):

Or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described above and below herein. The stereochemistry of the compound of formula (Ig) is 2s,3r,11br isomer.

Some embodiments provide compounds of formula (Ii):

or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described above and below herein. The stereochemistry of the compound of formula (Ii) is the 2r,3s,11bs isomer.

Some embodiments provide compounds of formula (Ik):

Or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described above and below herein. The stereochemistry of the compound of formula (Ik) is 2s,3s,11bs isomer.

Some embodiments provide a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an elimination t _1/2 of ≡420 minutes as determined using a Human Liver Microsomal (HLM) assay, such as the assay described in example 17. In some embodiments, the compound has an elimination t _1/2 of ≡400 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡375 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡350 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡325 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡300 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡275 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡250 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡225 minutes. In some embodiments, the compound has an elimination t _1/2 of ≡200 minutes.

Some embodiments provide a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an IC ₅₀ of >6,000nm for CYP2D6 and CYP3A4 as determined using the IC ₅₀ method (such as the method described in example 18). In some embodiments, the compound has an IC ₅₀ of >5,000nm for CYP2D 6. In some embodiments, the compound has an IC ₅₀ of >4,000nm for CYP2D 6. In some embodiments, the compound has an IC ₅₀ of >3,000nm for CYP2D 6. In some embodiments, the compound has an IC ₅₀ of >2,000nm for CYP2D 6. In some embodiments, the compound has an IC ₅₀ of >5,000nm for CYP3 A4. In some embodiments, the compound has an IC ₅₀ of >4,000nm for CYP3 A4. In some embodiments, the compound has an IC ₅₀ of >3,000nm for CYP3 A4. In some embodiments, the compound has an IC ₅₀ of >2,000nm for CYP3 A4. In some embodiments, the compound is substantially inactive against CYP2D 6. In some embodiments, the compound is substantially inactive against CYP3 A4.

Some embodiments provide a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an IC ₅₀ of >12,000nm for hERG (human ether-a-go-go-RELATED GENE) determined using the IC ₅₀ method (such as the method described in example 19). In some embodiments, the compound has an IC ₅₀ of >11,000nm for hERG. In some embodiments, the compound has >10,000nM IC ₅₀ to hERG. In some embodiments, the compound has an IC ₅₀ of >9,000nm for hERG. In some embodiments, the compound has an IC ₅₀ of >8,000nm for hERG. In some embodiments, the compound has an IC ₅₀ of >7,000nm for hERG. In some embodiments, the compound is substantially inactive against hERG.

The phrase "compound (compound as described herein) as described herein" or "compound (compounds as described herein) as described herein" refers to any one or more of the compounds above and below of the present disclosure. In some embodiments, the compound has formula (Ia). In some embodiments, the compound is of formula (Ic). In some embodiments, the compound has formula (Ie). In some embodiments, the compound has formula (Ig). In some embodiments, the compound has formula (Ii). In some embodiments, the compound has formula (Ik).

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl, C ₅-C₁₁ -spirocycloalkyl, cubic alkyl-C ₁-C₄ -alkylene, and 4-8 membered heterobicycloyl-C ₁-C₄ -alkylene;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₃-C₆ -cycloalkyl, hydroxy and C ₁-C₄ -alkoxy.

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl, and C ₅-C₁₁ -spirocycloalkyl;

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -and 6-membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl, and C ₇ -spirocycloalkyl;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

Wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -and 6-membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

In some embodiments, R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl, and C ₇ -spirocycloalkyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl, (cyclobutyl) ethyl, (cubic alkyl) methyl, (bicyclo [2.1.1] hexyl) methyl, (siloxane) methyl, and (2-oxabicyclo [2.1.1] hexyl) methyl;

wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl, and (cyclobutyl) ethyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl and (cyclobutyl) ethyl, (cubic) methyl, (bicyclo [2.1.1] hexyl) methyl, (siloxane) methyl and (2-oxabicyclo [2.1.1] hexyl) methyl;

Wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, (cyclobutyl) ethyl, (cubanyl) methyl, (bicyclo [2.1.1] hexyl) methyl, (siloxyalkyl) methyl and (2-oxabicyclo [2.1.1] hexyl) methyl;

Wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, and (cyclobutyl) ethyl;

Wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl, 1- (cyclobutyl) ethyl, (bicyclo [2.1.1] hex-1-yl) methyl, (bicyclo [1.1.1] hex-1-yl) methyl, 2- (methoxy) hex-2-en-1-yl) methyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl and 1- (cyclobutyl) ethyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, 1- (cyclobutyl) ethyl, (cuban-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, bicyclo [3.3] hept-2-3-yl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl and 1- (cyclobutyl) ethyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl) methyl 3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-Difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxet-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (2-methylpropyl) methylpropyl, (2- (methylsulfonyl) methylpropyl) methyl, 2- (methylsulfonyl) methyl, 3- (methylsulfonyl) ethyl 3, 3-difluorocyclobutyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl) methyl 3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

In some embodiments, R ¹ is (cyclopentyl) methyl. In some embodiments, R ¹ is isobutyl. In some embodiments, R ¹ is cyclopentyl. In some embodiments, R ¹ is (cyclobutyl) methyl. In some embodiments, R ¹ is (1- (cyanomethyl) cyclopropyl) methyl. In some embodiments, R ¹ is isopentyl. In some embodiments, R ¹ is (1-fluorocyclobutyl) methyl. In some embodiments, R ¹ is cyclobutyl. In some embodiments, R ¹ is 2- (cyano (cyclopropyl) methoxy) ethyl. In some embodiments, R ¹ is butyl. In some embodiments, R ¹ is propyl. In some embodiments, R ¹ is (1-hydroxycyclobutyl) methyl. In some embodiments, R ¹ is 2-cyclopropyloxyethyl. In some embodiments, R ¹ is 2-fluoro-2-methylpropyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is methyl-d ₃. In some embodiments, R ¹ is 2, 2-difluoropropyl. In some embodiments, R ¹ is 2, 2-trifluoroethyl. In some embodiments, R ¹ is 3, 3-trifluoropropyl. In some embodiments, R ¹ is cyclopropyl. In some embodiments, R ¹ is (1-fluorocyclopropyl) methyl. In some embodiments, R ¹ is 2-hydroxypropyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is ethyl-d ₅. In some embodiments, R ¹ is isopropyl. In some embodiments, R ¹ is 2-methoxyethyl. In some embodiments, R ¹ is (cyclopropyl) methyl. In some embodiments, R ¹ is (cyclopropyl) methyl-d ₂. In some embodiments, R ¹ is 3-fluoropropyl. In some embodiments, R ¹ is 2-fluoroethyl. In some embodiments, R ¹ is 2- ((2-cyanoprop-2-yl) oxy) ethyl. In some embodiments, R ¹ is 1, 1-trifluoropropan-2-yl. In some embodiments, R ¹ is 2, 2-difluoroethyl. In some embodiments, R ¹ is oxetan-3-yl. In some embodiments, R ¹ is oxetan-3-ylmethyl. In some embodiments, R ¹ is (oxetan-2-yl) methyl. In some embodiments, R ¹ is 3, 3-trifluoro-2-hydroxypropyl. In some embodiments, R ¹ is 4, 4-trifluorobutyl. In some embodiments, R ¹ is 3-methoxypropyl. In some embodiments, R ¹ is (3, 3-difluorocyclobutyl) methyl. In some embodiments, R ¹ is (1- (difluoromethyl) cyclopropyl) methyl. In some embodiments, R ¹ is 5, 5-trifluoropentyl. In some embodiments, R ¹ is (3-fluoro bicyclo [1.1.1] pent-1-yl) methyl. In some embodiments, R ¹ is fluoromethyl. In some embodiments, R ¹ is (2, 2-difluorocyclopropyl) methyl. In some embodiments, R ¹ is 2- (trifluoromethoxy) ethyl. In some embodiments, R ¹ is neopentyl. In some embodiments, R ¹ is (1-methylcyclobutyl) methyl. In some embodiments, R ¹ is (2-methylcyclopropyl) methyl. In some embodiments, R ¹ is (2, 2-difluorocyclopentyl) methyl. In some embodiments, R ¹ is 3-fluorocyclobut-2-en-1-yl. In some embodiments, R ¹ is 2-oxaspiro [3.3] hept-6-yl. In some embodiments, R ¹ is 3-cyanocyclobutyl. In some embodiments, R ¹ is 3-fluorocyclobutyl. In some embodiments, R ¹ is 3, 3-dimethylcyclobutyl. In some embodiments, R ¹ is spiro [3.3] hept-2-yl. In some embodiments, R ¹ is 1-methylpyrrolidin-3-yl. In some embodiments, R ¹ is (3-methyl oxetan-3-yl) methyl. In some embodiments, R ¹ is (1-methylcyclopropyl) methyl. In some embodiments, R ¹ is 1-methylcyclobutyl. in some embodiments, R ¹ is (2-fluorocyclopropyl) methyl. In some embodiments, R ¹ is (2, 2-difluoro-3-methylcyclopropyl) methyl. In some embodiments, R ¹ is 1-cyclobutylethyl. In some embodiments, R ¹ is (2, 2-dimethylcyclopropyl) methyl. In some embodiments, R ¹ is (3, 3-difluorocyclopentyl) methyl. In some embodiments, R ¹ is 3- (trifluoromethyl) cyclobutyl. In some embodiments, R ¹ is 2-fluoropropyl. In some embodiments, R ¹ is 3-methoxycyclobutyl. In some embodiments, R ¹ is 3- (dimethylamino) cyclobutyl. In some embodiments, R ¹ is cyanomethyl. In some embodiments, R ¹ is (1-cyanocyclobutyl) methyl. In some embodiments, R ¹ is (1-cyanocyclopropyl) methyl. In some embodiments, R ¹ is 2-methoxypropyl. In some embodiments, R ¹ is (1- (methylsulfonyl) cyclopropyl) methyl. In some embodiments, R ¹ is 3- (methylsulfonyl) propyl. In some embodiments, R ¹ is 2- (methylsulfonyl) ethyl. In some embodiments, R ¹ is 3, 3-difluorocyclobutyl. In some embodiments, R ¹ is (2, 2-difluorocyclobutyl) methyl. In some embodiments, R ¹ is (cuban-1-yl) methyl. In some embodiments, R ¹ is (bicyclo [1.1.1] pent-1-yl) methyl. In some embodiments, R ¹ is (bicyclo [2.1.1] hex-1-yl) methyl. In some embodiments, R ¹ is (1, 1-dimethylsiloxane-3-yl) methyl. In some embodiments, R ¹ is (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl. In some embodiments, R ¹ is (2-oxabicyclo [2.1.1] hex-1-yl) methyl. In some embodiments, R ¹ is (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl) methyl, 3-trifluoro-2-hydroxypropyl 4, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorobicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methylcyclobut-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, 3-difluorocyclobutyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅ isopropyl, 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3 r) -3-cyanocyclobutyl, (1 r, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, (1S, 3S) -3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3 s) -3-cyanocyclobutyl, (1 r, 3R) -3- (trifluoromethyl) cyclobutyl, (1 r, 3R) -3-methoxycyclobutyl, (1 r, 3R) -3- (dimethylamino) cyclobutyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, Cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methylioxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, (1S, 3S) -3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3S) -3-cyanocyclobutyl, (1 r, 3R) -3- (trifluoromethyl) cyclobutyl, (1 r, 3R) -3-methoxycyclobutyl and (1 r, 3R) -3- (dimethylamino) cyclobutyl.

It is to be understood that the stereochemistry of the R ¹ groups provided herein is specified based on the oxygen-bonded R ¹ groups shown in the formulae provided herein (e.g., formula (Ia), formula (Ic), formula (Ie), formula (Ig), formula (Ii), and formula (Ik)).

In some embodiments, R ¹ is (R) -2-hydroxypropyl. In some embodiments, R ¹ is ((R) -oxetan-2-yl) methyl. In some embodiments, R ¹ is (S) -3, 3-trifluoro-2-hydroxypropyl. In some embodiments, R ¹ is ((S) -2, 2-difluorocyclopropyl) methyl. In some embodiments, R ¹ is ((R) -2, 2-difluorocyclopropyl) methyl. In some embodiments, R ¹ is (1R, 3R) -3-cyanocyclobutyl. In some embodiments, R ¹ is (1R, 3R) -3-fluorocyclobutyl. In some embodiments, R ¹ is (1 s,3 s) -3-fluorocyclobutyl. In some embodiments, R ¹ is ((1R, 2 s) -2-fluorocyclopropyl) methyl. In some embodiments, R ¹ is ((1 s, 2R) -2-fluorocyclopropyl) methyl. In some embodiments, R ¹ is ((1 s, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl. In some embodiments, R ¹ is ((1R, 3 s) -2, 2-difluoro-3-methylcyclopropyl) methyl. In some embodiments, R ¹ is (S) -1-cyclobutylethyl. In some embodiments, R ¹ is (R) -1-cyclobutylethyl. In some embodiments, R ¹ is ((1 s,2 s) -2-fluorocyclopropyl) methyl. In some embodiments, R ¹ is ((1R, 2R) -2-fluorocyclopropyl) methyl. In some embodiments, R ¹ is ((S) -2, 2-dimethylcyclopropyl) methyl. In some embodiments, R ¹ is (1 s,3 s) -3- (trifluoromethyl) cyclobutyl. in some embodiments, R ¹ is (R) -2-fluoropropyl. In some embodiments, R ¹ is (S) -2-fluoropropyl. In some embodiments, R ¹ is (1 s,3 s) -3-methoxycyclobutyl. in some embodiments, R ¹ is (1 s,3 s) -3- (dimethylamino) cyclobutyl. In some embodiments, R ¹ is (R) -3, 3-trifluoro-2-hydroxypropyl. In some embodiments, R ¹ is (S) -2-hydroxypropyl. In some embodiments, R ¹ is (R) -2-methoxypropyl. In some embodiments, R ¹ is (S) -2-methoxypropyl. In some embodiments, R ¹ is (1 s,3 s) -3-cyanocyclobutyl. In some embodiments, R ¹ is (1R, 3R) -3- (trifluoromethyl) cyclobutyl. In some embodiments, R ¹ is (1R, 3R) -3-methoxycyclobutyl. In some embodiments, R ¹ is (1R, 3R) -3- (dimethylamino) cyclobutyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅ isopropyl, 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3 r) -3-cyanocyclobutyl, (1 r, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methylcyclobutan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3S) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl, (1R, 3R) -3-methoxycyclobutyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, Cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3S) -3-cyanocyclobutyl, (1 r, 3R) -3- (trifluoromethyl) cyclobutyl and (1 r, 3R) -3-methoxycyclobutyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl, cyano and C ₁-C₄ -alkylsulfonyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl, and cyano.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one, two or three substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl and cyano.

In some embodiments, R ¹ is C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene optionally substituted with one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C ₁ -haloalkyl, methyl, cyano and methylsulfonyl.

In some embodiments, R ¹ is C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene optionally substituted with one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C ₁ -haloalkyl, methyl and cyano.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) ethyl, wherein each group is optionally substituted with one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, methyl, and methylsulfonyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl, and (cyclobutyl) ethyl, each of which is optionally substituted with one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, methyl, and methylsulfonyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) ethyl, wherein each group is optionally substituted with one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, and methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl, and (cyclobutyl) ethyl, wherein each group is optionally substituted with one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, and methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2-difluoro-3-methylcyclopropyl) methyl, (2, 2-difluoro-methyl-cyclopropyl) methyl, (1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2-difluoro-3-methylcyclopropyl) methyl, (1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from the group consisting of (((cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R) -2, 2-difluorocyclopropyl) methyl, ((1R, 2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((R, 3-2-fluorocyclopropyl) methyl, 3, 2-fluoro-3-methyl, (R) ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, ((R) -1R-fluorocyclopropyl) methyl, ((1R, 2R) -2R-fluorocyclopropyl) methyl ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 2-difluoro-3-methylcyclopropyl) methyl, ((1R) -2, 2-difluorocyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2S) -2R-fluorocyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((R, 2-fluorocyclopropyl) methyl, ((R, 3-fluorocyclopropyl) methyl, 2R, 2-fluorocyclopropyl) methyl, 2r, 2R, 2-fluorocyclopropyl) ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, ((R) -1R-fluorocyclopropyl) methyl, ((1R, 2R) -2R-fluorocyclopropyl) methyl ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is C ₁-C₆ -alkyl.

In some embodiments, R ¹ is C ₁-C₆ -alkyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₁-C₆ -alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C ₁-C₄ -alkoxy, and C ₁-C₄ -alkylsulfonyl.

In some embodiments, R ¹ is C ₁-C₆ -alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, and C ₁-C₄ -alkoxy.

In some embodiments, R ¹ is C ₁-C₆ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, and C ₁-C₄ -alkoxy.

In some embodiments, R ¹ is C ₁-C₅ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is C ₁-C₅ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, and methoxy.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl-d ₃, ethyl-d ₅, isopropyl, pentyl, and neopentyl, wherein each group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl, wherein each group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl-d ₃, ethyl-d ₅, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and methoxy.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and methoxy.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl-d ₅ isopropyl, 3-fluoropropyl, 2-fluoroethyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl 2, 2-trifluoroethyl group, 3-trifluoropropyl group, 2-hydroxypropyl group, ethyl group-d ₅, isopropyl group, 3-fluoropropyl group 2, 2-trifluoroethyl group, 3-trifluoropropyl group, 2-hydroxypropyl group ethyl, ethyl-d ₅, isopropyl, 3-fluoropropyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl 5, 5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl and 2-methoxypropyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (R) -2-hydroxypropyl ethyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl, (S) -3, 3-trifluoro-2-hydroxypropyl 4, 4-trifluorobutyl, 5-trifluoropentyl, fluoromethyl, neopentyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, cyanomethyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3- (methylsulfonyl) propyl and 2- (methylsulfonyl) ethyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (R) -2-hydroxypropyl ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl, (S) -3, 3-trifluoro-2-hydroxypropyl 4, 4-trifluorobutyl, 5-trifluoropentyl, fluoromethyl, neopentyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, cyanomethyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3- (methylsulfonyl) propyl and 2- (methylsulfonyl) ethyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl.

In some embodiments, R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl (R) -2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl (R) -2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, ethyl, and ethyl-d ₅.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, and ethyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, and C ₁-C₄ -alkoxy.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, and C ₁-C₄ -alkoxy.

In some embodiments, R ¹ is C ₃-C₅ -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl, methoxy, and dimethylamino.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl and methoxy.

In some embodiments, R ¹ is selected from cyclopentyl, cyclobutyl, and cyclopropyl, wherein each group is optionally substituted with one or two substituents selected from cyano, fluoro, methyl, trifluoromethyl, methoxy, and dimethylamino.

In some embodiments, R ¹ is selected from cyclopentyl, cyclobutyl, and cyclopropyl, wherein each group is optionally substituted with one or two substituents selected from cyano, fluoro, methyl, trifluoromethyl, and methoxy.

In some embodiments, R ¹ is selected from the group consisting of cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl) cyclobutyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl and 3, 3-difluorocyclobutyl.

In some embodiments, R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl) cyclobutyl, 3-methoxycyclobutyl and 3, 3-difluorocyclobutyl.

In some embodiments, R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl, (1 s, 3S) -3-methoxycyclobutyl, (1 s, 3S) -3- (dimethylamino) cyclobutyl, 3-difluorocyclobutyl, (1S, 3 s) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl, (1R, 3R) -3-methoxycyclobutyl and (1R, 3R) -3- (dimethylamino) cyclobutyl.

In some embodiments, R ¹ is selected from the group consisting of cyclopentyl, cyclobutyl, cyclopropyl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl, (1 s, 3S) -3-methoxycyclobutyl, 3-difluorocyclobutyl, (1 s,3 s) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl and (1R, 3R) -3-methoxycyclobutyl.

In some embodiments, R ¹ is C ₁-C₄ alkyl-O-C ₂-C₄ -alkylene.

In some embodiments, R ¹ is C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and C ₃-C₆ -cycloalkyl.

In some embodiments, R ¹ is C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and cyclopropyl.

In some embodiments, R ¹ is C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene optionally substituted with one, two or three substituents selected from cyano, halogen and cyclopropyl.

In some embodiments, R ¹ is selected from methoxyethyl, ((propyl) oxy) ethyl and methoxypropyl, wherein each group is optionally substituted with one, two or three substituents selected from cyano, fluoro and cyclopropyl.

In some embodiments, R ¹ is selected from the group consisting of 2- (methoxy) ethyl, 2-methoxyethyl, 2- ((prop-2-yl) oxy) ethyl, and 3-methoxypropyl, wherein each group is optionally substituted with one, two, or three substituents selected from the group consisting of cyano, fluoro, and cyclopropyl.

In some embodiments, R ¹ is selected from the group consisting of 2- (cyano (cyclopropyl) methoxy) ethyl, 2-methoxyethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 3-methoxypropyl, and 2- (trifluoromethoxy) ethyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is cyclopropyloxyethyl.

In some embodiments, R ¹ is a 3-7 membered heterocyclyl.

In some embodiments, R ¹ is a 3-7 membered heterocyclyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is a 3-7 membered heterocyclyl optionally substituted with one or more C ₁-C₄ -alkyl substituents.

In some embodiments, R ¹ is 4-5 membered heterocyclyl optionally substituted with one or more C ₁-C₄ -alkyl substituents.

In some embodiments, R ¹ is 4-5 membered heterocyclyl optionally substituted with one C ₁-C₄ -alkyl substituent.

In some embodiments, R ¹ is 4 membered heterocyclyl.

In some embodiments, R ¹ is oxetan-3-yl or pyrrolidin-3-yl, wherein each group is optionally substituted with one methyl substituent.

In some embodiments, R ¹ is oxetan-3-yl or 1-methylpyrrolidin-3-yl.

In some embodiments, R ¹ is 3-7 membered heterocyclyl-C ₁-C₄ -alkylene.

In some embodiments, R ¹ is 3-7 membered heterocyclyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is 3-7 membered heterocyclyl-C ₁-C₄ -alkylene optionally substituted with one or more C ₁-C₄ alkyl substituents.

In some embodiments, R ¹ is (4-5 membered heterocyclyl) CH ₂ -, optionally substituted with one or more methyl substituents.

In some embodiments, R ¹ is (4 membered heterocyclyl) CH ₂ -, optionally substituted with one or more methyl substituents.

In some embodiments, R ¹ is (4-5 membered heterocyclyl) CH ₂ -, optionally substituted with one methyl substituent.

In some embodiments, R ¹ is (4 membered heterocyclyl) CH ₂ -, optionally substituted with one methyl substituent.

In some embodiments, R ¹ is (oxetanyl) methyl or (siloxy) methyl, wherein each group is optionally substituted with one or two methyl substituents.

In some embodiments, R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, and (siloxane-3-yl) methyl, wherein each group is optionally substituted with one or two methyl substituents.

In some embodiments, R ¹ is (oxetan-3-yl) methyl or (oxetan-2-yl) methyl, wherein each group is optionally substituted with one methyl substituent.

In some embodiments, R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, (3-methyl-oxetan-3-yl) methyl, and (1, 1-dimethylsiloxane-3-yl) methyl.

In some embodiments, R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl and (3-methyloxetan-3-yl) methyl.

In some embodiments, R ¹ is selected from the group consisting of oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (3-methyloxetan-3-yl) methyl, and (1, 1-dimethylsiloxane-3-yl) methyl.

In some embodiments, R ¹ is selected from the group consisting of oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, and (3-methyloxetan-3-yl) methyl.

In some embodiments, R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene.

In some embodiments, R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from halogen and C ₁-C₄ -haloalkyl.

In some embodiments, R ¹ is (C ₅-C₆ -bicycloalkyl) CH ₂ - [ fluoro ] and trifluoromethyl ] optionally substituted with one or more substituents selected from the group consisting of fluoro and fluoro.

In some embodiments, R ¹ is (C ₅-C₆ -bicycloalkyl) CH ₂ - [ fluoro ] and trifluoromethyl ] optionally substituted with one substituent selected from the group consisting of fluoro and fluoro.

In some embodiments, R ¹ is (bicyclo [1.1.1] pentyl) methyl or (bicyclo [2.1.1] hexyl) methyl, wherein each group is optionally substituted with one substituent selected from fluoro and trifluoromethyl.

In some embodiments, R ¹ is (bicyclo [1.1.1] pent-1-yl) methyl or (bicyclo [2.1.1] hex-1-yl) methyl, wherein each group is optionally substituted with one substituent selected from the group consisting of fluoro and trifluoromethyl.

In some embodiments, R ¹ is selected from (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, and (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl.

In some embodiments, R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more halo substituents.

In some embodiments, R ¹ is (C ₅ -bicycloalkyl) CH ₂ -optionally substituted with one or more fluoro substituents.

In some embodiments, R ¹ is (C ₅ -bicycloalkyl) CH ₂ -optionally substituted with one fluoro substituent.

In some embodiments, R ¹ is (bicyclo [1.1.1] pentyl) methyl optionally substituted with one fluoro substituent.

In some embodiments, R ¹ is (bicyclo [1.1.1] pent-1-yl) methyl optionally substituted with one fluoro substituent.

In some embodiments, R ¹ is C ₄-C₇ -cycloalkenyl.

In some embodiments, R ¹ is C ₄-C₇ -cycloalkenyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₄-C₇ -cycloalkenyl optionally substituted with one or more halo substituents.

In some embodiments, R ¹ is C ₄ -cycloalkenyl optionally substituted with one halogen substituent.

In some embodiments, R ¹ is cyclobutenyl optionally substituted with one fluoro substituent.

In some embodiments, R ¹ is cyclobut-2-en-1-yl optionally substituted with one fluoro substituent.

In some embodiments, R ¹ is a 5-11 membered spiroheterocyclyl.

In some embodiments, R ¹ is a 5-11 membered spiroheterocyclyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is a 5-11 membered spiroheterocyclyl.

In some embodiments, R ¹ is 7 membered spiroheterocyclyl.

In some embodiments, R ¹ is oxaspiro [3.3] heptyl.

In some embodiments, R ¹ is C ₅-C₁₁ -spirocycloalkyl.

In some embodiments, R ¹ is C ₅-C₁₁ -spirocycloalkyl optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₁-C₄ -alkylsulfonyl, C ₃-C₆ -cycloalkyl, hydroxy, C ₁-C₄ -alkoxy, and C ₂-C₄ -dialkylamino.

In some embodiments, R ¹ is C ₅-C₁₁ -spirocycloalkyl.

In some embodiments, R ¹ is C ₇ -spirocycloalkyl.

In some embodiments, R ¹ is spiro [3.3] heptyl.

In some embodiments, R ¹ is cuban-C ₁-C₄ -alkylene.

In some embodiments, R ¹ is (cuban-1-yl) methyl.

In some embodiments, R ¹ is 4-8 membered heterobicycloyl-C ₁-C₄ -alkylene.

In some embodiments, R ¹ is 6 membered heterobicycloyl-CH ₂ -.

In some embodiments, R ¹ is (2-oxabicyclo [2.1.1] hexyl) methyl.

In some embodiments, R ¹ is (2-oxabicyclo [2.1.1] hex-1-yl) methyl or (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

One aspect of the present disclosure encompasses, inter alia, compounds of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₅-C₁₁ -spirocycloalkyl and cubanyl-C ₁-C₄ -alkylene;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, cyano, C ₃-C₆ -cycloalkyl and hydroxy.

One embodiment relates to compounds of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene and C ₅-C₁₁ -spirocycloalkyl;

In some embodiments, R ¹ is selected from the group consisting of R ¹ is selected from (C ₃-C₅ -cycloalkyl) CD ₂-、(C₃-C₅ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, (4-membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₇ -spirocycloalkyl and (cubanyl) CH ₂ -;

wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

In some embodiments, R ¹ is selected from the group consisting of R ¹ is selected from (C ₃-C₅ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -and C ₇ -spirocycloalkyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, ((propyl) oxy) ethyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, spiro [3.3] heptyl, (cubic) methyl, and (bicyclo [2.1.1] hexyl) methyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, ((propyl) oxy) ethyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, and spiro [3.3] heptyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, 2- ((propan-2-yl) oxy) ethyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, spiro [3.3] hept-2-yl, (cuban-1-yl) methyl, and (bicyclo [2.1.1] hex-1-yl) methyl;

In some embodiments, R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, and spiro [3.3] hept-2-yl;

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl and (bicyclo [2.1.1] hex-1-yl) methyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 2, 2-difluoroethyl, (oxetan-2-yl) methyl, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl (3-Fluorobicyclo [1.1.1] pent-1-yl) methyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl and 2-fluoropropyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl ethyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl (2, 2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, (cuban-1-yl) methyl and (bicyclo [1.1.1] pent-1-yl) methyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl cyclopropyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl (2, 2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, 3- (trifluoromethyl) cyclobutyl and 2-fluoropropyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl ethyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluorocyclopropyl, (1-methyl, (1.1-bicyclo [ 1.1-methyl ] methyl, 1-bicyclo [ 1.1-methyl ].

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 2, 2-difluoroethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl and (S) -2-fluoropropyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl-d ₅, isopropyl (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl (2-methylcyclopropyl) methyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl and (R) -2-fluoropropyl, (cuban-1-yl) methyl and (bicyclo [1.1.1] pent-1-yl) methyl.

In some embodiments, R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, isopropyl (cyclopropyl) methyl, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl and (R) -2-fluorocyclopropyl.

One embodiment relates to compounds of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, and C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁-C₄ -haloalkyl, cyano and hydroxy.

In some embodiments, R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₃-C₄ -cycloalkyl-CD ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -;

Wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -haloalkyl, cyano and hydroxy.

In some embodiments, R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -;

In some embodiments, R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₃-C₄ -cycloalkyl-CD ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, and (4-membered heterocyclyl) CH ₂ -;

Wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from halogen, C ₁ -haloalkyl, cyano and hydroxy.

In some embodiments, R ¹ is selected from the group consisting of methyl, methyl-d ₃, propyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, methoxyethyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, butyl, methoxypropyl, (cyclobutyl) methyl, and pentyl;

Wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

In some embodiments, R ¹ is selected from the group consisting of methyl, propyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, methoxyethyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, butyl, methoxypropyl, (cyclobutyl) methyl, pentyl, and (bicyclo [1.1.1] pentyl) methyl;

In some embodiments, R ¹ is selected from the group consisting of methyl, methyl-d ₃, propyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, 2-methoxyethyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, butyl, 3-methoxypropyl, (cyclobutyl) methyl, and pentyl;

In some embodiments, R ¹ is selected from the group consisting of methyl, propyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, 2-methoxyethyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, butyl, 3-methoxypropyl, (cyclobutyl) methyl, pentyl, and (bicyclo [1.1.1] pent-1-yl) methyl;

In some embodiments, R ¹ is selected from: methyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl.

In some embodiments, R ¹ is selected from: methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl.

In some embodiments, R ¹ is selected from: methyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from: methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

One embodiment relates to compounds of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

R ¹ is selected from the group consisting of C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl and C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, each of which is optionally substituted with one or more halo substituents.

In some embodiments, R ¹ is selected from the group consisting of C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, and C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, wherein each group is optionally substituted with one, two, or three halo substituents.

In some embodiments, R ¹ is selected from the group consisting of C ₂-C₃ -alkyl, cyclopropyl, C ₃-C₄ -cycloalkyl-CD ₂ -and C ₃-C₄ -cycloalkyl-CH ₂ -, wherein each group is optionally substituted with one, two or three halo substituents.

In some embodiments, R ¹ is selected from the group consisting of C ₂-C₃ -alkyl, cyclopropyl, and C ₃-C₄ -cycloalkyl-CH ₂ -, wherein each group is optionally substituted with one, two, or three halo substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, where each group is optionally substituted with one, two, or three halo substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl, and (cyclobutyl) methyl, where each group is optionally substituted with one, two, or three halo substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, where each group is optionally substituted with one, two, or three fluoro substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl, and (cyclobutyl) methyl, where each group is optionally substituted with one, two, or three fluoro substituents.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, and (2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, and (2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or two halo substituents.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, where each group is optionally substituted by one or two halo substituents.

In some embodiments, R ¹ is (cyclopropyl) methyl or (cyclobutyl) methyl, where each group is optionally substituted with one or two halo substituents.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, where each group is optionally substituted with one or two fluoro substituents.

In some embodiments, R ¹ is (cyclopropyl) methyl or (cyclobutyl) methyl, where each group is optionally substituted with one or two fluoro substituents.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, and (2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is selected from (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl and (2, 2-difluorocyclopropyl) methyl.

In some embodiments, R ¹ is C ₁-C₆ -alkyl optionally substituted with one, two, or three halo substituents. In some embodiments, R ¹ is ethyl or propyl, wherein each group is optionally substituted with one, two, or three halo substituents. In some embodiments, R ¹ is ethyl or propyl, wherein each group is optionally substituted with one, two, or three fluoro substituents. In some embodiments, R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, and ethyl.

In some embodiments, R ¹ is C ₃-C₇ -cycloalkyl.

In some embodiments, R ¹ is cyclopropyl.

Some embodiments include each combination of one or more compounds selected from the group of compounds shown in table a below, and pharmaceutically acceptable salts thereof. Some embodiments include each combination of one or more compounds selected from the group shown in table a below.

Table A

¹ A mixture of trans isomers (cyclopropyl).

² A mixture of cis-isomers (cyclopropyl).

Some embodiments of the present invention comprise each combination of one or more compounds selected from (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 1); (2R, 3R,11 bR) -3- (tert-butoxy) -9-isobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 3); (2R, 11 bR) -3- (tert-butoxy) -9- (cyclopentyloxy) -10-methoxy-1, 3, 6,7,11 b-hexahydro-2H-pyrido-2H-quino-ol (compound 1); (compound 3); (2R, 3) and (2R, 11 bR) -3- (tert-b-1-yl) and (1-yl) 1-yl ] isoquinolin-yl (1-yl) 1 ) (2R, 3R,11 bR) -3- (tert-butoxy) -9- (isopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 6), 2- (2- (((2R, 3R,11 bR) -9- ((1-fluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 7), 2R,3R,11 bR) -9-cyclobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 8), 2- (2- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 7), and 2R, 11 b-10-methoxy-1, 3,4, 7,11 b-cyclobutoxy) -9-cyclobutoxy-10-methoxy-1, 3-methoxy-1, 7,11 b-pyrido-10-methoxy-1-amino-pyrido [2,1-a ] isoquinolin (compound 8), 2R,3R, 4,6,7,11 b-hexahydro-2H-pyrido [ 2-a ] isoquinolin-2-ol (compound 2R) ) -10-methoxy-9-propoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 11), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1-hydroxycyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-cyclopropyloxy ethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 13), a (2R, 11 bR) -3- (tert-butoxy) -9- (2-fluoro-2-methylpropoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-fluoro-2-methylpropoxy) -10-methoxy-1, 3,4, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (compound 2) of (2R, 3, 11 b-hydro-2, 11 b-hexahydro-9- (tert-butoxy) -9-pyrido-2H-pyrido-2-yl-2-ol (compound 1) -pyrido [2,1-a ] isoquinolin-2-ol (compound 16); (2R, 3R,11 bR) -3- (tert-Butoxy) -10-methoxy-9- (2, 2-trifluoroethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 17), (2R, 3R,11 bR) -3- (tert-Butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 18), a (2R, 3R,11 bR) -3- (tert-Butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 19), a (2R, 3R,11 bR) -3- (tert-Butoxy) -9- ((1-fluorocyclopropyl) -10-methoxy-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 18), and (2R, 3R,11 bR) -9-cyclopropoxy-10-methoxy-2-ol (Compound 20) by-1, 7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-ol (Compound 19) (2R, 3R,11 bR) -3- (tert-butoxy) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 22), and (2R, 3R,11 bR) -3- (tert-butoxy) -9-isopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 23); (2R, 3R,11 bR) -10-methoxy-9- (2-methoxyethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 24), (2R, 3R,11 bR) -9- (cyclopropylmethoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 25), the (2R, 3R,11 bR) -9- (3-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 26), the (2R, 3R,11 bR) -9- (tert-butyloxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 25), the (2R, 3R,11 bR) -9- (3-fluoropropoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1, 11-a ] isoquinolin-2-ol (Compound 28), the (2R, 3R,11 bR) -10-hexahydro-2-H-pyrido [ 2-1, 1-a ] isoquinol-ol (Compound 28) (1, 1-trifluoropropan-2-yl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 29), (2R, 3R,11 bR) -3- (tert-butoxy) -9- (ethoxy-d ₅) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 30), (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2, 2-difluoroethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 31), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (oxetan-3, 4, 11 b-hexahydro-2-yl) -1,3, 6, 11 b-hexahydro-2-pyrido [2,1-a ] isoquinolin-2-ol (compound 30), and (2R, 3R,11 b-hexahydro-2-1-a-pyrido-2-ol (compound 3, 6,7,11 b-hexahydro-2-pyrido-1-a ] isoquinolin-2-ol (compound 33) Oxetan-2-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 34), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((S) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 35), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (4, 4-trifluorobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 36), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3-methoxypropoxy) -1,3,4, 11 b-hexahydro-2-H-pyrido [2,1-a ] isoquinolin-2-ol (compound 35), and (2R, 3R,11 b-hexahydro-9- (tert-butoxy) -1, 4-b-methoxy-H-pyrido-9- (tert-butoxy) -1, 1-b-pyrido-H-pyrido [ 2-pyrido-l (compound 3, 1-a ] isoquinolin-2-ol (compound 36) Fluoromethyl) cyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 39), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((5, 5-trifluoropentyl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 40), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3-fluoro-bicyclo [ 1.1.1.1 ] pent-1-yl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 41), 2R,3R,11 bR) -3- (tert-butoxy) -9- (fluoromethoxy) -10-methoxy-1, 3,4, 7,11 b-isoquinolin-2-ol (compound 40), and (2R, 3R,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 41), 2R,3R,11 b-methoxy-2-1, 11 b-isoquinolin-2-ol (compound 4) 2R, 11 b-methoxy-1, 11b ] isoquinolin-2-ol (compound 43) 9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2- (trifluoromethoxy) ethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 45); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (neopentyloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 46); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylcyclobutyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 47); 2R,3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((2-methylcyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 48); 2R,3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 49); 2R, 11 bR) -3- (tert-butoxy) -9-fluorocyclobutyl-2-oxy) -10-H-pyrido [2,1-a ] isoquinolin-ol (compound 48); 2R, 11 bR) -9- ((2-difluorocyclopentyl) methoxy-1, 3, 7,11 b-hexahydro-2H-pyrido-2-ol (compound (2R, 3R,11 bR) -9- ((2-oxaspiro [3.3] hept-6-yl) oxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 51), and (1R, 3 r) -3- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) cyclobutane-1-carbonitrile (compound 52), and (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 r,3, 4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 53), and (2R, 3R,11 b-hydroxy-10-methoxy-1, 3, 6, 11 b-isoquinolin-9-yl) cyclobutane-1-carbonitrile (compound 52), and (2R, 3R,11 bR) -3- (tert-butoxy) -3-fluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido-isoquinolin-2- (-3- (-2R, 3-yl) by (compound 53) Pyrido [2,1-a ] isoquinolin-2-ol (compound 55); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (spiro [3.3] hept-2-yloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 56); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylpyrrolidin-3-yl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 57); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((3-methyloxybutan-3-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] quinolin-ol (compound 56); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-2H-pyrido-2-ol (compound 58); (2R, 3, 6,7,11 b-hexahydro-2H-pyrido-2-ol (compound 57); 2R, 11 b-hexahydro-2-methoxy-9- ((3, 1-b-methoxy) -1-methoxy-3-yl) oxy-2-ol (compound 58); 1R, 11 b-methoxy-methyl-1-b-methyl-isoquinolin-2-ol (compound 1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 60), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 2S) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 61), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1S, 2R) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 62), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1S, 4,6,7,11 b-hexahydro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 4, 7,11 b-pyrido-2-methoxy-1, 3- (-3, 3-b-methoxy-1, 3- (-2-m-ol (compound 63), a (2R, 3, 6,7,11 b-hexahydro-2H-pyrido [ 2-1, 1-a ] isoquinolin-ol (compound 2) and (compound 3) 3- (tert-butoxy) -9- ((S) -1-cyclobutylethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 65), 2R,3R,11 bR) -9- ((R) -1-cyclobutylethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 66), and (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1S, 2S) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 67); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 2R) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 68); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((S) -2, 2-dimethylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 69), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 70), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1S, 3S) -3- (trifluoromethyl) cyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 71), and (2R, 11 bR) -3- (tert-butoxy) -3- (3-a ] pyridin-2-ol (compound 70), and (2R, 11bR, 11 b) -10-methoxy-9- ((1, 1-a) isoquinolin-2-ol 2,1-a ] isoquinolin-2-ol (compound 72), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((S) -2-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 73), a (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1S, 3S) -3-methoxycyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 74), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1S, 3S) -3- (dimethylamino) cyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 75), a (2R, 11 b-hexahydro-2H-pyrido [2, 7,11b ] isoquinolin-2-ol (compound 74), a (2R, 3R,11 b-hexahydro-2H-pyrido-2-ol (compound 10) and a (compound 10) of (2R, 3, 11bR, 11 b-hexahydro-2H-pyrido-2-ol) - (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 78); 2- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) acetonitrile (compound 79), 3 (R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (methoxy-d ₃) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 80), 1- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) methyl) cyclobutane-1-carbonitrile (compound 81), 1- ((((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) methyl) cyclobutane-1-carbonitrile (compound 81), and 1- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 1-a ] isoquinolin-2-yl) methyl) propan (compound 82) - (tert-butoxy) -10-methoxy-9- ((R) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 83), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((S) -2-hydroxypropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 84), a (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((R) -2-methoxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 85), a (2R, 3R,11 bR) -10-methoxy-9S) -2-methoxy-pyrido [2,1-a ] isoquinolin-2-ol (compound 84), a (2R, 3R,11 bR) -10-methoxy-9- ((R) -1, 1-a) isoquinolin-2-ol (compound 86), a (2R, 3, 11 b-methoxy-9- ((R) -10-methoxy-9- ((R) -2, 6, 11 b-methoxy-i-pyrido-2-ol (compound 86) and a (2, 1, 11 b-methoxy-pyrido) -10-methoxy-9- ((R) -2-methoxy-9- ((R, 1-b-methoxy-b) i) isoquinoline-ol (compound -alcohol (compound 87), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3- (methylsulfonyl) propoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 88), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2- (methylsulfonyl) ethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 89); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (3, 3-difluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 90), 2R,3R,11 bR) -3- ((2, 2-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 91), 1S,3 s) -3- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) cyclobutane-1-carbonitrile (compound 92), 3R,11 b-tert-butoxy) -10-methoxy-1, 3, 1-a ] isoquinolin-2-ol (compound 91), and 2R,3R,11 b-hexahydro-2H-pyrido-9-yl (compound 92), 3R,11 b-2, 3R) -3- ((3, 1-a) isoquinolin-2-ol (compound 3S, 3 s) -3- (((2R, 3R,11 bR) -3 b-2- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3, 6,7, 11H-pyrido-2H-pyrido-9-yl) on (compound 2) a ] isoquinolin-2-ol (compound 94), and (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 r, 3R) -3- (dimethylamino) cyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 95), trans- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 96), cis- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 97), and salts thereof which are pharmaceutically acceptable to the 2R,3R,11 bR) -9- ((2, 1-a ] isoquinolin-2-ol (compound 96).

Some embodiments of the present invention comprise each combination of one or more compounds selected from (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 1); (2R, 3R,11 bR) -3- (tert-butoxy) -9-isobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 3); (2R, 11 bR) -3- (tert-butoxy) -9- (cyclopentyloxy) -10-methoxy-1, 3, 6,7,11 b-hexahydro-2H-pyrido-2H-quino-ol (compound 1); (compound 3); (2R, 3) and (2R, 11 bR) -3- (tert-b-1-yl) and (1-yl) 1-yl ] isoquinolin-yl (1-yl) 1 ) (2R, 3R,11 bR) -3- (tert-butoxy) -9- (isopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 6), 2- (2- (((2R, 3R,11 bR) -9- ((1-fluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 7), 2R,3R,11 bR) -9-cyclobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 8), 2- (2- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 7), and 2R, 11 b-10-methoxy-1, 3,4, 7,11 b-cyclobutoxy) -9-cyclobutoxy-10-methoxy-1, 3-methoxy-1, 7,11 b-pyrido-10-methoxy-1-amino-pyrido [2,1-a ] isoquinolin (compound 8), 2R,3R, 4,6,7,11 b-hexahydro-2H-pyrido [ 2-a ] isoquinolin-2-ol (compound 2R) ) -10-methoxy-9-propoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 11), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1-hydroxycyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-cyclopropyloxy ethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 13), a (2R, 11 bR) -3- (tert-butoxy) -9- (2-fluoro-2-methylpropoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-fluoro-2-methylpropoxy) -10-methoxy-1, 3,4, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12), a (compound 2) of (2R, 3, 11 b-hydro-2, 11 b-hexahydro-9- (tert-butoxy) -9-pyrido-2H-pyrido-2-yl-2-ol (compound 1) -pyrido [2,1-a ] isoquinolin-2-ol (compound 16); (2R, 3R,11 bR) -3- (tert-Butoxy) -10-methoxy-9- (2, 2-trifluoroethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 17), (2R, 3R,11 bR) -3- (tert-Butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 18), a (2R, 3R,11 bR) -3- (tert-Butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 19), a (2R, 3R,11 bR) -3- (tert-Butoxy) -9- ((1-fluorocyclopropyl) -10-methoxy-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 18), and (2R, 3R,11 bR) -9-cyclopropoxy-10-methoxy-2-ol (Compound 20) by-1, 7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-ol (Compound 19) (2R, 3R,11 bR) -3- (tert-butoxy) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 22), and (2R, 3R,11 bR) -3- (tert-butoxy) -9-isopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 23); (2R, 3R,11 bR) -10-methoxy-9- (2-methoxyethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 24), (2R, 3R,11 bR) -9- (cyclopropylmethoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 25), the (2R, 3R,11 bR) -9- (3-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 26), the (2R, 3R,11 bR) -9- (tert-butyloxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 25), the (2R, 3R,11 bR) -9- (3-fluoropropoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1, 11-a ] isoquinolin-2-ol (Compound 28), the (2R, 3R,11 bR) -10-hexahydro-2-H-pyrido [ 2-1, 1-a ] isoquinol-ol (Compound 28) (1, 1-trifluoropropan-2-yl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 29), (2R, 3R,11 bR) -3- (tert-butoxy) -9- (ethoxy-d ₅) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 30), (2R, 3R,11 bR) -3- (tert-butoxy) -9- (2, 2-difluoroethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 31), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (oxetan-3, 4, 11 b-hexahydro-2-yl) -1,3, 6, 11 b-hexahydro-2-pyrido [2,1-a ] isoquinolin-2-ol (compound 30), and (2R, 3R,11 b-hexahydro-2-1-a-pyrido-2-ol (compound 3, 6,7,11 b-hexahydro-2-pyrido-1-a ] isoquinolin-2-ol (compound 33) Oxetan-2-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 34), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((S) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 35), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (4, 4-trifluorobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 36), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3-methoxypropoxy) -1,3,4, 11 b-hexahydro-2-H-pyrido [2,1-a ] isoquinolin-2-ol (compound 35), and (2R, 3R,11 b-hexahydro-9- (tert-butoxy) -1, 4-b-methoxy-H-pyrido-9- (tert-butoxy) -1, 1-b-pyrido-H-pyrido [ 2-pyrido-l (compound 3, 1-a ] isoquinolin-2-ol (compound 36) Fluoromethyl) cyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 39), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((5, 5-trifluoropentyl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 40), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3-fluoro-bicyclo [ 1.1.1.1 ] pent-1-yl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 41), 2R,3R,11 bR) -3- (tert-butoxy) -9- (fluoromethoxy) -10-methoxy-1, 3,4, 7,11 b-isoquinolin-2-ol (compound 40), and (2R, 3R,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 41), 2R,3R,11 b-methoxy-2-1, 11 b-isoquinolin-2-ol (compound 4) 2R, 11 b-methoxy-1, 11b ] isoquinolin-2-ol (compound 43) 9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2- (trifluoromethoxy) ethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 45); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (neopentyloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 46); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylcyclobutyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 47); 2R,3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((2-methylcyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 48); 2R,3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 49); 2R, 11 bR) -3- (tert-butoxy) -9-fluorocyclobutyl-2-oxy) -10-H-pyrido [2,1-a ] isoquinolin-ol (compound 48); 2R, 11 bR) -9- ((2-difluorocyclopentyl) methoxy-1, 3, 7,11 b-hexahydro-2H-pyrido-2-ol (compound (2R, 3R,11 bR) -9- ((2-oxaspiro [3.3] hept-6-yl) oxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 51), and (1R, 3 r) -3- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) cyclobutane-1-carbonitrile (compound 52), and (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 r,3, 4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 53), and (2R, 3R,11 b-hydroxy-10-methoxy-1, 3, 6, 11 b-isoquinolin-9-yl) cyclobutane-1-carbonitrile (compound 52), and (2R, 3R,11 bR) -3- (tert-butoxy) -3-fluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido-isoquinolin-2- (-3- (-2R, 3-yl) by (compound 53) Pyrido [2,1-a ] isoquinolin-2-ol (compound 55); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (spiro [3.3] hept-2-yloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 56); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((3-methyloxybutan-3-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 58); (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylcyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 56); (2R, 3R,11 bR) -10-methoxy-9- ((3, 4,6,7,11 b-hexahydro-2H-pyrido-2-ol (compound 59); (2R, 3, 1-b-methoxy) -1-2H-pyrido-ol (compound 58); 1R, 1-b-methoxy-10-methoxy-9- (-1-b-methoxy) -1- (tert-butoxy) -2-yl) 1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 61); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1S, 2R) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 62), the (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 63), the (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 64), and the (2R, 11 b-hexahydro-2H-pyrido-2-ol (compound 3, 7,11 b-hexahydro-pyrido-1, 11-a) isoquinolin-2-ol (compound 63) Tert-butoxy) -9- ((R) -1-cyclobutylethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 66), 2R,3R,11 bR) -3- (tert-butoxy) -9- (((1S, 2S) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 67), 2R,3R,11 bR) -3- (tert-butoxy) -9- (((1R, 2R) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 68); (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((S) -2, 2-dimethylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 69), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 70), and (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1S, 3S) -3- (trifluoromethyl) cyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 71), and (2R, 11 bR) -3- (tert-butoxy) -10-methoxy-1, 4, 7,11 b-hexahydro-2H-pyrido [ 2-a ] isoquinolin-2-ol (compound 71), and (2R, 11 b-methoxy-9- ((1, 1-a) isoquinolin-2-ol (compound 70) In-2-ol (Compound 73), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 s, 3S) -3-methoxycyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 74), (2S, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 76), 2- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy), acetonitrile (2R, 3R,11 bR) -3- (tert-butoxy) -10-dimethoxy-1, 3,4, 7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 79), and (2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3, 6,7,11 b-methoxy-1-isoquinolin-ol (Compound 80) Compound 81), 1- ((((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) methyl) cyclopropane-1-carbonitrile (compound 82), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((R) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 83), 2R,3R,11 bR) -3- (tert-butoxy) -9- ((S) -2-hydroxypropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 84), 2R, 11 b-hexahydro-2-3, 1-a ] isoquinolin-2-ol (compound 84), and (2R, 3R,11 b-hexahydro-2H-pyrido-2, 1-a ] isoquinolin-2-ol (compound 83), and (2R, 3R,11 b-hexahydro-2H-pyrido-2, 1-a ] isoquinol-2-ol (compound 3, 7,11 b-hexahydro-1, 11-yl) hexahydro-2-yl) isoquinol-2-ol (compound 3 -2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 86), (2R, 3R,11 bR) -3- (tert-butoxy) -9- (3, 3-difluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 90), (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 91), and (1S, 3 s) -3- (((2R, 3R,11 bR) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy-10-methoxy-1, 3R, 4, 11 b-hexahydro-2H-pyrido [ 2-a ] isoquinolin-2-ol (compound 90), and (3R, 11 b-hexahydro-2H-pyrido-2-ol (compound 92) of formula (compound 91), and (1S, 3 s) -3- (. 1-b-hexahydro-2H-isoquinolin-2-ol (compound 92) of formula (1, 1-b-1-b) or-1-yl) ) -3-methoxycyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 94), trans- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 96); Trans- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 97), and cis- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 98), or a pharmaceutically acceptable salt thereof.

Some embodiments of the invention comprise each combination of one or more compounds selected from (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 99), a (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cubic-1-ylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 100), a (2R, 3R,11 bR) -9- (bicyclo [1.1.1] pent-1-ylmethoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6, 11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 101), and a (2R, 11 b-hexahydro-2H-pyrido-1, 3, 1-a ] isoquinolin-2-ol (compound 101), a (2R, 3R,11 b-hexahydro-2H-pyrido-2-ol) (compound 1) and a (compound 1) of (2R, 3R,11 bR) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4, 7,11 b-hexahydro-2H-pyrido-2-ol -2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 103), (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 104), (2R, 3R,11 bR) -9- ((2-oxabicyclo [2.1.1] hex-1-yl) methoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 105), and (2R, 11 bR) -9- ((2-oxabicyclo [2.1.1] hex-4-yl) methoxy) -3- (tert-butoxy) -10-methoxy-1, 3, 11 b-isoquinolin-2-ol or a pharmaceutically acceptable salt thereof.

Intermediate suitable for use

Certain intermediates as described hereinabove and hereinbelow are novel and useful in the preparation of compounds such as compounds of formula (Ia), formula (Ic), formula (Ie), formula (Ig), formula (Ii) and formula (Ik). Some intermediates are shown in fig. 2A and 2B.

In some embodiments, the compound is selected from 3- (tert-butoxy) -4- (dimethylamino) butan-2-one, 1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one, 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, 3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof.

In some embodiments, the compound is 3- (tert-butoxy) -4- (dimethylamino) butan-2-one or a salt thereof:

In some embodiments, the compound is (R) -3- (tert-butoxy) -4- (dimethylamino) butan-2-one or a salt thereof. In some embodiments, the compound is (S) -3- (tert-butoxy) -4- (dimethylamino) butan-2-one or a salt thereof.

In some embodiments, the compound is selected from 1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one, 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, and 3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof.

In some embodiments, the compound is 1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one or a salt thereof:

In some embodiments, the compound is (R) -1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one or a salt thereof. In some embodiments, the compound is (S) -1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one or a salt thereof.

In some embodiments, the compound is 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one or a salt thereof. In some embodiments, the compound is (3R, 11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one or a salt thereof:

In some embodiments, the compound is (3S, 11 bS) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one or a salt thereof.

In some embodiments, the compound is 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a salt thereof. In some embodiments, the compound is (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a salt thereof:

In some embodiments, the salt is a (2 s,3 s) -2, 3-bis (4-methylbenzyloxy) succinic acid (DPTTA) salt. In some embodiments, the compound is:

In some embodiments, the compound is (2 s,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a salt thereof. In some embodiments, the compound is (2R, 3S,11 bS) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a salt thereof. In some embodiments, the compound is (2 s,3s,11 bs) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or a salt thereof.

In some embodiments, the compound is 3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof. In some embodiments, the compound is (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22), or a salt thereof:

in some embodiments, the compound is (2S, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof. In some embodiments, the compound is (2R, 3S,11 bS) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof. In some embodiments, the compound is (2S, 3S,11 bS) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol, or a salt thereof.

It is also to be appreciated that certain features, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Pharmaceutical composition, formulation and dosage form

The present disclosure also provides pharmaceutical products, such as pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound as described herein, or a pharmaceutically acceptable salt thereof.

The present disclosure also provides pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in the methods described herein, such as for treating hyperkinesia. Pharmaceutically acceptable excipients are physiologically and pharmaceutically suitable non-toxic and inactive materials or ingredients that do not interfere with the activity of the drug substance, and may also be referred to as carriers. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, properties, AND SAFETY, 5 th edition, 2006 and Remington: THE SCIENCE AND PRACTICE of Pharmacy (Gennaro, 21 st edition Mack Pub. Co., easton, pa., 2005).

The compositions may also be formulated as pills, capsules, granules or tablets, containing diluents, dispersants and surfactants, binders and lubricants in addition to the VMAT2 inhibitor. The VMAT2 inhibitor may also be further formulated by those skilled in the art in a suitable manner and in accordance with accepted practices, such as those disclosed in Remington, supra.

Methods of administration include systemic administration of the VMAT2 inhibitors described herein, preferably in the form of a pharmaceutical composition as discussed above. Systemic administration as used herein includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, and liquids, syrups, suspensions and emulsions.

Pharmaceutical formulations for oral administration may be obtained by any suitable method, typically by uniformly mixing the compound with a liquid or finely divided solid carrier or both in the desired proportions, and if desired, treating the mixture after the addition of suitable adjuvants, and if desired, shaping the resulting mixture into the desired shape to obtain tablets or dragee cores.

Conventional excipients, such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants, can be used in the tablets and capsules for oral administration. Liquid formulations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral formulation may be in the form of a dry powder which may be reconstituted with water or another suitable liquid vehicle prior to use. Parenteral dosage forms may be prepared by dissolving the compound in a suitable liquid vehicle and filter sterilizing the solution prior to lyophilization, or simply filling and sealing the appropriate vial or ampoule.

Some embodiments provide a method for preparing a pharmaceutical composition comprising the step of admixing a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the drug substance such carriers as are known in the art to be appropriate.

In preparing pharmaceutical compositions, the drug substance is typically mixed (i.e., admixed) with an excipient, diluted with an excipient, or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material, which serves as a vehicle, carrier, or medium for the drug substance. Thus, the compositions may be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For preparing pharmaceutical compositions in solid form, such as powders, tablets, capsules, cachets, suppositories, and dispersible granules, the excipient can be one or more substances that can also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Also included are solid form preparations for conversion immediately prior to use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example water or water-propylene glycol solutions. Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent.

The pharmaceutical compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the pharmaceutical composition may be in powder form, obtained by sterile isolation of sterile solids or by lyophilization from solution, for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use.

The pharmaceutical compositions may be formulated as aqueous solutions, aqueous-alcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or lyophilized powders for reconstitution. Such pharmaceutical compositions may be administered directly or as a further diluted/reconstituted mixture. Routes of administration include intravenous bolus injection, intravenous infusion, and instillation.

Aqueous formulations suitable for oral use may be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided drug substance with the viscous substance in water.

For topical application to the epidermis, the compounds described herein or pharmaceutically acceptable salts thereof may be formulated as a gel, ointment, cream or lotion, or as a transdermal patch. In addition, formulations suitable for topical application in the oral cavity include lozenges comprising a drug substance in a flavored basis.

The solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be presented in single or multiple dose forms. In the latter case of a dropper or pipette, this may be achieved by administering an appropriate predetermined volume of solution or suspension to the patient. In the case of a nebulizer, this can be achieved, for example, by metering an atomizing spray pump.

Administration to the respiratory tract may also be achieved by providing an aerosol formulation with a suitable propellant in a pressurized package. If the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, are administered as an aerosol, e.g., as a nasal aerosol or by inhalation, this can be done, for example, using a nebulizer, pump nebulizer, inhalation device, metered dose inhaler, or dry powder inhaler.

Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder matrix (such as lactose, starch derivatives). Suitably, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in a gelatin capsule or cartridge, or in a blister pack from which the powder may be administered by an inhaler.

The compounds as described herein, or pharmaceutically acceptable salts thereof, may also be administered via a fast dissolving or slow release composition, wherein the composition comprises a biodegradable fast dissolving or slow release carrier.

The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the drug substance. The unit dosage form may be an encapsulated formulation containing discrete amounts of the formulation, such as an encapsulated tablet, capsule, and powder in a vial or ampoule. Furthermore, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these dosage forms in encapsulated form. In some embodiments, the pharmaceutical formulation is a tablet or capsule for oral administration. In some embodiments, the pharmaceutical formulation is a liquid formulated for intravenous administration.

The composition may be formulated in unit dosage form, each dosage containing a drug substance or equivalent mass of drug substance. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable excipient as described herein.

Liquid forms including pharmaceutical substances, including aqueous solutions, suitably flavoured syrups, aqueous or oily suspensions, and flavoured emulsions with edible oils, may be incorporated for oral administration or administration by injection.

The pharmaceutical compositions described herein may be sterilized by conventional sterilization techniques, or may be sterile filtered. The aqueous solution may be packaged for use as such, or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effects. The composition may be atomized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a mask holder or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

If desired, the composition may be present in a packaging or dispenser device, which may contain one or more unit dosage forms containing the drug substance. The package may for example comprise a metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice associated with the container in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency of the pharmaceutical form for human or veterinary administration. Such notice may be, for example, a label for a prescription drug approved by the U.S. food and drug administration, or an approved product specification. Compositions that may include the compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

For preparing solid compositions, such as tablets, the drug substance may be mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of components. When referring to these preformulated compositions as homogeneous, the drug substance is typically dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets and capsules.

Kits are provided having a unit dose of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, typically an oral or injectable dose. Such kits may include a container containing a unit dose, a package insert of information describing the use and attendant benefits of the drug in treating the associated pathological condition, and optionally an instrument or device for delivering the composition.

The compounds described herein, or pharmaceutically acceptable salts thereof, may be effective over a wide dosage range and are generally administered in therapeutically effective amounts. However, it will be appreciated that the amount of the compound actually administered will generally be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual, the severity of the individual's symptoms, and the like.

The amount of the compound or composition administered to an individual will also vary depending on the drug being administered, the purpose of administration (such as prophylaxis or treatment), the state of the individual, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to an individual already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and/or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease condition being treated and the discretion of the attending clinician based on factors such as the severity of the disease, the age, weight and general condition of the individual, and the like.

The required dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals (e.g. in sub-doses of two, three, four or more times a day). The sub-doses themselves may be further divided into, for example, a plurality of discrete, loosely spaced applications. The daily dose may be divided into several, for example two, three or four-part administration, especially when a relatively large amount of administration is considered suitable. If appropriate, depending on the individual behaviour, it may be desirable to deviate upwards or downwards from the indicated daily dose.

It will be apparent to those skilled in the art that the dosage forms described herein may comprise the compounds described herein or pharmaceutically acceptable salts thereof.

Formulations

As used herein, a "formulation" is the product of a process for preparing or isolating a compound as disclosed and described herein, wherein the formulation comprises at least one other component in addition to the compound. In some embodiments, the formulation comprises a chemical entity.

As used herein, a "chemical entity" defined in the context of a "formulation" refers to a compound as disclosed and described herein as well as at least one other component in addition to the compound. For example, the chemical entity may be a co-crystal or salt of a compound as disclosed and described herein.

Some embodiments provide formulations comprising a compound as disclosed and described herein. In some embodiments, the compound is a component of a chemical entity. In some embodiments, the chemical entity is a salt of a compound as disclosed and described herein. In some embodiments, the chemical entity is a (2 s,3 s) -2, 3-bis (4-methylbenzyloxy) succinic acid (DPTTA) salt of a compound as disclosed and described herein.

In some embodiments, the compound of the formulation is in an enantiomeric excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, 99.9%, or 100%, or an enantiomeric excess within a range defined by any of the foregoing numbers. In some embodiments, the compound of the formulation is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or 100% enantiomeric excess, or an enantiomeric excess within a range defined by any of the foregoing numbers.

In some embodiments, the compound of the formulation is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 99.9% diastereomeric excess, or diastereomeric excess within a range defined by any one of the foregoing numbers. In some embodiments, the compound of the formulation is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% diastereomeric excess, or diastereomeric excess within a range defined by any of the foregoing numbers.

In some embodiments, the formulation comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 93% by weight of the compound, or a percentage of the compound within a range defined by any of the foregoing figures. In some embodiments, the formulation comprises at least 50%, 60%, 70%, 80%, 90% or 93% by weight of the compound, or a percentage of the compound within a range defined by any of the foregoing figures. In some embodiments, the formulation comprises up to 50%, 60%, 70%, 80%, 90%, 93% or 95% by weight of the compound, or a percentage of the compound within a range defined by any of the foregoing figures.

In some embodiments, the formulation comprises at least 50% by weight of the compound. In some embodiments, the formulation is in a solid form, i.e., a solid formulation. In some embodiments, the formulation is used to prepare a pharmaceutical composition.

Application method

The compounds described herein are inhibitors of VMAT 2. Accordingly, the present disclosure includes methods of inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing expression of VMAT 2) by contacting VMAT2 with a compound as disclosed and described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting can be performed in vitro, such as VMAT 2in a purified preparation or in a cell located outside of the organism (e.g., in a tissue sample or cell preparation). In some embodiments, the contacting can be performed in vivo, such as VMAT2 being located in an organism.

The VMAT2 inhibitors described herein may reduce monoamine levels in the central nervous system. Accordingly, the present disclosure includes methods of reducing monoamine levels in the central nervous system of an individual comprising administering to the individual a compound as described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce monoamine levels relative to levels prior to administration.

VMAT2 inhibitors as disclosed and described herein are believed to have utility in a wide range of therapeutic applications and may be useful in the treatment or prevention of various disorders caused by or associated with inhibition of human vesicle monoamine transporter isoform 2. These disorders include neurological and psychiatric disorders such as hyperkinesias, schizophrenia, and mood disorders. The compounds as described herein, or pharmaceutically acceptable salts thereof, may be used in any of the methods of treatment disclosed and described herein.

Thus, in various embodiments as disclosed herein, there is provided a method of treating or preventing a neurological and/or psychiatric disease or disorder in a subject in need thereof by administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof. The neurological and/or psychiatric disease or disorder may be, for example, hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-related tremor-ataxia syndrome, autism spectrum disorders (e.g., restricted and repetitive behaviors associated with Autism Spectrum Disorders (ASD)), rate syndrome or chorea-acanthocytosis.

In various other embodiments as disclosed herein, methods are provided for treating or preventing a vesicle monoamine transporter-2 (VMAT 2) disease or disorder in a subject in need thereof by administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof. The VMAT2 disease or disorder may be, for example, ataxia or spinal muscular atrophy, chorea, congenital malformations, deformations or abnormalities, dementia, diseases of the mouth, salivary glands or jaw, movement disorders, dystonias, endocrine, nutritional or metabolic diseases, epilepsy, habit or impulse disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and somatoform disorders, degenerative diseases of the basal ganglia, extrapyramidal and movement disorders, neurological or psychiatric diseases or disorders, neurological or movement disorders, parkinson's disease/parkinsonism, childhood onset behavioral and mood disorders, pervasive developmental disorders, and substance abuse or dependency disorders.

Thus, in various embodiments as disclosed herein, there is provided a method of treating or preventing hyperkinesia in a subject in need thereof by administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the hyperkinesia is tardive dyskinesia, tourette's syndrome, huntington's disease, chorea associated with huntington's disease, or tics. In other embodiments, the hyperkinesia is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, or tremor.

In some embodiments, methods are provided for treating or preventing a mood disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the mood disorder is bipolar disorder, major depressive disorder, mania in a mood disorder, or depression in a mood disorder.

In some embodiments as disclosed herein, methods are provided for treating or preventing schizophrenia or schizoaffective disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the neurological or psychiatric disease or disorder is hyperkinesia.

In some embodiments, the hyperkinesia is tardive dyskinesia.

In some embodiments, the hyperkinesia is tourette's syndrome.

In some embodiments, the hyperkinesia is huntington's disease.

In some embodiments, the hyperkinesia is tics.

In some embodiments, the hyperkinesia is chorea associated with huntington's disease.

In some embodiments, the hyperkinesia is ataxia, chorea, dystonia, hemifacial spasm, huntington's disease, myoclonus, restless leg syndrome, or tremor.

In some embodiments, the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder.

In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.

In some embodiments, the neurological or psychiatric disease or disorder is a schizoaffective disorder.

In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder.

In some embodiments, the neurological or psychiatric disease or disorder is restricted and repetitive behavior associated with Autism Spectrum Disorder (ASD).

In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive ideas and compulsions in partial and non-responders (or complete refractory) to obsessive-compulsive disorder (OCD). In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive ideas and compulsions in partial and non-responders (or complete refractory) to obsessive-compulsive disorder (OCD), and the compounds described herein are administered as adjuvant therapy. In some embodiments, the compounds described herein may be used as an adjunct therapy or adjunct therapy for schizophrenia. In some embodiments, the compounds described herein are administered as an adjuvant therapy, wherein the primary therapy is treatment with an antidepressant.

In some embodiments, the neurological or psychiatric disease or disorder is a bipolar I disorder. In some embodiments, the compounds described herein are administered as monotherapy for the treatment of bipolar I disorder. In some embodiments, the compounds described herein are administered as maintenance therapy for the treatment of bipolar I disorder. In some embodiments, the compounds described herein are administered as monotherapy or maintenance therapy for the treatment of bipolar I disorder.

In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat or prevent a disease or disorder selected from the group consisting of:

ataxia or spinal muscular atrophy, such as spinocerebellar ataxia 17/HDL 4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital bulbar amyotrophy, dentate nucleus-pallidum atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia;

Chorea such as benign hereditary chorea, chorea associated with mitochondrial diseases/etiology, chorea associated with wilson's disease, gestational chorea, chorea-acanthocytosis, drug-induced chorea, hemitossing disease, rheumatic/chorea and thyrotoxic chorea/hyperthyroidism chorea;

Congenital malformations, deformations or abnormalities, such as angel's syndrome, congenital neurological disorders, eichhorns syndrome, neurofibromas, congenital facial nerve dysplasia, moebius syndrome type II, cokaen's syndrome, sjogren-larson syndrome, laus Meng Bizeng syndrome, fragile X syndrome and prader-willi syndrome;

Dementia, such as AIDS-related dementia, alzheimer's disease, congenital neurodegeneration, dementia with lewy bodies, micro-infarct dementia, presenile dementia, senile dementia and vascular dementia;

Oral, salivary gland and jaw diseases such as glowing syndrome and temporomandibular joint disorders;

movement disorders such as pharyngeal movement disorders, movement disorders (newborns), movement disorders (oesophagus), levodopa-induced movement disorders, paroxysmal non-movement disorder movement disorders and respiratory movement disorders;

dystonia, such as blepharospasm, cheek-tongue syndrome, drug-induced acute dystonia, early onset primary dystonia, hereditary torqueous dystonia, hand dystonia/writer cramps, idiopathic non-familial dystonia, idiopathic orofacial dystonia/mezzo, laryngeal dystonia, oromandibular dystonia, and spasmodic torticollis/cervical dystonia;

Endocrine, nutritional and metabolic diseases such as wilson's disease, diabetes, obesity, syndrome X and Lesch-Nyhan syndrome;

Epilepsy such as baldric sea myoclonus epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, love nale myoclonus epilepsy, severe myoclonus epilepsy in infancy and convulsions;

Habit and impulse disorders such as binge eating, kleptomania, impulse control disorders, trichotillomania, intermittent explosive disorders, pathological gambling and firebreak;

Huntington's disease or related disorders such as huntington's disease, huntington's disease-like syndrome 1-3, huntington's disease and X-chromosome linked mclude syndrome;

Mood or psychotic disorders such as schizophrenia, psychosis, mania, bipolar disorders, depression and mood disorders;

other diseases or conditions such as groggy disorders, hypokinesia (neonatal), dyskinesia, rabbit syndrome, spasticity, excitation and hypokinesia, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders and rheumatoid arthritis;

Neurological disorders, stress-related disorders and somatoform disorders such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive compulsive disorder, post traumatic stress disorder and psychomotor disorders;

Other degenerative diseases of the basal ganglia such as pantothenate kinase-associated neurodegenerative diseases, progressive supranuclear palsy, multiple system atrophy, dysreading, basal ganglia degenerative diseases, and neuroferritosis;

Other extrapyramidal and dyskinesias such as hemifacial throwing disorders, extrapyramidal disorders, essential tremors, chin tremors, startle excess, akathisia, throwing disorders/hemifacial throwing disorders, myoclonus and restless leg syndrome/wils-exsiccator syndrome;

Other nervous system or motor functions such as sleep-related bruxism, abnormal involuntary movement disorder, heterolimb syndrome, alzheimer's disease (agitation), clumsiness, clonic hemifacial spasm, olfactory nerve hypoplasia, congenital cranial nerve paralysis, ataxia syndrome, familial periodic paralysis, congenital hemiplegia, fine motor delay, fine motor skill dysfunction, coarse motor delay, multiple sclerosis, congenital achalasia, congenital Huo Nazeng syndrome, childhood alternating hemiplegia, motor development retardation, cerebral paralysis, hand-foot type cerebral paralysis, posture disorders, pseudoparalysis, psychomotor hyperactivity, bradykinesia, linkage, akinesia, lisi-dydrome and athetosis;

Parkinson's disease/parkinsonism, such as parkinsonism, drug-induced parkinsonism, undersea writing and parkinsonism;

Childhood onset behavioral and mood disorders such as attention deficit hyperactivity disorder, attention deficit disorder, hyperkinesia (neonatal), oppositional defiant disorder, transient tic disorder, persistent (long-term) movement or vocal tic disorder, notch board type movement disorder, notch board type and tourette's syndrome;

Pervasive developmental disorders such as autism spectrum disorder, rate syndrome, alsberg syndrome, pervasive developmental disorder NOS and dyskinesia, and

Substance abuse or dependence such as addiction disorders, alcoholism, cocaine dependence, illicit substance abuse, methamphetamine addiction/dependence, methamphetamine use disorders, morphine abuse, morphine analog abuse, nicotine dependence, multi-substance abuse, and prescription substance abuse.

In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat or prevent paralysis. In some embodiments, the paralysis is selected from spastic cerebral palsy (including but not limited to spastic hemiplegic cerebral palsy, spastic bilateral paralytic cerebral palsy, and spastic quadriplegic cerebral palsy), dyskinesic cerebral palsy, ataxia cerebral palsy, and "mixed" cerebral palsy.

In some embodiments, the paralysis is spastic cerebral paralysis.

In some embodiments, the paralysis is dyskinesia cerebral paralysis.

In some embodiments, the paralysis is ataxia cerebral paralysis.

In some embodiments, the paralysis is a "mixed" cerebral paralysis.

The phrase "mixed" cerebral palsy includes a mixture of symptoms associated with other types of cerebral palsy.

In some embodiments, the treated patient has been determined to have 22q11.2 deficiency syndrome. In some embodiments, the patient is predisposed to developing a psychotic disorder as the patient suffers from 22q11.2 deficiency syndrome. In some embodiments, the patient has been determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to developing psychotic disorders due to the patient having insufficient COMT haploids.

In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in the body of a mammal to a compound that can inhibit human vesicle monoamine transporter isoform 2. Thus, these VMAT2 inhibitors may have additional utility in altering in vivo properties of metabolites in mammals, such as maximum concentration or duration of action.

Characterization of any VMAT2 inhibitor described herein can be determined using the methods described herein and by one of skill in the art. For example, the activity of exercise (LMA) assay may be used to determine dopamine consumption. Another in vivo animal model includes a Conditional Avoidance Response (CAR) test, which has proven to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds.

Combination therapy

The compounds of the present disclosure and pharmaceutically acceptable salts thereof may be used as monotherapy, or in combination with one or more other agents. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is administered (simultaneously or sequentially) with one or more drugs selected from the group consisting of antidepressants, antipsychotics (typical or atypical), antiepileptics, antibacterial agents, antiarrhythmic agents, mood stabilizers, and gastrointestinal drugs. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is used in an adjuvant therapy, which refers to a treatment used in combination with a primary treatment, and the purpose of which is to aid the primary treatment. Adjuvant therapy is typically co-administered therapy. As an example of adjuvant therapy, if obsessive-compulsive disorder is being treated, the primary therapy may be, for example, an antidepressant, and co-administration of a compound described herein will be considered adjuvant therapy.

Synthesis of Compounds

Detailed methods of compound synthesis are described herein in the examples. Typically, the starting components are commercially available chemicals and may be obtained from commercial sources or may be prepared starting from commercially available chemicals and/or from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art.

In general, the compounds used in the reactions described herein may be prepared starting from commercially available chemicals and/or from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. Methods known to those of ordinary skill in the art can be identified by various reference books and databases. Details of synthesis of reactants that may be used to prepare compounds of the present disclosure or to provide a suitable reference book and paper describing the preparation include, for example, "SYNTHETIC ORGANIC CHEMISTRY," John Wiley & Sons, inc., new York; S.R. Sandler et al, "Organic Functional Group Preparations," 2 nd edition, ACADEMIC PRESS, new York,1983; H.O. House, "Modern Synthetic Reactions," 2 nd edition, W.A.Benjamin, inc.Menlo Park, calif.1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2 nd edition ,John Wiley&Sons,New York,1992;J.March,"Advanced Organic Chemistry:Reactions,Mechanisms and Structure,", 4 th edition, wiley-Interscience, new York,1992.

Specific and similar reactants can also be identified by an index of known chemicals prepared by the american Society of chemistry abstract (Chemical Abstract Service of THE AMERICAN CHEMICAL Society), which is available in most public and university libraries, and by an online library, which can be contacted by the american Society of chemistry (AMERICAN CHEMICAL Society), washington, d.c. to obtain further details. Chemicals that are known but not listed in the catalog may be prepared by custom chemical synthesis institutions according to known methods, with many standard chemical supply institutions (such as those listed above) providing custom synthesis services.

Examples

The following examples are included to demonstrate embodiments of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Other exemplary syntheses of the compounds of the present invention are illustrated in the accompanying drawings, wherein the symbols have the same definition as used in the present disclosure.

Analytical HPLC analysis was performed on an LC-MS system with a UV detector (Dionex ^TM UVD 170u UV/VIS detector), a corona array detector (Thermo ^TMVeo^TM RS) and a mass spectrometer (Dionex MSQ Plus ^TM). Reverse phase preparative HPLC purification was performed on a Phenomenex liquid chromatography-mass spectrometry (LCMS) system C ₁₈ Kinetix μ 100a 150x 21.2mm column using ACN/water gradient with 0.05% TFA. Supercritical fluid chromatography purification (SFC) was performed using a Waters ^TM Prep 100q^TM system equipped with a UV detector (Waters ^TM 2998Photodiode Array Detector^TM) and a mass spectrometer (Waters ^TM Acquity QDa Detector^TM). Use of Waters ^TM Viridis^TM BEH 2-ethylpyridineA5 μm,30mm x100mm column was run with CO2 and 0.3% NH ₄ OH/MeOH gradient at 100mL/min,40℃and 105 bar back pressure regulator. All final compounds were analyzed by analytical HPLC and peaks of purity were monitored at 210, 254 and 280 nm. The Z gradient was used to record ¹H.¹ H chemical signals given in parts per million (ppm) in an appropriate NMR solvent such as dimethylsulfoxide-d ₆ (DMSO-d 6) on a Bruker 400MHz spectrometer equipped with a broadband NMR probe, or on a Bruker500MHz spectrometer equipped with a 5mm QNP probe, with the residual solvent signal used as a reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Unless otherwise indicated, the reaction was carried out under a dry nitrogen atmosphere.

Example 1 (2R, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 15), 2S,3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 76), 2S,3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 77), and 2R,3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 4, 7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 78).

Step 1 preparation of N, N-trimethyl-3-oxobutan-1-ium iodide (Compound 2-2).

To a solution of 4- (dimethylamino) butan-2-one (compound 2-1,15.0g,130mmol,1.0 eq.) in EtOAc (260 mL) was added methyl iodide (55.4 g,390mmol,3.0 eq.) and the mixture was stirred at Room Temperature (RT) overnight. The mixture was concentrated in vacuo to give crude N, N, N-trimethyl-3-oxobut-1-ium iodide (compound 2-2,31.51g,123mmol, 94%) as a pale red solid, which was used without further purification .¹H NMR(400MHz,DMSO-d₆):δ(ppm)3.50(t,J＝7.5Hz,2H),3.12-3.09(t,J＝7.0Hz,2H),3.04(s,9H),2.18(s,3H).

Step 2 preparation of (+ -) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (Compound 2-4).

To a solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (compound 2-3,6.60g,34.5mmol,1.0 eq.) in MeOH (66 mL) was added N, N, N-trimethyl-3-oxobutan-1-ammonium iodide (compound 2-2,13.3g,51.8mmol,1.5 eq.) and the mixture stirred under reflux for 1 hour. The mixture was cooled to RT and stirred for 1 hour. The mixture was concentrated in vacuo, suspended in water, and extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations using a DCM-loaded silica gel column (220 g), run with an increasing gradient of MeOH (0-5%, over 20 min)/DCM, and a DCM-loaded silica gel column (40 g), run with an increasing gradient of EtOAc (0-100%, over 20 min)/hexane, to further purify the combined fractions to give (+ -) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-4,6.89g,26.4mmol, 77%) as an off-white solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.71(s,1H),6.70(s,1H),3.72(s,6H),3.46(br d,J＝11.1Hz,1H),3.25-3.16(m,1H),3.14-3.05(m,1H),2.98-2.83(m,2H),2.71-2.56(m,3H),2.49-2.42(m,1H),2.34(dd,J＝12.0,14.2Hz,1H),2.23(br d,J＝11.2Hz,1H).

Step 3 preparation of (+ -) -3- ((dimethylamino) methylene) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-5).

To a solution of (±) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-4,4.40g,16.8mmol,1.0 eq.) in THF (44 mL) was added 1-tert-butoxy-N, N' -tetramethylenediamine (3.52 g,20.2mmol,1.2 eq.) and the mixture was stirred under reflux overnight. The mixture was cooled to RT and diluted with water (40 mL) and aqueous HCl (1 m,50.5mL,50.5mmol,3.0 eq.) and stirred for 1h. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted three times with 5:1 DCM:i-PrOH. The aqueous layer was adjusted to ph=7 and extracted three times with 5:1 dcm:i-PrOH. The organic layer was discarded. The aqueous layer was concentrated in vacuo and then left under vacuum overnight to give (±) -3- ((dimethylamino) methylene) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-5,4.39g,13.9mmol, 83%) as a viscous yellow solid, which was used further without further purification.

Preparation of sodium (+ -) - (9, 10-dimethoxy-2-oxo-1, 6,7,11 b-tetrahydro-2H-pyrido [2,1-a ] isoquinolin-3 (4H) -ylidene) methoxide (Compound 2-6).

To a solution of (. + -.) -3- ((dimethylamino) methylene) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-5,4.19g,13.2mmol,1.0 eq.) in water (80 mL) at 0deg.C was added aqueous HCl (12.1M, 2.7mL,33.0mmol,2.5 eq.) and stirred for 30 min. The mixture was warmed to RT and stirred overnight. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted three times with EtOAc. The organic extract was discarded. The aqueous layer was basified with aqueous NaOH (6M) to ph=11. The aqueous layer was concentrated. The crude material was slurried in MeOH (50 mL). The solid precipitate was collected by vacuum filtration through celite. The filtrate was concentrated to give crude (+ -) - (9, 10-dimethoxy-2-oxo-1, 6,7,11 b-tetrahydro-2H-pyrido [2,1-a ] isoquinolin-3 (4H) -ylidene) sodium methoxide (compound 2-6,5.61 g) as a solid, of which 2.10g was directly used in the next step (i.e., synthesis of (+ -) -3-diazonium-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-7)).

Step 5 preparation of (+ -) -3-diazo-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (Compound 2-7).

To a solution of crude (. + -.) - (9, 10-dimethoxy-2-oxo-1, 6,7,11 b-tetrahydro-2H-pyrido [2,1-a ] isoquinolin-3 (4H) -ylidene) sodium methoxide (compound 2-6,2.10 g) in DCM (6.5 mL) was added triethylamine (1.97 mL,14.1 mmol). The mixture was cooled to 0 ℃ and then tosyl azide (1.27 g,6.42 mmol) was added. The reaction was stirred at 0 ℃ for 1h, then allowed to warm to RT and stirred for 2h. Aqueous KOH (1.4 m,4.81ml,6.74 ml) was added and the reaction was stirred for an additional 15 minutes. The mixture was extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. Silica gel column (24 g) was loaded with DCM and run on an ascending gradient of EtOAc (0-100%, 12 min)/hexane to give (+ -) -3-diazo-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (Compound 2-7,0.337g,1.17mmol, two step yield 24%) as a brown solid .¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.75(s,1H),6.68(s,1H),4.01(d,J＝12.6Hz,1H),3.76-3.69(m,2H),3.71(s,6H),3.05(td,J＝4.6,11.1Hz,1H),2.97(dd,J＝4.1,17.5Hz,1H),2.88-2.81(m,1H),2.68(td,J＝4.0,15.9Hz,1H),2.53(m,1H),2.14(dd,J＝11.2,17.5Hz,1H).

Step 6 preparation of (+ -) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (+ -) -2-8).

To a solution of (. + -.) -3-diazo-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound 2-7,0.140g,0.487mmol,1.0 eq.) in t-butanol (1.0 mL) was added rhodium tetraacetate (10.8 mg,0.0244mmol,0.050 eq.). The mixture was heated with stirring at 80 ℃ for 2h. The mixture was cooled to RT, filtered through celite, and concentrated in vacuo. Silica gel column (4 g) was loaded with DCM and run on an ascending gradient of EtOAc (0-50%, 20 min)/hexane to give (+ -) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (Compound (+ -) -2-8,0.027g,0.0810mmol, 17%) as a white solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.72(s,1H),6.69(s,1H),4.37(dd,J＝6.8,11.0Hz,1H),3.72(s,6H),3.46(br d,J＝11.0Hz,1H),3.21-3.10(m,2H),2.96-2.84(m,2H),2.72-2.64(m,1H),2.58-2.42(m,3H),1.15(s,9H).

Step 7 preparation of (+ -) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (+ -) -2-9) and isolation of compound 15, compound 76, compound 77 and compound 78.

To a solution of (. + -.) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (. + -.) -2-8,27mg,0.0810mmol,1.0 eq.) in MeOH (2.0 mL) was added NaBH ₄ (4.6 mg,0.121mmol,1.5 eq.) at 0deg.C. The mixture was warmed to RT and stirred overnight. The reaction mixture was quenched with water and extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. Silica gel column (4 g) was loaded with DCM and run with an ascending gradient of EtOAc (0-100%, 20 min)/hexanes to give (±) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (±) -2-9,22mg,0.066mmol, 81%) as a mixture of diastereomers. The separation of the four isomers obtained was achieved by preparing a solution in a minimum volume of MeOH and performing preparative chiral SFC. Chiral compound separation was performed using Pic Solution ^TM SFC-PICLAB-Prep 200^TM Supercritical Fluid Chromatography (SFC) system equipped with a UV detector and Advion ^TM mass spectrometer. Using Chiral Technologies Inc ^TM ChiralPak^TM IG/SFC 5 μm,20mm by 250mm column, at 150mL/min,55℃and 110 bar back pressure regulator with an isocratic gradient of 85% CO ₂ and 15%0.5% DMEA/MeOH.

The following amounts of compound 15, compound 76, compound 77 and compound 78 were obtained:

(2R, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 15,6mg,0.0179mmol,22%, latest retention time of four isomers);

(2S, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 76,3mg,0.00894mmol,11%, earliest retention time of four isomers);

(2S, 3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 77,6mg,0.0179mmol,22%, second earliest retention time of the four isomers);

(2R, 3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 78,4mg,0.0119mmol,15%, second latest retention time of four isomers).

Example 2 preparation of (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21).

Step 1 preparation of 4- (tert-butoxy) -3-oxobutanoic acid (Compounds 2-15).

To a mixture of ethyl 4- (tert-butoxy) -3-oxobutanoate (compound 2-14,39.4g,195mmol,1.0 eq.) and water (600 mL) was added aqueous NaOH (6 n,68.3mL,410mmol,2.1 eq.) and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0 ℃ and then acidified to pH 1-2 with concentrated H ₂SO₄. The aqueous layer was extracted 5 times with MTBE. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo to give crude 4- (tert-butoxy) -3-oxobutanoic acid (compound 2-15,33.1g,190mmol, 97%) as a clear brown oil, which was carried out without any further purification. ¹H NMR(400MHz,DMSO-d₆ ) Delta (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

Step 2 preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (+ -) -2-18).

To a solution of 6- (benzyloxy) -7-methoxy-3, 4-dihydroisoquinoline hydrochloride (compound 2-16,28.9g,95mmol,1.0 eq.) in water (289 mL) was added NaOAc (0.779 g,9.50mmol,0.1 eq.) at 50 ℃. A solution of 4- (tert-butoxy) -3-oxobutanoic acid (compound 2-15,33.1g,190mmol,2.0 eq.) was added dropwise and the mixture stirred at 50℃for 3 hours. The mixture was cooled to RT and quenched with saturated aqueous NaHCO ₃. The aqueous layer was extracted three times with MTBE. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo to give crude (±) -1- (6- (benzyloxy) -7-methoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) -3- (tert-butoxy) propan-2-one (compound 2-17) as a brown oil. To a solution of the crude material in MeOH (378 mL) was added acetic acid (5.4 mL,95mmol,1.0 eq.) and 37% (w/w) aqueous formaldehyde (6.6 mL,80.8mmol,0.85 eq.). The mixture was stirred at 40 ℃ overnight. The mixture was cooled to RT, quenched with saturated aqueous NaHCO ₃ and extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo. Two silica gel columns (330 g) were loaded with DCM and run on an ascending gradient of EtOAc (0-50%, 20 min)/hexane to give (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (+ -) -2-18,13.1g,32.0mmol, 34% yield over two steps) as an off-white solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.46-7.31(m,5H),6.81(s,1H),6.75(s,1H),5.03(s,2H),4.37(dd,J＝7.0,10.9Hz,1H),3.74(s,3H),3.46(br d,J＝11.9Hz,1H),3.23-3.09(m,2H),2.95-2.84(m,2H),2.70-2.62(m,1H),2.59-2.42(m,3H),1.15(s,9H).

(Reduction, method A)

Preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (+ -) -2-19).

To a solution of 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (. + -.) -2-18,10.9g,26.6mmol,1.0 eq.) in MeOH (110 mL) was added NaBH ₄ (2.01 g,53.2mmol,2.0 eq.) in portions at 0 ℃. The mixture was stirred for 30 min, then warmed to RT and stirred for 1h. The reaction mixture was diluted with water (100 mL) and NaOH (1 m,100 mL) and filtered. Then extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo. The column was packed with DCM (220 g) and run on EtOAc (0-80%, 20 min)/hexane increasing gradient to give (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.) -2-19) (8.64 g,21.0mmol, 79%) as a 1.4:1 mixture of diastereomers.

(Reduction, method B)

Preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (+ -) -2-19).

DIBAL-H (1.0M in hexane, 42.8mL,42.8mmol,1.5 eq.) was added dropwise to a solution of 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (. + -.) -2-18,11.7g,28.5mmol,1.0 eq.) in THF (184 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 1h. The reaction mixture was quenched with acetone. The mixture was diluted with aqueous rochelle salt (10% w/w) and vigorously stirred for 30 minutes. The mixture was extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo to give (±) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (±) -2-19) (11.70 g,28.4mmol, 99%) as a 6.5:1 mixture of diastereomers, which was used directly in the next step (i.e., (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol synthesis).

Preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (+ -) -2-20).

Diastereomerically pure compound (+ -) -2-20 can be obtained by chromatography of compound (+ -) -2-19 (0.432 g,1.05mmol,1.4:1 dr). The column was packed with DCM (4 g) and run on EtOAc (0-100%, 20 min)/hexane increasing gradient to give (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound) (±)-2-20,166mg,0.403mmol,38％).¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.45-7.41(m,2H),7.41-7.37(m,2H),7.34-7.31(m,1H),6.77(s,1H),6.74(s,1H),5.01(s,2H),4.61(d,J＝4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J＝11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J＝10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

Step 4 preparation of (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21).

To a solution of crude (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.) -2-19,6.5:1dr,11.70g,28.5mmol,1 eq.) in EtOH (250 mL) was added (2S, 3S) -2, 3-bis (4-methylbenzyloxy) butanedioic acid (DPTTA, 11.00g,28.5mmol,1.0 eq.). The solution was heated to reflux with stirring, which became a suspension upon heating. After the addition of MeOH (60 mL), the mixture was kept at reflux until a clear solution was obtained. The solution was cooled to 75 ℃ and then inoculated with compound 2-21-DPTTA (0.050 g, see example 3 below) and maintained at constant temperature for 1 hour 30 minutes. The mixture was cooled to room temperature at a rate of 8 ℃ per hour, and stirring was continued for two days. The resulting precipitate was collected by vacuum filtration and dried to afford compound 2-21· DPTTA (7.317 g,6.26mmol, 32% over two steps from compound (±) -2-18 prepared in example 2, step 2 above) as a white solid. The optical purity of 100% ee was determined by chiral Supercritical Fluid Chromatography (SFC) analysis and the diastereomeric purity was 99% or more. The chiral salt pair was suspended in DCM and water was added. And alkalizing the mixture by using a saturated NH ₄ OH aqueous solution until the pH value is 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO ₄, filtered and concentrated in vacuo to give the title compound (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21,3.78g,6.12mmol, 32% yield over two steps) as a white solid from the compound (. + -.) -2-18 prepared in step 2 of example 2 above .¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.45-7.41(m,2H),7.41-7.37(m,2H),7.34-7.31(m,1H),6.77(s,1H),6.74(s,1H),5.01(s,2H),4.61(d,J＝4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J＝11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J＝10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

Example 3 preparation of (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol salt and (2S, 3S) -2, 3-bis (4-methylbenzoyloxy) butanedioic acid (Compound 2-2. DPTTA).

To a solution of (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.) -2-20,0.166g,0.403mmol,1.0 eq.) in MeOH (2 mL) was added (2S, 3S) -2, 3-bis (4-methylbenzyloxy) succinic acid (DPTTA, 0.156g,0.403mmol,1.0 eq.). The mixture was heated to 50 ℃ with stirring and held at that temperature for 10 minutes. The mixture was cooled to rt and then concentrated in vacuo to give an off-white solid. The salt pairs were suspended in EtOH (4 mL) and heated to 70 ℃ with stirring to give a suspension. MeOH (3 mL) was added and the mixture was stirred at 70 ℃ at which point the mixture became a clear solution. The sample was cooled to RT with stirring over 30 min, then stirred at RT overnight. The resulting precipitate was collected by vacuum filtration and washed with EtOH (0.5 mL) and dried to afford compound 2-21. DPTTA (0.116 g,0.145mmol, 36%) as a white solid. Chiral purity analysis was performed using a Waters ^TM Ultra-Performance Convergence Chromatography(UPC2)^TM Supercritical Fluid Chromatography (SFC) system equipped with a UV Detector (WatersTM Acquity UPC PDA Detector ^TM) and a mass spectrometer (Waters ^TM Acquity QDa Detector^TM). Using Chiral Technologies Inc ^TM ChiralPak^TM IBU/SFC 1.6 μm,2.1mm x 50mm column, and with an isocratic gradient of 95% CO2 and 5%0.5% DMEA/MeOH at 1.5mL/min,40℃and 1500psi back pressure regulator. An extraction wavelength of 281nm was used for% ee quantification and analysis. The optical purity of the single diastereoisomer was determined by chiral SFC analysis to be 100% ee. The specified structure is confirmed by the single crystal x-ray structure.

Single crystal X-ray structure of (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol DPTTA salt (compound 2-21· DPTTA).

(2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol DPTTA salt (compound 2-21. DPTTA, <1 mg) was combined with a 50:50 EtOH/MeOH mixture (0.2 mL). The sample was heated to about 50 ℃ in a capped vial to obtain a clear solution, which was then allowed to cool to RT. After 2 days, the solution was kept clear at RT and evaporated slowly. On day 3, the solution was found to contain single crystal quality pieces.

The crystal structure of compound 2-21· DPTTA was determined to be a mixed ethanol and methanol solvate having formula C₂₅H₃₄NO₄·C₂₀H₁₇O₈·0.851(C₂H₆O)·0.149(CH₄O). The solvate is refined to a disordered state between a major amount of ethanol and a minor amount of methanol. The chiral centers at N1 (protonated), C2, C3, and C5 were all determined to have the R configuration. Chiral centers at both C27 and C28 (O, O' -di-p-toluoyl-tartaric acid) have S configuration. The unit systems and space groups for compounds 2-21. DPTTA are shown in Table 1. Data collection and improvement parameters for compounds 2-21. DPTTA are shown in Table 2.

EXAMPLE 4A preparation of 6- (benzyloxy) -7-methoxy-3, 4-dihydroisoquinoline hydrochloride (Compounds 2-16).

To a solution of 6- (benzyloxy) -7-methoxy-3, 4-dihydroisoquinoline (23.2 g,86.6mmol,1.0 eq.) in 1:1MTBE/THF (230 mL) was added dropwise HCl (4M in dioxane, 22.7mL,91.0mmol,1.05 eq.) over 20 min at RT. The mixture was stirred at RT for 16 h. The precipitate was filtered and washed with MTBE (100 mL) to give 6- (benzyloxy) -7-methoxy-3, 4-dihydroisoquinoline hydrochloride (compound 2-16,25.8g,84.9mmol, 98%) as a yellow solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)12.94(br s,1H),8.94(s,1H),7.54(s,1H),7.49-7.46(m,2H),7.45-7.40(m,2H),7.40-7.35(m,1H),7.29(s,1H),5.27(s,2H),3.88-3.84(m,2H),3.81(s,3H),3.06(t,J＝8.4Hz,2H).

Example 4B preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (Compound 2-22).

To a solution of (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21,1.950g,4.74mmol,1.0 eq.) in 3:1meoh: H ₂ O (20 mL) was added dropwise aqueous HCl (12.1 m,0.47mL,5.69mmol,1.2 eq.) with stirring at 0 ℃. The mixture was stirred for 10 minutes. Palladium on carbon (10% w/w,0.252g,0.237mmol,0.05 eq.) and ammonium formate (2.988 g,47.4mmol,10 eq.) are added and the mixture stirred at 50℃for 30 minutes. The mixture was cooled to 0 ℃ and acidified with aqueous HCl (12.1M) to ph=1. The suspension was filtered and the solid was rinsed with MeOH (4 mL). The filtrate was transferred to a round bottom flask equipped with a stir bar and basified with aqueous NaOH (6M) to ph=7. The volume was reduced to 20mL by concentration in vacuo, at which point a white solid precipitated. The solid was collected by vacuum filtration to give (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,1.041g,3.24mmol, 68%) as a white solid .¹H NMR(500MHz,DMSO-d₆):δ(ppm)8.70(s,1H),6.69(s,1H),6.45(s,1H),4.58(d,J＝4.9Hz,1H),3.72(s,3H),3.32-3.25(m,2H),2.98(br d,J＝11.0Hz,1H),2.90-2.77(m,3H),2.47-2.42(m,2H),2.32-2.26(m,1H),2.02(t,J＝10.4Hz,1H),1.23(q,J＝11.6Hz,1H),1.17(s,9H).

Example 4C preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (Compound 2-22).

Step 1 preparation of 4- (tert-butoxy) -3-oxobutanoic acid (Compounds 2-15).

To a suspension of ethyl 4- (tert-butoxy) -3-oxobutanoate (compound 2-14,100g, 495 mmol,1.0 eq.) in water (1L) at 0℃was added over 5min an aqueous solution of 6N NaOH (173 mL,1040mmol,2.1 eq.) and the mixture was stirred at RT for 16h. The reaction mixture was acidified to pH 1-2 with aqueous H ₂SO₄ (18.1M) and extracted 5 times with MTBE. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 4- (tert-butoxy) -3-oxobutanoic acid (compound 2-15,83.8g,481 mol, 97%) as a clear light brown oil which was used without further purification. ¹H NMR(500MHz,DMSO-d₆ ) Delta (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

Step 2 preparation of 1- (tert-butoxy) propan-2-one (Compound 2-25).

A solution of 4- (tert-butoxy) -3-oxobutanoic acid (compound 2-15,83.8g, 481mmol) in DMSO (166 mL) was heated with stirring at 45℃for 20h. The mixture was distilled in vacuo to give 1- (tert-butoxy) propan-2-one (compound 2-25,55.1g,423mmol, 88%) as a clear colorless oil having a boiling point of 50 ℃ at 12 mmHg. ¹H NMR(400MHz,CDCl₃ ) Delta (ppm) 3.96 (s, 2H), 2.20 (s, 3H), 1.25 (s, 9H).

Step 3 preparation of 3- (tert-butoxy) -4- (dimethylamino) butan-2-one (Compound 2-26).

To a solution of 1- (tert-butoxy) propan-2-one (compound 2-25,55.1g,423.3mmol,1.0 eq.) in EtOH (275 mL) was added dimethylamine hydrochloride (51.8 g, 630 mmol,1.5 eq.), paraformaldehyde (25.4 g,847mmol,2.0 eq.) and aqueous HCl (12.1N, 1.75mL,21.2mmol,0.05 eq.) and the mixture was stirred at 75deg.C for 22h. The mixture was cooled to RT, diluted with water, basified with aqueous NaOH (1M) to ph=12, and extracted 5 times with MTBE. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. The crude material was separated and subjected to two separate separations, a silica gel column (330 g) was loaded with DCM, run with an increasing gradient of MeOH (0-10%, over 20 min)/DCM, and a silica gel column (220 g) was loaded with DCM, run with an increasing gradient of MeOH (0-10%, over 20 min)/DCM, to give 3- (tert-butoxy) -4- (dimethylamino) butan-2-one (compound 2-26,25.1g,83% purity (w/w), 111mmol, 26%) as an oil .¹H NMR(400MHz,DMSO-d₆):δ(ppm)3.94(t,J＝6.6Hz,1H),2.45–2.35(m,2H),2.13(s,6H),2.08(s,3H),1.10(s,9H).

Step 4 preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (+ -) -2-18).

To a solution of 3- (tert-butoxy) -4- (dimethylamino) butan-2-one (compound 2-26,25.1g,83% purity (w/w), 111mmol,1.2 eq.) in MeOH (110 mL) and water (58 mL) was added 6- (benzyloxy) -7-methoxy-3, 4-dihydroisoquinoline hydrochloride (compound 2-16,28.3g,93.0mmol,1.0 eq.), sodium acetate (9.27 g,113mmol,1.2 eq.) and acetic acid (6.5 mL,113mmol,1.2 eq.). The mixture was stirred at 45 ℃ for 40 hours, at which time a precipitate formed. The mixture was cooled to room temperature and the precipitate was filtered. The solid was washed with 50% (v/v) MeOH/water (200 mL) and dried in vacuo for 16H to give (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound) (±)-2-18,20.6g,50.3mmol,54％).¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.46-7.31(m,5H),6.81(s,1H),6.75(s,1H),5.03(s,2H),4.37(dd,J＝7.0,10.9Hz,1H),3.74(s,3H),3.46(br d,J＝11.9Hz,1H),3.23-3.09(m,2H),2.95-2.84(m,2H),2.70-2.62(m,1H),2.59-2.42(m,3H),1.15(s,9H).

Step 5 preparation of (+ -) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (+ -) -2-19).

DIBAL-H (1.0M in hexane, 75.4mL,75.4mmol,1.5 eq.) was added dropwise to a solution of 9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one (compound (. + -.) -2-18,20.6g,50.3mmol,1.0 eq.) in THF (200 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 2h. The mixture was warmed to RT and then additional DIBAL-H (1.0M in hexane, 25.1mL,25.1mmol,0.5 eq.) was added dropwise. The mixture was stirred at RT for 16 h. The reaction mixture was cooled to 0 ℃ and then quenched with acetone. The mixture was warmed to room temperature, diluted with DCM (200 mL) and aqueous Rochelle salt (10% w/w) and stirred vigorously until the emulsion disappeared. The mixture was extracted three times with MTBE. The combined organic extracts were dried over MgSO ₄, filtered and concentrated in vacuo to give crude (±) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (±) -2-19,20.5g,49.8mmol, 99%) as a mixture of diastereomers which was used directly in the next step (synthesis of compound 2-21).

Step 6 preparation of (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21).

To a solution of crude (. + -.) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound (. + -.) -2-19,20.5g,49.8mmol,1.0 eq.) in EtOH (440 mL) was added (2S, 3S) -2, 3-bis (4-methylbenzyloxy) succinic acid (DPTTA, 19.2g,49.8mmol,1.0 eq.). The solution was heated to reflux with stirring, which became a suspension upon further heating. After the addition of MeOH (150 mL), the mixture was kept at reflux until a clear solution was obtained. The solution was cooled to 75 ℃ and then inoculated with compound 2-21· DPTTA (0.070 g, see example 1) and maintained at constant temperature for 30 minutes. The mixture was cooled to room temperature at a rate of 8 ℃ per hour, and stirring was continued for 16h. The resulting precipitate was collected by vacuum filtration, washed with MTBE (100 mL) and EtOH (40 mL), and dried in vacuo for 16h to afford compound 2-21. DPTTA (16.1 g,20.1mmol, 40% yield from compound (+ -) -2-18) as a white solid. The optical purity of 100% ee was determined by chiral Supercritical Fluid Chromatography (SFC) analysis and the diastereomeric purity was 99% or more. The chiral salt pair was suspended in DCM and water was added. And alkalizing the mixture by using a saturated NH ₄ OH aqueous solution until the pH value is 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO ₄, filtered and concentrated in vacuo to give (2R, 3R,11 bR) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21,8.13g,19.8mmol, 39% yield from compound (. + -.) -2-18) as a white solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.45-7.41(m,2H),7.41-7.37(m,2H),7.34-7.31(m,1H),6.77(s,1H),6.74(s,1H),5.01(s,2H),4.61(d,J＝4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J＝11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J＝10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

Step 6 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22).

To a solution of (2 r,3r,11 br) -9- (benzyloxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2-21,8.13g,19.8mmol,1.0 eq.) in 3:1meoh: H ₂ O (42 mL) was added dropwise aqueous HCl (12.1 m,1.97mL,23.8mmol,1.2 eq.) with stirring at 0 ℃. The mixture was stirred for 10 minutes. Palladium on carbon (10% w/w,1.06g,0.994mmol,0.05 eq.) and ammonium formate (12.5 g, 39 mmol,10 eq.) were added and the mixture stirred at 50℃for 30 minutes. The mixture was cooled to 0 ℃ and acidified with aqueous HCl (12.1M) to ph=1. The suspension was filtered and the solid was rinsed with MeOH. The filtrate was transferred to a round bottom flask equipped with a stirring bar and basified with aqueous NaOH (6M) to ph=8, at which point a white solid precipitated. The solid was collected by vacuum filtration and dried in vacuo to afford (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,5.74g,17.9mmol, 90%) as a white solid .¹H NMR(500MHz,DMSO-d₆):δ(ppm)8.70(s,1H),6.69(s,1H),6.45(s,1H),4.58(d,J＝4.9Hz,1H),3.72(s,3H),3.32-3.25(m,2H),2.98(br d,J＝11.0Hz,1H),2.90-2.77(m,3H),2.47-2.42(m,2H),2.32-2.26(m,1H),2.02(t,J＝10.4Hz,1H),1.23(q,J＝11.6Hz,1H),1.17(s,9H).

Example 5 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2, 2-trifluoroethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 17).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.060g,0.187mmol,1.0 eq.) in DMF (1.8 mL) was added cesium carbonate (0.183g, 0.561mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, 2-trifluoroethyl triflate (0.056 g,0.243mmol,1.3 eq.) was added and the mixture stirred for 3h. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was subjected to three chromatographic separations, loading the silica gel column (4 g) with DCM, running on an ascending gradient of EtOAc (0-60% over 20 min)/hexane, loading the silica gel column (4 g) with DCM, running on an ascending gradient of EtOAc (0-70% over 25 min), and loading the reverse phase C ₁₈ column (6 g) with DMSO, running on an ascending gradient of ACN (10-50%, over 20 min)/water, to give (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2, 2-trifluoroethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-2-ol (compound 17,0.042g,0.104mmol, 56%) as a white solid. Observed ions (m/z)＝404.3[M+H]⁺.¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.83(s,1H),6.78(s,1H),4.66-4.58(m,3H),3.76(s,3H),3.38-3.26(m,2H),3.04(br d,J＝11.0Hz,1H),2.93-2.81(m,3H),2.57-2.46(m,2H),2.35-2.29(m,1H),2.08-2.02(m,1H),1.29-1.20(m,1H),1.17(s,9H).

Example 6 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 18).

Batch A

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22, see example 4b,0.150g,0.467mmol,1.0 eq.) in MeOH (1.5 mL) was added cesium carbonate (0.406 g,1.40mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, 3-trifluoropropyl triflate (0.149 g,0.607mmol,1.3 eq.) was added and the mixture stirred at RT for 2h, then a second portion (0.230 g,0.934mmol,2.0 eq.) was added and the mixture stirred for an additional 1h. The mixture was diluted with water and extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. The crude material was chromatographed twice using DCM to load a silica gel column (4 g) and a reverse phase C ₁₈ column (16 g) was loaded with DMSO, running on an increasing gradient of ACN (10-40%, over 20 minutes)/water to give (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 18,0.147g,0.352mmol, 75%) as a white solid. Observed ions (m/z)＝418.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.77(s,1H),6.69(s,1H),4.58(d,J＝4.8Hz,1H),4.12(t,J＝6.1Hz,2H),3.72(s,3H),3.36-3.24(m,2H),3.02(br d,J＝10.9Hz,1H),2.93-2.81(m,3H),2.81-2.69(m,2H),2.59-2.42(m,2H),2.36-2.27(m,1H),2.09-2.00(m,1H),1.24(q,J＝14.5Hz,1H),1.17(s,9H).

Batch B

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22, see example 4c,0.450g,1.40mmol,1.0 eq.) in MeOH (4.5 mL) was added cesium carbonate (1.37 g,4.20mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, 3-trifluoropropyl triflate (0.689 g,2.80mmol,2.0 eq.) was added and the mixture stirred at RT for 16h, then a second portion (0.689 g,2.80mmol,2.0 eq.) was added and the mixture stirred for an additional 3h. The mixture was diluted with water and extracted three times with DCM. The combined organic extracts were dried over MgSO ₄, filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations, loading a silica gel column (12 g) with DCM, running on an ascending gradient of EtOAc (0-60% over 20 min)/hexane, and loading a reverse phase C ₁₈ column (16 g) with DMSO, running on an ascending gradient of ACN (10-40%, over 20 min)/water, to give (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 18, 0.4476 g,1.07mmol, 76%) as a white solid .¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.77(s,1H),6.69(s,1H),4.58(d,J＝4.8Hz,1H),4.12(t,J＝6.1Hz,2H),3.72(s,3H),3.36-3.24(m,2H),3.02(br d,J＝10.9Hz,1H),2.93-2.81(m,3H),2.81-2.69(m,2H),2.59-2.42(m,2H),2.36-2.27(m,1H),2.09-2.00(m,1H),1.24(q,J＝14.5Hz,1H),1.17(s,9H).

Example 7 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 19).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.120g,0.373mmol,1.0 eq.) in DMF (4 mL) was added cesium carbonate (0.365 g,1.12mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, cyclopropyltriflate (0.106 g,0.559mmol,1.5 eq.) was added and the mixture was stirred overnight. An additional portion of cyclopropanetriflate (0.071 g,0.373mmol,1.0 eq.) was added and the mixture stirred at 50 ℃ for 2h. The mixture was cooled to RT, diluted with EtOAc, and rinsed five times with water. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. Silica gel column (4 g) was loaded with DCM and run on an ascending gradient of EtOAc (0-100% over 25 min)/hexane to give crude (2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 19,0.130g,0.360 mmol) as an off-white solid. To remove trace impurities, crude compound 19 (0.130 g,0.360mmol,1.0 eq.) was dissolved in anhydrous THF (2.8 mL) under stirring at 0 ℃ under nitrogen atmosphere. A solution of lithium aluminum hydride in THF (2M, 0.40mL, 0.81mmol, 2.25 eq.) was added dropwise over 10 minutes. The temperature was raised to 60 ℃ and stirred for 3h. An additional portion of lithium aluminum hydride in THF (2 m,0.18ml,0.360mmol,1.0 eq.) was added and the mixture was stirred briefly overnight at 60 ℃. The mixture was cooled to 0 ℃ and then sodium sulfate decahydrate (0.116 g,0.360mmol,1.0 eq.) was added over 10 minutes, which was then allowed to stir for 20 minutes. The mixture was filtered through celite, the filter cake was rinsed with EtOAc, and the solvent was removed in vacuo. Silica gel column (4 g) was loaded with DCM and run on an ascending gradient of EtOAc (0-100% over 25 min)/hexane to give (2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 19,0.074g,0.205mmol, 57%) as a white solid. Observed ions (m/z)＝362.3[M+H]⁺.¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.89(s,1H),6.73(s,1H),4.60(d,J＝4.9Hz,1H),3.75(tt,J＝2.9,6.0Hz,1H),3.69(s,3H),3.31-3.25(m,2H),3.02(br d,J＝11.5Hz,1H),2.96-2.82(m,3H),2.58-2.43(m,2H),2.38-2.28(m,1H),2.08-2.01(m,1H),1.30-1.20(m,1H),1.17(s,9H),0.75-0.70(m,2H),0.64-0.59(m,2H).

Example 8 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 22).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.150g,0.467mmol,1.0 eq.) in DMF (1.5 mL) was added cesium carbonate (0.266 g,1.40mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, ethyl iodide (0.058 g,0.375mmol,0.8 eq.) was added and the mixture stirred at RT for 1h. The mixture was diluted with EtOAc (100 mL) and rinsed five times with water (5 mL). The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was chromatographed twice using a DCM for a silica gel column (4 g) running on an increasing gradient of EtOAc (0-100% over 20 min)/hexane and a DMSO for a reverse phase C ₁₈ column (16 g) running on an increasing gradient of ACN (10-30% over 15 min)/water to give (2R, 3R,11 bR) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-2-ol (compound 22,0.123g,0.352mmol, 75%) as a white solid. Observed ions (m/z)＝350.3[M+H]⁺.¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.73(s,1H),6.61(s,1H),4.60(d,J＝4.7Hz,1H),3.97-3.91(m,2H),3.71(s,3H),3.31-3.25(m,1H),3.01(br d,J＝10.7Hz,1H),2.92-2.81(m,3H),2.54-2.44(m,2H),2.35-2.28(m,1H),2.07-2.01(m,1H),1.29(t,J＝6.8Hz,3H),1.23-1.23(m,1H),1.24(q,J＝11.7Hz,1H),1.17(s,9H).

Example 9 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 25).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.150g,0.467mmol,1.0 eq.) in DMF (1.5 mL) was added cesium carbonate (0.266 g,1.40mmol,3.0 eq.) and the resulting mixture stirred at RT for 10min. (bromomethyl) cyclopropane (0.069 g,0.514mmol,1.1 eq) was then added and the mixture stirred at RT overnight. The mixture was diluted with EtOAc (100 mL) and rinsed five times with water (5 mL). The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. Silica gel column (12 g) was loaded with DCM and run on an ascending gradient of EtOAc (0-100% over 20 min)/hexane to give (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 25,0.107g, 0.284 mmol, 61%) as a white solid. Observed ions (m/z)＝376.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.73(s,1H),6.59(s,1H),4.57(d,J＝4.8Hz,1H),3.76-3.68(m,2H),3.72(s,3H),3.35-3.24(m,2H),3.01(br d,J＝11.1Hz,1H),2.94-2.78(m,3H),2.55-2.43(m,2H),2.38-2.24(m,1H),2.04(br t,J＝10.3Hz,1H),1.28-1.18(m,1H),1.17(s,9H),0.58-0.49(m,2H),0.33-0.23(m,2H).

Example 10 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 38).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.150g,0.467mmol,1.0 eq.) in DMF (4.5 mL) was added cesium carbonate (0.266 g,1.40mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, 3- (bromomethyl) -1, 1-difluorocyclobutane (0.173 g,0.934mmol,2 eq.) was added and the mixture stirred at 50 ℃ for 3h. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was subjected to three chromatographic separations, loading a silica gel column (4 g) with DCM, running on an ascending gradient of EtOAc (0-70% over 20 min)/hexane, and loading two reversed phase C18 columns (6 g) with DMSO, running on an ascending gradient of MeCN (10-50%, over 20 min)/water, to give (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 38,0.120g,0.282mmol, 60%) as a white solid. Observed ions (m/z)＝426.3[M+H]⁺.¹HNMR(500MHz,DMSO-d₆):δ(ppm)6.76(s,1H),6.67(s,1H),4.59(d,J＝4.5Hz,1H),3.96(br d,J＝6.2Hz,2H),3.73(s,3H),3.36-3.25(m,4H),3.02(br d,J＝11.1Hz,1H),2.94-2.81(m,3H),2.76-2.63(m,2H),2.60-2.28(m,4H),2.05(br t,J＝10.3Hz,1H),1.30-1.20(m,1H),1.18(s,9H).

Example 11 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((S) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 43).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.088g,0.274mmol,1.0 eq.) in DMF (2.5 mL) was added cesium carbonate (0.268 g,0.82 mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, (2R) -2- (bromomethyl) -1, 1-difluorocyclopropane (0.070 g,0.411mmol,1.5 eq.) was added and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed 5 times with water. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was chromatographed twice using a DCM for a silica gel column (4 g), run on an ascending gradient of EtOAc (0-70% over 12 min)/hexane, and a DMSO for a reverse phase C ₁₈ column (6 g), run on an ascending gradient of ACN (10-70%, over 20 min)/water, to give (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((S) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 43,0.023g,0.056mmol, 20%) as a white solid. Observed ions (m/z)＝412.3[M+H]⁺.¹HNMR(500MHz,DMSO-d₆):δ(ppm)6.76(s,1H),6.65(s,1H),4.61(d,J＝4.7Hz,1H),4.04(ddd,J＝3.1,6.8,10.3Hz,1H),3.90(t,J＝9.6Hz,1H),3.73(s,3H),3.38–3.28(m,2H),3.02(br d,J＝11.0Hz,1H),2.93-2.81(m,3H),2.54–2.46(m,2H),2.35-2.28(m,1H),2.25-2.13(m,1H),2.04(br t,J＝10.4Hz,1H),1.70(ddt,J＝4.8,7.8,12.0Hz,1H),1.46-1.38(m,1H),1.24(q,J＝11.5Hz,1H),1.17(s,9H).

Example 12 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44).

Method A

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.130g,0.404mmol,1.0 eq.) in DMF (4.0 mL) was added cesium carbonate (0.390 g,1.21mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, (2S) -2- (bromomethyl) -1, 1-difluorocyclopropane (0.104 g,0.606mmol,1.5 eq.) was added and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed 5 times with water. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was chromatographed twice using a DCM to load a silica gel column (4 g), run on an ascending gradient of EtOAc (0-70% over 15 min)/hexane, and using a DCM to load a silica gel column (4 g), run on an ascending gradient of EtOAc (0-70% over 20 min)/hexane, to give (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44,0.131g,0.318mmol, 79%) as a white solid. Observed ions (m/z)＝412.3[M+H]⁺.¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.76(s,1H),6.65(s,1H),4.60(d,J＝4.9Hz,1H),4.09-4.03(m,1H),3.89(t,J＝9.7Hz,1H),3.73(s,3H),3.36–3.26(m,2H),3.01(br d,J＝11.2Hz,1H),2.93-2.80(m,3H),2.56-2.44(m,2H),2.35-2.28(m,1H),2.24-2.13(m,1H),2.07-2.01(m,1H),1.69(ddt,J＝4.7,7.8,12.0Hz,1H),1.46-1.38(m,1H),1.30-1.20(m,1H),1.17(s,9H).

Method B

To a solution of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.200g,0.622mmol,1.0 eq.) in degassed toluene (4.0 mL) in a capped microwave vial was added (R) - (2, 2-difluorocyclopropyl) methanol (0.134 g,1.24mmol,2.0 eq.) and (tributylphosphoranylidene) acetonitrile (0.299 g,1.24mmol,2.0 eq.). The headspace was evacuated and backfilled three times with nitrogen. The resulting mixture was stirred under microwave radiation at 100 ℃ for 2h. The mixture was filtered through celite and concentrated in vacuo. The crude material was subjected to three chromatographic separations, loading a silica gel column (4 g) with DCM, running on an ascending gradient of EtOAc (0-70% over 15 min)/hexane, and loading two reversed phase C18 columns (6 g) with DMSO, running on an ascending gradient of MeCN (10-50%, over 20 min), to give (2R, 3R,11 bR) -3- (tert-butoxy) -9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44,0.108g,0.262mmol, 42%) as a white solid. Observed ions (m/z)＝412.3[M+H]⁺.¹H NMR(500MHz,DMSO-d₆):δ(ppm)6.76(s,1H),6.65(s,1H),4.60(d,J＝4.9Hz,1H),4.09-4.03(m,1H),3.89(t,J＝9.7Hz,1H),3.73(s,3H),3.36–3.26(m,2H),3.01(br d,J＝11.2Hz,1H),2.93-2.80(m,3H),2.56-2.44(m,2H),2.35-2.28(m,1H),2.24-2.13(m,1H),2.07-2.01(m,1H),1.69(ddt,J＝4.7,7.8,12.0Hz,1H),1.46-1.38(m,1H),1.30-1.20(m,1H),1.17(s,9H).

Example 12A preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9-isopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 23).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,0.300g,0.933mmol,1.0 eq.) in DMF (10 mL) was added cesium carbonate (0.912 g,2.80mmol,3.0 eq.) and the resulting mixture stirred at RT for 10 min. Then, 2-iodopropane (0.206 g,1.21mmol,1.3 eq.) was added and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo, then diluted with EtOAc and rinsed twice with water. The aqueous washes were extracted twice with EtOAc. The combined organic extracts were washed twice with 10% aqueous LiCl. The organic layer was dried over MgSO ₄, filtered and concentrated in vacuo. The crude material was chromatographed twice using celite dry loaded silica gel column (12 g), run with an ascending gradient of EtOAc (0-55% over 15 min)/hexane, and reverse phase C ₁₈ column (16 g) was loaded with DMSO, run with ACN (0-55%, over 20 min)/water, to give (2 r,3r,11 br) -3- (tert-butoxy) -9-isopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 23,0.188g,0.517mmol, 55%) as a white solid. Observed ions (m/z)＝364.3[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ(ppm)6.73(s,1H),6.62(s,1H),4.58(d,J＝4.8Hz,1H),4.45(spt,J＝6.1Hz,1H),3.70(s,3H),3.31-3.25(m,2H),3.01(br d,J＝11.0Hz,1H),2.93-2.80(m,3H),2.56-2.43(m,2H),2.35-2.27(m,1H),2.08-2.00(m,1H),1.29-1.23(m,1H),1.22(dd,J＝6.0,1.8Hz,6H),1.17(s,9H).

Example 12B preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 99).

Step 1 (iodomethyl-d ₂) preparation of cyclopropane.

To a solution of triphenylphosphine (7.40 g,28.2mmol,1.2 eq.) in DCM (100 mL) at RT was added I ₂ (6.57 g,25.9mmo1,1 eq.). The reaction mixture was stirred at RT for 30 min. Imidazole (2.40 g,35.3mmol,1.5 eq.) and cyclopropylmethane-d ₂ -ol (1.74 g,23.5mmol,1.0 eq.) were added sequentially at RT. The reaction mixture was stirred at RT for 16 h. The mixture was quenched with saturated aqueous Na ₂S₂O₃. The aqueous layer was extracted three times with diethyl ether. The combined organic extracts were dried over Na ₂SO₄, filtered and concentrated under reduced pressure. The silica gel column (24 g) was loaded with hexane and run with pentane to give (iodomethyl-d ₂) cyclopropane (2.30 g,12.5mmol,53% yield) as a colourless oil. ¹ H NMR (400 MHz, benzene-d ₆): delta (ppm) 0.87 (ddtdd, J=9.1, 5.7,4.7,2.4,1.0Hz, 1H), 0.42-0.33 (m, 2H), -0.11-0.18 ppm (m, 2H).

Step 2 preparation of (2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 99).

To a solution of (2 r,3r,11 br) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2, 9-diol (compound 2-22,2.00g,6.22mmol,1.0 eq.) in DMF (60 mL) was added cesium carbonate (5.05 g,15.5mmol,2.5 eq.) and the resulting mixture stirred at 0 ℃ for 30 min. Then, (iodomethyl-d ₂) cyclopropane (1.20 g,6.53mmol,1.05 eq.) was added and the mixture was stirred overnight at 0 ℃. The mixture was diluted with water (200 mL) and extracted with DCM (5×100 mL). The combined organic layers were dried over Na ₂SO₄, filtered and concentrated in vacuo. The residue was purified by a silica gel column (24 g), which was loaded with DCM (24 g), run with an ascending gradient of EtOAc (0-100% over 20 min)/hexane, followed by reverse phase C ₁₈ column (150 g) loaded with DMSO, run with an ascending gradient of MeCN (5-60%, over 20 min)/water, followed by recrystallisation in hexane/ethyl acetate to give (2 r,3r,11 br) -3- (tert-butoxy) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 99,1.80g,4.76mmol,77% yield, 97.6% as d ₂, 1.2% as d ₁, and 1.2% non-deuterated, each as determined by MS (QTOF)) as a white solid. Observed ions (m/z)＝378.4[M+H]⁺.¹H NMR(400MHz,DMSO-d):δ(ppm)6.73(s,1H),6.58(s,1H),4.57(d,J＝4.8Hz,1H),3.72(s,3H),3.31-3.22(m,2H),3.01(br d,J＝11.0Hz,1H),2.94-2.78(m,3H),2.56-2.51(m,1H),2.46(br d,J＝9.0Hz,1H),2.36-2.25(m,1H),2.04(br t,J＝10.4Hz,1H),1.30-1.20(m,1H),1.20–1.06(m,10H),0.58-0.49(m,2H),0.31-0.23ppm(m,2H).

Example 13 reagents for the preparation of certain Compounds described in Table A

Other compounds shown in table a were prepared using a similar method to that described in the examples above and the following reagents shown in table 3.

Table 3 also provides the observed ionic m/z ratio of the title compound (Obs).

TABLE 3 Table 3

Example 14 methods for determining VMAT2 inhibitory Activity of compounds.

Examples of techniques for determining the ability of a compound to inhibit VMAT2 are provided below. The procedure was adapted from the previously described procedure (see, e.g., near, (1986), mol. Pharmacol.30:252-57; teng, et al, J. Neurochem.71,258-65,1998). Homogenates from human platelets are prepared by homogenization and then washed by centrifugation as described previously (see, e.g., hoare et al, (2003) Peptides 24:1881-97).

The human VMAT 2K _i values for the compounds listed in table a were determined using the following procedure. The compound dilutions in DMSO were generated either by manual powder stock or direct dilution using Echo 655 (Beckman). Twelve concentrations of test compound were competing against 10nM ³ H-dihydrotetrabenazine (American Radiolabeled Chemicals) on human platelet homogenates (30 μg membrane protein per well) in VMAT2 binding buffer (Dulbecco's phosphate buffered saline, 1mM EDTA, pH 7.4) in a total volume of 0.145mL in a low binding 96 well plate (Corning # 3605). After incubation at 25 ℃ for 90 minutes, bound radioligand was collected by rapid filtration on GF/C glass fiber filters pretreated with 0.1% polyethylenimine using a Microlab Star (Hamilton). After harvest, the filter plates were washed with 0.8ml VMAT2 binding buffer and bound radioligand was quantified by scintillation counting using microplate counter Microbeta (PerkinElmer). Data from the 12-point concentration response curve was analyzed using a four-parameter logistic regression algorithm to calculate IC ₅₀, with the top limited to 100 and the bottom limited to 0. K _i values for each compound were calculated using the Cheng-Prusoff equation using K _d of 4.06nM for ³ H-dihydrotetrabenazine.

Compound K _i (nM) values are provided in table 4.

TABLE 4 Table 4

NT = untested

¹ Determined as a mixture of trans isomers (cyclopropyl).

² A mixture of cis-isomers (cyclopropyl) was determined.

Example 15 VMAT2 inhibitor-induced open field hypokinesia.

The effect of VMAT2 inhibitors on dopamine consumption was measured using a locomotor activity (LMA) assay. After a pretreatment time of 60 or 120 minutes, male Sprague-Dawley rats (250 to 350 g) were placed in a locomotor activity room surrounded by an infrared beam (Med Associates). Rat locomotor activity was detected by automatically counting successive beam breaks and activity was defined as the number of beam breaks in 60 minutes. Post hoc testing of Dunnett for significance was followed by one-way analysis of variance (ANOVA; GRAPHPAD PRISM). Calculate ED ₅₀ of (2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 18 (0.036 mg/kg, see FIG. 5) and (2R, 3R,11 bR) -3- (tert-butoxy) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 22 (0.013 mg/kg, see FIG. 5).

ED ₅₀ of (2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 19 (0.04 mg/kg), of (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound 38 (0.06 mg/kg), of (2R, 3R,11 bR) -9- (((S) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-e-1, 3, 7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinol-e compound 3 (0.06 mg/kg), and of (2R, 3, 11 b-hexahydro-2-1-H-pyrido-2-ol compound 38 (0.06 mg/kg) and (0.03 mg/kg) were calculated in a similar manner to that described in this example.

Example 16 conditioned avoidance response assay of neuroleptic Activity.

The Conditional Avoidance Response (CAR) test has been shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds. In the CAR paradigm, rats were trained in a dual chamber shuttle box to respond to conditional stimuli (hearing) by negative enhancement. If the animal cannot move to another room in the presence of auditory stimulus, a mild foot shock is applied to the side of the rat. Rats learn to avoid mild foot shocks, called conditioned avoidance responses, by moving to another room when activating an auditory signal. The passage through the other chamber during the application of an electric shock is known as an escape response. A rat is considered to have failed to escape if it cannot move to another room even when a foot shock is applied. Many studies have shown that typical and atypical antipsychotics selectively inhibit CAR, making it an ideal assay for screening potential antipsychotics (see, e.g., wadenberg et al, biobehav. Rev. (1999) 23:851-62)

Male Wistar rats were trained daily for 3 to 4 weeks. During the training phase, the large scale was placed in a CAR bi-directional shuttle box followed by a training phase of 20 trials. The trial consisted of a disturbed 0.6mA foot shock exhibiting 80dB white noise for 10 seconds followed by a duration of up to 20 seconds. The interval between trials ranged from 20 to 60 seconds. Rats learn to move from one compartment to another upon the occurrence of conditional stimulation to avoid shocks (conditional avoidance response). Rats are considered fully trained if they avoid shock at least 19 out of 20 trials when conditioned stimulus is present. Rats that failed these criteria were not used.

On the test day, the trained animals were acclimatized in the test chamber for 30 minutes prior to testing. Compounds were then administered and placed in CAR shuttle bi-directional boxes. In the test, 20 trials were performed on each rat. In each trial, a conditional stimulus (80 dB white noise for 10 seconds) was applied, followed by a foot shock (scrambled 0.6mA foot shock lasting up to 20 seconds). If the animal moves to another chamber in the presence of the conditional stimulus, it is noted as a conditional avoidance response. If it moves when a foot strike occurs, it is noted as escaping. If the foot shock fails to move when it occurs, it is noted as escape failure. Antipsychotic efficacy is demonstrated by an increase in the number of escapes. Data were analyzed by analysis of variance (ANOVA) and then compared post hoc with Bonferroni test as appropriate. If p <0.05, the effect is considered significant. Outliers, defined as two standard deviations above or below the mean, were detected and removed from all analyses.

Example 17 method for determining stability of a compound in human liver microsomes.

Test compounds (0.5. Mu.M) were incubated with mixed sex liver microsomes (0.5 mg/mL total protein) from humans at 37℃in the presence of an NADPH generating system containing 50mM potassium phosphate buffer pH7.4, 3mM magnesium chloride, 1mM EDTA, 1mM NADP, 5mM glucose-6-phosphate and 1 unit/mL glucose-6-phosphate dehydrogenase. All concentrations were relative to the final incubation volume of 125 μl. Incubation was performed in a water bath at 37 ℃ for 0 min, 5 min, 10 min, 20 min, 40 min and 60 min and terminated by rapid mixing with 150 μl ice-cold acetonitrile containing internal standard. The precipitated proteins were removed by centrifugation prior to LC-MS/MS analysis. An aliquot of the resulting supernatant fraction was analyzed by LC-MS/MS monitoring the consumption of the parent compound. The resulting peak area ratio-time data was fitted to non-linear regression using XLfit scientific curve fitting software (IDBS ltd., surrey, UK) and the elimination half-life was calculated from the slope (t _1/2, min). Pharmacokinetic parameters were predicted using the method described by Obach et al (J.Pharmcol. Exp. Ther.1997; 283:46.58). Briefly, values for intrinsic clearance were calculated from elimination half-life data, which were then scaled to represent the expected clearance in the whole animal, see table 5 (human). The calculated additional values include a predicted extraction rate and a predicted maximum bioavailability.

For very stable compounds, the in vitro half-life calculated by HLM method was maximum at 420 minutes. Thus, for these stable compounds, the in vitro half-life is at least 420 minutes, but may be longer. Furthermore, for these stable compounds, the predicted systemic clearance and scaled intrinsic clearance are at least 2.59 and 2.97, respectively, but may be lower, and the predicted maximum bioavailability (F%) is at least 87, but may be higher.

Table 5 (human LM)

¹ Determined as a mixture of trans isomers (cyclopropyl).

² A mixture of cis-isomers (cyclopropyl) was determined.

Example 18 methods for the measurement of cytochrome P4502D6 3A4 (CYP 3A 4) and (CYP 2D 6) inhibition in expressed human enzymes using a fluorogenic labeling substrate.

The test compounds were incubated with the human recombinant CYP enzyme system expressed alone in the presence of NADPH and the IC ₅₀ values of inhibition were determined using the labeled substrate method.

For CYP3A4, the test compound is incubated with expressed human CYP3A4 (Gentest Supersomes (Corning, woburn, MA)) and the IC ₅₀ value of inhibition is determined using a labeled substrate, 7-benzyloxy-4- (trifluoromethyl) -coumarin (BFC), which is dealkylated by CYP3A4 to form the fluorescent product 7-hydroxy-4- (trifluoromethyl) -coumarin (7-HFC). The amount of 7-HFC formed during the incubation was detected by excitation at 400nm and emission at 528nm using a 96 Kong Yingguang plate reader (BioTek Synergy LX, agilent, SANTA CLARA, CA).

For CYP2D6, the test compound is incubated with expressed human CYP2D6 (Gentest Supersomes, (Corning, woburn, MA)) and the IC ₅₀ value of inhibition is determined using a labeling substrate 3- [2- (N, N-diethyl-N-methylamino) ethyl ] -7-methoxy-4-methylcoumarin (AMMC), which is demethylated by CYP2D 6O-to form the fluorescent product 3- [2- (N, N-diethyl-N-methylammonium) ethyl ] -7-hydroxy-4-methylcoumarin (AHMC). The amount of AHMC formed during incubation was monitored with a 96 Kong Yingguang plate reader (BioTek Synergy LX, agilent, SANTA CLARA, CA), excitation λ360nm and emission λ460 nm.

For each enzyme assay, four concentrations of test compound (ranging from 0.048 to 6 μm) were evaluated at a single concentration of substrate (K _m), BFC at 50 μm and AMMC at 1.5 μm, each repeated twice. The reaction (total volume 200. Mu.L) included 100. Mu.L of NADPH-generating system containing 75mM potassium phosphate buffer pH7.4, 3mM magnesium chloride, 1mM NADP, 5mM glucose-6-phosphate and 1 unit/mL glucose-6-phosphate, and was started with 100. Mu.L of CYP enzyme solution (10 pmol) which was added immediately before incubating the samples at 37 ℃. After 30 minutes the incubation was terminated by adding 75 μl of stop solution (80% acetonitrile/20% 0.5m Tris base). Ketoconazole and quinidine were used as positive controls for CYP3A4 and CYP2D6, respectively.

For each CYP, the extent of inhibition in percent was calculated, and the data was then plotted on a semilogarithmic curve [ percent of log (inhibitor) on x-axis and control activity on y-axis ] and fitted using the following Levenberg-Marquardt algorithm:

Where "a" is the bottom plateau of the curve and is generally equal to 0, "B" is the top plateau of the curve and is typically 100, "C" represents the "X" value in the middle of the curve, which represents the concentration of inhibitor that causes 50% inhibition, and "D" is the slope factor. IC ₅₀ values were calculated using XLfit scientific curve fitting software (IDBS ltd., surrey, UK). IC ₅₀ values for certain compounds for CYP2D6 and CYP3A4 are provided in table 6.

TABLE 6

¹ Determined as a mixture of trans isomers (cyclopropyl).

² A mixture of cis-isomers (cyclopropyl) was determined.

Example 19 protocol for testing the activity of compounds against hERG.

The purpose of these studies was to detect the in vitro effects of compounds on hERG (human ether-a-go-go-RELATED GENE) channel currents (an alternative to I _Kr, i.e., rapidly activated, delayed rectifier cardiac potassium currents; see, e.g., redfern et al Cardiovascular Research (2003) 58 (1): 32-45). The concentration-response relationship of certain compounds to hERG potassium channel current was evaluated in stably transfected mammalian cells expressing cloned hERG potassium channel encoded by KCNH2 gene at room temperature. The hERG potassium channel is expressed in Chinese Hamster Ovary (CHO) cells lacking endogenous I _Kr.

The heart potassium channel hERG is responsible for the rapid delayed rectified current in the human ventricle (inhibition of I _Kr).I_Kr is the most common cause of prolongation of cardiac action potential caused by non-cardiac drugs (see, e.g., brown and Rampe, pharmaceutical News (2000) 7:15-20; weirich and Antoni, basic res. Cardiol. (1998) 93Suppl 1:125-132; yap and cam, clin exp. Allegy (1999) 29Suppl 3:174-181). Increased action potential duration causes prolongation of QT interval and is associated with torsade ventricular tachycardia (torsade de pointes) (see, e.g., brown and Rampe, pharmaceutical News (2000) 7:15-20).

HERG positive control stock solutions of positive control preparations were prepared in DMSO and stored at room temperature.

CHO/hERG cell line:

CHO culture CHO cells were stably transfected with hERG cDNA. The stable transfectants are maintained in medium with appropriate selection pressure and antibiotics.

The testing method comprises the following steps:

1. Cell treatment all experiments were performed at room temperature. Each cell was treated as its own control. Complete blocking was achieved by adding 20 μm verapamil.

The treatment group of articles was tested to generate a 6-point dose response curve. A1:4 serial dilution was prepared from the highest concentration of 12. Mu.M.

2. Automatic patch clamp program

A. Platform for all hERG tests 384-well based automated patch clamp system SyncroPatch 384PE with PatchControl software (data acquisition) and DataControl software (data analysis) from Nanion Technologies was used. Recordings were made at room temperature (22 ℃) on planar NPC-384 multi-well wafers of 4 wells per well at moderate resistance.

B. Recordings were performed in whole cell patch mode. The composition of the internal solution was 10mM EGTA, 10mM HEPES, 10mM KCl, 10mM NaCl and 110mM KF,pH7.2,mOsm =285. The composition of the external solution was 10mM HEPES, 80mM NaCl, 60mM NMDG, 5mM glucose, 4mM KCl, 5mM CaCl ₂ and 1mM MgCl ₂, pH7.4, mOsm=298.

C. Compound preparation all compounds were solvated in 100% DMSO. Serial dilutions in DMSO were prepared manually on the day of the experiment. The pre-diluted compound was further diluted into an external solution (0.2% DMSO by volume) at a dilution factor of 1:500.

D. compound collection mode-a single application of compound is used at a concentration throughout the wafer. Each well received once compound concentration followed by verapamil that was completely blocked to assess leakage flow. Each compound at a different concentration was spread across the wafer to create a separate dose response relationship.

E. The onset and blocking of hERG current was measured using a stimulus voltage pattern consisting of 500ms pre-pulse to-40 mV (leakage subtraction), 2 seconds activation pulse to +40mV, followed by 2 seconds test pulse to-40 mV. The pulse pattern was repeated continuously from a clamping potential of-80 mV at 6s intervals. The peak tail current was calculated from the current amplitude caused by the-40 mV pre-pulse and subtracted from the total film current record. A small hyperpolarized voltage step from-80 to-90 mV was implemented during the clamp potential to calculate resistance according to ohm's law for quality control.

3. Data analysis

The data is stored on Neurocrine Biosciences computer networks for offline analysis. Data acquisition and analysis were performed using Nanion Data Control software. Steady state is defined by a limiting constant rate over time (linear time dependence). The steady state before and after application of the test article was used to calculate the percentage of current inhibited at each concentration.

The IC ₅₀ values for hERG for certain compounds are provided in table 7.

TABLE 7

¹ Determined as a mixture of trans isomers (cyclopropyl).

² A mixture of cis-isomers (cyclopropyl) was determined.

The various embodiments described above may be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and/or listed in the application data sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the present disclosure.

Claims

1. A compound of formula (Ia):

or a pharmaceutically acceptable salt thereof,

Wherein:

2. The compound of claim 1, wherein the compound is of formula (Ic):

Or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is a compound of formula (Ie):

Or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is a compound of formula (Ig):

Or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is a compound of formula (Ii):

Or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is a compound of formula (Ik):

Or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl and C ₅-C₁₁ -spirocycloalkyl;

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl, C ₅-C₁₁ -spirocycloalkyl, cubic alkyl-C ₁-C₄ -alkylene, and 4-8 membered heterobicycloyl-C ₁-C₄ -alkylene;

9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene, C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene, 3-7 membered heterocyclyl-C ₁-C₄ -alkylene, C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene, C ₄-C₇ -cycloalkenyl, 5-11 membered spiroheterocyclyl and C ₅-C₁₁ -spirocycloalkyl;

10. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -, and 6 membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

11. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl and C ₇ -spirocycloalkyl;

12. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -, and 6 membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

13. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl and C ₇ -spirocycloalkyl;

14. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -, and 6 membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

15. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-5 membered heterocyclyl, (4 membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7 membered spiroheterocyclyl and C ₇ -spirocycloalkyl;

16. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl, C ₇ -spirocycloalkyl, (cubic alkyl) CH ₂ -and 6-membered heterobicycloyl-C ₁-C₄ -alkylene-CH ₂ -;

17. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene, C ₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-CH ₂CH₂ -, cyclopropyl-O-CH ₂CH₂ -, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂-、C₄ -cycloalkenyl, 7-membered spiroheterocyclyl and C ₇ -spirocycloalkyl;

18. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl, (cyclobutyl) ethyl, (cubanyl) methyl, (bicyclo [2.1.1] hexyl) methyl, (siloxane) methyl, and (2-oxabicyclo [2.1.1] hexyl) methyl;

19. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl, and (cyclobutyl) ethyl;

20. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl and (cyclobutyl) ethyl, (cubic) methyl, (bicyclo [ 2.1.1.1 ] hexyl) methyl, (siloxane) methyl, and (2-oxabicyclo [2.1.1] hexyl) methyl;

21. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, pyrrolidinyl, and (cyclobutyl) ethyl;

22. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, (cyclobutyl) ethyl, (cubic) methyl, (bicyclo [2.1.1] 1] hexyl) methyl, (siloxane) methyl, and (2-oxabicyclo [2.1.1] hexyl) methyl;

23. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, and (cyclobutyl) ethyl;

24. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, (cyclobutyl) ethyl, (cubic) methyl, (bicyclo [2.1.1] 1] hexyl) methyl, (siloxane) methyl, and (2-oxabicyclo [2.1.1] hexyl) methyl;

25. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, neopentyl, cyclobutenyl, oxaspiro [3.3] heptyl, spiro [3.3] heptyl, and (cyclobutyl) ethyl;

26. The compound according to any one of claim 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl, 1- (cyclobutyl) ethyl, (cuban-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, and bicyclo [2.1.1] hex-yl;

27. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl and 1- (cyclobutyl) ethyl;

28. The compound according to any one of claim 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl, 1- (cyclobutyl) ethyl, (cuban-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, and bicyclo [2.1.1] hex-yl;

29. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, pyrrolidin-3-yl and 1- (cyclobutyl) ethyl;

30. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, 1- (cyclobutyl) ethyl, (bicyclo [1.1 ] methyl, (bicyclo [ 1.3 ] hex-1-yl) methyl, (bicyclo [1.1.1] hex-yl) methyl;

31. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl and 1- (cyclobutyl) ethyl;

32. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl-d ₃, ethyl-d ₅, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl, 1- (cyclobutyl) ethyl, (bicyclo [1.1 ] methyl, (bicyclo [ 1.3 ] hex-1-yl) methyl, (bicyclo [1.1.1] hex-yl) methyl;

33. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2- ((propan-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, neopentyl, cyclobutan-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, spiro [3.3] hept-2-yl and 1- (cyclobutyl) ethyl;

34. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl) methyl 3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-Difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

35. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, (3-Fluorobicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl and (2, 2-difluorocyclobutyl) methyl.

36. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl) methyl 3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, 2-methoxypropyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

37. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl (oxetan-2-yl) methyl, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methylcyclobutyl-3-yl) methyl, (1-methylcyclopropyl) methyl, (1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, 3-methoxybutyl, 3-cyano, (1-methoxybutyl) methyl, (2-fluorocyclopropyl) methyl, 2-fluorocyclopropyl and (2-fluorocyclopropyl).

38. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅ isopropyl, 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3 r) -3-cyanocyclobutyl, (1 r, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, (1S, 3S) -3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3 s) -3-cyanocyclobutyl, (1 r, 3R) -3- (trifluoromethyl) cyclobutyl, (1 r, 3R) -3-methoxycyclobutyl, (1 r, 3R) -3- (dimethylamino) cyclobutyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

39. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3R) -3-cyanocyclobutyl ], (1 r, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methylcyclooxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-Cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, (1S, 3S) -3- (dimethylamino) cyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, (1- (methylsulfonyl) cyclopropyl) methyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonyl) ethyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3S) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl, (1R, 3R) -3-methoxycyclobutyl and (1R, 3R) -3- (dimethylamino) cyclobutyl.

40. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅ isopropyl, 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3 r) -3-cyanocyclobutyl, (1 r, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methylcyclobutan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3S) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl, (1R, 3R) -3-methoxycyclobutyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, (1, 1-dimethylsiloxane-3-yl) methyl, (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl, (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

41. The compound according to any one of claims 1 to 6, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-Difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, neopentyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro [3.3] hept-6-yl, (1R, 3R) -3-cyanocyclobutyl ], (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (3-methyloxetan-3-yl) methyl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, (R) -1-cyclobutylethyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, (1S, 3S) -3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3, 3-difluorocyclobutyl, (2, 2-difluorocyclobutyl) methyl, (1S, 3 s) -3-cyanocyclobutyl, (1 r, 3R) -3- (trifluoromethyl) cyclobutyl and (1 r, 3R) -3-methoxycyclobutyl.

42. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl, cyano and C ₁-C₄ -alkylsulfonyl.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl and cyano.

44. The compound of claim 42, wherein R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one, two or three substituents selected from cyano-C ₁-C₄ -alkylene, halogen, hydroxy, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkyl and cyano, or a pharmaceutically acceptable salt thereof.

45. The compound of claim 42, wherein R ¹ is C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene optionally substituted with one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C ₁ -haloalkyl, methyl, cyano and methylsulfonyl, or a pharmaceutically acceptable salt thereof.

46. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₅ -cycloalkyl-C ₁-C₂ -alkylene optionally substituted with one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C ₁ -haloalkyl, methyl and cyano.

47. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) ethyl, wherein each group is optionally substituted by one, two or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, methyl and methylsulfonyl.

48. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl, and (cyclobutyl) ethyl, wherein each is optionally substituted by one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, methyl, and methylsulfonyl.

49. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) ethyl, wherein each group is optionally substituted by one, two or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy and methyl.

50. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (cyclopropyl) methyl, and (cyclobutyl) ethyl, wherein each group is optionally substituted by one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxy, and methyl.

51. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

52. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

53. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, 1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

54. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, (2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (1-cyclobutylethyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, and (2, 2-difluorocyclobutyl) methyl.

55. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: ((cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclobutyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, (S) -1-cyclobutylethyl, ((R) -1-fluorocyclopropyl) methyl, ((S, 2S) -2-fluorocyclopropyl) methyl ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

56. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((R) -2, 2R) -2-fluorocyclopropyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((R, 2-fluorocyclopropyl) methyl, 2-fluorocyclopropyl, ((R) methyl, 2-fluorocyclopropyl) or a pharmaceutically acceptable salt thereof ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl, (1- (methylsulfonyl) cyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

57. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, ((1S, 2-fluorocyclopropyl) methyl, ((R) -2-fluorocyclopropyl) methyl, ((R) ((1R, 2R) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

58. The compound of claim 42, wherein R ¹ is selected from (cyclopentyl) methyl, (cyclobutyl) methyl, (1- (cyanomethyl) cyclopropyl) methyl, (1-fluorocyclobutyl) methyl, (1-hydroxycyclopropyl) methyl, (1-fluorocyclopropyl) methyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((R) -2, 2R) -2-fluorocyclopropyl, ((1R, 2R) -2-fluorocyclopropyl) methyl, ((R, 2-fluorocyclopropyl) methyl, 2-fluorocyclopropyl, ((R) methyl, 2-fluorocyclopropyl) or a pharmaceutically acceptable salt thereof ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1-cyanocyclobutyl) methyl, (1-cyanocyclopropyl) methyl and (2, 2-difluorocyclobutyl) methyl.

59. The compound of claim 42, wherein R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

60. The compound of claim 42, wherein R ¹ is selected from (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

61. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₆ -alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C ₁-C₄ -alkoxy and C ₁-C₄ -alkylsulfonyl.

62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₆ -alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and C ₁-C₄ -alkoxy.

63. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₆ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, and C ₁-C₄ -alkoxy.

64. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₅ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, methoxy, and methylsulfonyl.

65. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₅ -alkyl optionally substituted with one, two, three, or four substituents selected from halogen, hydroxy, cyano, and methoxy.

66. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of isobutyl, isopentyl, butyl, propyl, methyl-d ₃, ethyl-d ₅, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of fluoro, hydroxy, cyano, methoxy and methylsulfonyl.

67. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano, methoxy and methylsulfonyl.

68. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of isobutyl, isopentyl, butyl, propyl, methyl-d ₃, ethyl-d ₅, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of fluoro, hydroxy, cyano and methoxy.

69. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl and neopentyl, wherein each group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and methoxy.

70. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl-d ₅ isopropyl, 3-fluoropropyl, 2-fluoroethyl.

71. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl 3, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl.

72. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl 2, 2-trifluoroethyl group, 3-trifluoropropyl group, 2-hydroxypropyl group, ethyl group-d ₅, isopropyl group, 3-fluoropropyl group 2, 2-trifluoroethyl group, 3-trifluoropropyl group, 2-hydroxypropyl group ethyl, ethyl-d ₅, isopropyl, 3-fluoropropyl.

73. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl 5, 5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl and 2-methoxypropyl.

74. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (R) -2-hydroxypropyl ethyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl, (S) -3, 3-trifluoro-2-hydroxypropyl 4, 4-trifluorobutyl, 5-trifluoropentyl, fluoromethyl, neopentyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, cyanomethyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3- (methylsulfonyl) propyl and 2- (methylsulfonyl) ethyl.

75. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (R) -2-hydroxypropyl ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl, (S) -3, 3-trifluoro-2-hydroxypropyl 4, 4-trifluorobutyl, 5-trifluoropentyl, fluoromethyl, neopentyl, (R) -2-fluoropropyl, (S) -2-fluoropropyl, cyanomethyl, (R) -3, 3-trifluoro-2-hydroxypropyl, (S) -2-hydroxypropyl, (R) -2-methoxypropyl, (S) -2-methoxypropyl, 3- (methylsulfonyl) propyl and 2- (methylsulfonyl) ethyl.

76. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl, 3-fluoropropyl 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl.

77. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl (R) -2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl (R) -2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl 2-fluoroethyl, 1-trifluoropropan-2-yl, 2-difluoroethyl.

78. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, ethyl, and ethyl-d ₅.

79. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl and ethyl.

80. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl, C ₁-C₄ -alkoxy and C ₂-C₄ -dialkylamino.

81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl optionally substituted by one or more substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl and C ₁-C₄ -alkoxy.

82. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl optionally substituted by one or two substituents selected from cyano, halogen, C ₁-C₄ -alkyl, C ₁-C₄ -haloalkyl and C ₁-C₄ -alkoxy.

83. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₅ -cycloalkyl optionally substituted by one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl, methoxy and dimethylamino.

84. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl optionally substituted by one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl and methoxy.

85. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of cyclopentyl, cyclobutyl, and cyclopropyl, wherein each group is optionally substituted by one or two substituents selected from the group consisting of cyano, fluoro, methyl, trifluoromethyl, methoxy, and dimethylamino.

86. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of cyclopentyl, cyclobutyl, and cyclopropyl, wherein each group is optionally substituted by one or two substituents selected from the group consisting of cyano, fluoro, methyl, trifluoromethyl, and methoxy.

87. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl) cyclobutyl, 3-methoxycyclobutyl, 3- (dimethylamino) cyclobutyl and 3, 3-difluorocyclobutyl.

88. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl) cyclobutyl, 3-methoxycyclobutyl and 3, 3-difluorocyclobutyl.

89. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl, (1 s, 3S) -3-methoxycyclobutyl, (1 s, 3S) -3- (dimethylamino) cyclobutyl, 3-difluorocyclobutyl, (1S, 3 s) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl, (1R, 3R) -3-methoxycyclobutyl and (1R, 3R) -3- (dimethylamino) cyclobutyl.

90. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from cyclopentyl, cyclobutyl, cyclopropyl, (1R, 3R) -3-cyanocyclobutyl, (1R, 3R) -3-fluorocyclobutyl, (1 s, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, 1-methylcyclobutyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl, (1 s, 3S) -3-methoxycyclobutyl, 3-difluorocyclobutyl, (1S, 3 s) -3-cyanocyclobutyl, (1R, 3R) -3- (trifluoromethyl) cyclobutyl and (1R, 3R) -3-methoxycyclobutyl.

91. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₄ -alkyl-O-C ₂-C₄ -alkylene optionally substituted with one or more substituents selected from cyano, halogen and C ₃-C₆ -cycloalkyl.

92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and cyclopropyl.

93. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene optionally substituted with one, two or three substituents selected from cyano, halogen and cyclopropyl.

94. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methoxyethyl, ((propyl) oxy) ethyl, and methoxypropyl, wherein each group is optionally substituted with one, two, or three substituents selected from cyano, fluoro, and cyclopropyl.

95. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2- (methoxy) ethyl, 2-methoxyethyl, 2- ((prop-2-yl) oxy) ethyl, and 3-methoxypropyl, wherein each group is optionally substituted with one, two, or three substituents selected from the group consisting of cyano, fluoro, and cyclopropyl.

96. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2- (cyano (cyclopropyl) methoxy) ethyl, 2-methoxyethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 3-methoxypropyl, and 2- (trifluoromethoxy) ethyl.

97. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl-O-C ₂-C₄ -alkylene.

98. The compound of claim 97, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 2-cyclopropyloxyethyl.

99. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 3-7 membered heterocyclyl optionally substituted with one or more C ₁-C₄ -alkyl substituents.

100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-5 membered heterocyclyl optionally substituted with one or more C ₁-C₄ -alkyl substituents.

101. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-5 membered heterocyclyl optionally substituted with one C ₁-C₄ -alkyl substituent.

102. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-membered heterocyclyl.

103. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is oxetan-3-yl or pyrrolidin-3-yl, wherein each group is optionally substituted with one methyl substituent.

104. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is oxetan-3-yl or 1-methylpyrrolidin-3-yl.

105. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 3-7 membered heterocyclyl-C ₁-C₄ -alkylene optionally substituted with one or more C ₁-C₄ alkyl substituents.

106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (4-5 membered heterocyclyl) CH ₂ -, optionally substituted with one or more methyl substituents.

107. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (4-membered heterocyclyl) CH ₂ -, optionally substituted with one or more methyl substituents.

108. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (4-5 membered heterocyclyl) CH ₂ -, optionally substituted with one methyl substituent.

109. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (4 membered heterocyclyl) CH ₂ -, optionally substituted with one methyl substituent.

110. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (oxetanyl) methyl or (siloxy) methyl, wherein each group is optionally substituted with one or two methyl substituents.

111. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl and (siloxane-3-yl) methyl, wherein each group is optionally substituted with one or two methyl substituents.

112. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (oxetan-3-yl) methyl or (oxetan-2-yl) methyl, wherein each group is optionally substituted with one methyl substituent.

113. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, (3-methyl oxetan-3-yl) methyl, and (1, 1-dimethylsiloxane-3-yl) methyl.

114. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, and (3-methyl-oxetan-3-yl) methyl.

115. The compound of claim 98, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (3-methyl-oxetan-3-yl) methyl, and (1, 1-dimethylsiloxane-3-yl) methyl.

116. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, and (3-methyl-oxetan-3-yl) methyl.

117. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more substituents selected from halogen and C ₁-C₄ -haloalkyl.

118. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅-C₆ -bicycloalkyl) CH ₂ -fluoro and trifluoromethyl, optionally substituted with one or more substituents selected from.

119. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅-C₆ -bicycloalkyl) CH ₂ -fluoro and trifluoromethyl, optionally substituted with one substituent selected from.

120. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (bicyclo [1.1.1] pentyl) methyl or (bicyclo [2.1.1] hexyl) methyl, wherein each group is optionally substituted with one substituent selected from fluoro and trifluoromethyl.

121. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (bicyclo [1.1.1] pent-1-yl) methyl or (bicyclo [2.1.1] hex-1-yl) methyl, wherein each group is optionally substituted with one substituent selected from fluoro and trifluoromethyl.

122. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, (bicyclo [2.1.1] hex-1-yl) methyl, and (3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methyl.

123. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄-C₈ -bicycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or more halo substituents.

124. The compound of claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅ -bicycloalkyl) CH ₂ -optionally substituted with one or more fluoro substituents.

125. The compound according to claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅ -bicycloalkyl) CH ₂ -optionally substituted with one fluoro substituent.

126. The compound according to claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (bicyclo [1.1.1] pentyl) methyl optionally substituted with one fluoro substituent.

127. The compound according to claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (bicyclo [1.1.1] pent-1-yl) methyl optionally substituted with one fluoro substituent.

128. The compound according to claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (3-fluoro bicyclo [1.1.1] pent-1-yl) methyl.

129. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄-C₇ -cycloalkenyl optionally substituted with one or more halo substituents.

130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄ -cycloalkenyl optionally substituted with one halogen substituent.

131. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cyclobutenyl optionally substituted with one fluoro substituent.

132. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cyclobut-2-en-1-yl optionally substituted with one fluoro substituent.

133. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 3-fluorocyclobut-2-en-1-yl.

134. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 5-11 membered spiroheterocyclyl.

135. The compound of claim 134, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 7-membered spiroheterocyclyl.

136. The compound or pharmaceutically acceptable salt thereof according to claim 134, wherein R ¹ is oxaspiro [3.3] heptyl.

137. The compound or pharmaceutically acceptable salt thereof according to claim 134, wherein R ¹ is 2-oxaspiro [3.3] hept-6-yl.

138. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₅-C₁₁ -spirocycloalkyl.

139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₇ -spirocycloalkyl.

140. The compound or pharmaceutically acceptable salt thereof according to claim 138, wherein R ¹ is spiro [3.3] heptyl.

141. The compound or pharmaceutically acceptable salt thereof according to claim 138, wherein R ¹ is spiro [3.3] hept-2-yl.

142. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cubanyl-C ₁-C₄ -alkylene.

143. The compound of claim 142, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cuban-1-yl) methyl.

144. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-8 membered heterobicycloyl-C ₁-C₄ -alkylene.

145. The compound of claim 144, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 6-membered heterobicyclic-CH ₂ -.

146. The compound of claim 144, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (2-oxabicyclo [2.1.1] hexyl) methyl.

147. The compound of claim 144, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (2-oxabicyclo [2.1.1] hex-1-yl) methyl or (2-oxabicyclo [2.1.1] hex-4-yl) methyl.

148. The compound of claim 1, wherein the compound is a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

149. The compound or pharmaceutically acceptable salt thereof according to claim 148, wherein:

150. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from R ¹ is selected from (C ₃-C₅ -cycloalkyl) CD ₂-、(C₃-C₅ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, (4-membered heterocyclyl) CH ₂-、(C₅-C₆ -bicycloalkyl) CH ₂-、C₇ -spirocycloalkyl and (cubanyl) CH ₂ -, wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

151. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from R ¹ is selected from (C ₃-C₅ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₅ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -and C ₇ -spirocycloalkyl, wherein each R ¹ group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

152. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of ((cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, ((propyl) oxy) ethyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, spiro [3.3] heptyl, (cubic alkyl) methyl, and (bicyclo [2.1.1] hexyl) methyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxy.

153. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, ((propyl) oxy) ethyl, (oxetanyl) methyl, methoxypropyl, pentyl, (bicyclo [1.1.1] pentyl) methyl, and spiro [3.3] heptyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxy.

154. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, 2- ((propan-2-yl) oxy) ethyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, spiro [3.3] hept-2-yl, (cube-1-yl) methyl, and (bicyclo [2.1.1] hex-1-yl) methyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxy.

155. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, 2- ((prop-2-yl) oxy) ethyl, (oxetan-2-yl) methyl, 3-methoxypropyl, pentyl, (bicyclo [1.1.1] pent-1-yl) methyl, 2- (methoxy) ethyl, and spiro [3.3] hept-2-yl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxy.

156. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl ethyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, (cuban-1-yl) methyl, (bicyclo [1.1.1] pent-1-yl) methyl and (bicyclo [2.1.1] hex-1-yl) methyl.

157. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 2, 2-difluoroethyl, (oxetan-2-yl) methyl, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl (3-Fluorobicyclo [1.1.1] pent-1-yl) methyl, (2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, 3- (trifluoromethyl) cyclobutyl and 2-fluoropropyl.

158. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl ethyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl (2, 2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, 3- (trifluoromethyl) cyclobutyl, 2-fluoropropyl, (cuban-1-yl) methyl and (bicyclo [1.1.1] pent-1-yl) methyl.

159. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl cyclopropyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl (2, 2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, 3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, (2-fluorocyclopropyl) methyl, (2, 2-difluoro-3-methylcyclopropyl) methyl, (2, 2-dimethylcyclopropyl) methyl, 3- (trifluoromethyl) cyclobutyl and 2-fluoropropyl.

160. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂ 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl (1-fluorocyclopropyl) methyl, ethyl-d ₅, isopropyl, (cyclopropyl) methyl-d ₂, 2- (trifluoromethoxy) ethyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluoropropyl, (S) -2-fluorocyclopropyl, (1-bicyclo [ 1.1-methyl ] methyl, 1-bicyclo [ 1.1-pentyl ] methyl.

161. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2- (cyano (cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl 2- ((2-cyanoprop-2-yl) oxy) ethyl, 2-difluoroethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluoro-bicyclo [1.1.1] pent-1-yl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl, 2- (trifluoromethoxy) ethyl, (1-methylcyclobutyl) methyl, (2-methylcyclopropyl) methyl, (2, 2-difluorocyclopentyl) methyl, (1R, 3R) -3-fluorocyclobutyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, 1-methylcyclobutyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (3, 3-difluorocyclopentyl) methyl, (1S, 3S) -3- (trifluoromethyl) cyclobutyl, (R) -2-fluorocyclopropyl and (S) -2-fluorocyclopropyl.

162. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl-d ₅, isopropyl (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl (2-methylcyclopropyl) methyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl and (R) -2-fluoropropyl, (cuban-1-yl) methyl and (bicyclo [1.1.1] pent-1-yl) methyl.

163. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, cyclobutyl, butyl, propyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, isopropyl (cyclopropyl) methyl, 3-fluoropropyl, 2-difluoroethyl, 4-trifluorobutyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, ((R) -2, 2-difluorocyclopropyl) methyl (2-methylcyclopropyl) methyl, (1S, 3S) -3-fluorocyclobutyl, 3-dimethylcyclobutyl, spiro [3.3] hept-2-yl, (1-methylcyclopropyl) methyl, ((1R, 2S) -2-fluorocyclopropyl) methyl, ((1S, 2R) -2-fluorocyclopropyl) methyl, ((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methyl, ((1S, 2S) -2-fluorocyclopropyl) methyl, ((S) -2, 2-dimethylcyclopropyl) methyl, (1 s, 3S) -3- (trifluoromethyl) cyclobutyl and (R) -2-fluoropropyl.

164. The compound of claim 1, wherein the compound is a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₃-C₄ -cycloalkyl-CD ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -;

166. The compound of claim 164 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -;

167. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₃-C₄ -cycloalkyl-CD ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, and (4-membered heterocyclyl) CH ₂ -;

168. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃-C₄ -cycloalkyl) CH ₂-、C₁-C₅ -alkyl, C ₃-C₄ -cycloalkyl, C ₁-C₃ -alkyl-O-C ₂-C₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl) CH ₂-、(C₅ -bicycloalkyl) CH ₂ -, wherein each R ¹ group is optionally substituted by one, two, three or four substituents selected from halogen, C ₁ -haloalkyl, cyano and hydroxy.

169. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, methyl-d ₃, propyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, methoxyethyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, butyl, methoxypropyl, (cyclobutyl) methyl, and pentyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, and difluoromethyl.

170. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, propyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, methoxyethyl, ((propyl) oxy) ethyl, oxetanyl, (oxetanyl) methyl, butyl, methoxypropyl, (cyclobutyl) methyl, pentyl, and (bicyclo [1.1.1] pentyl) methyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, and difluoromethyl.

171. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, methyl-d ₃, propyl, ethyl-d ₅, cyclopropyl, (cyclopropyl) methyl-d ₂, isopropyl, 2-methoxyethyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, butyl, 3-methoxypropyl, (cyclobutyl) methyl, and pentyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, and difluoromethyl.

172. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, propyl, ethyl, cyclopropyl, (cyclopropyl) methyl, isopropyl, 2-methoxyethyl, 2- ((prop-2-yl) oxy) ethyl, oxetan-3-yl, (oxetan-3-yl) methyl, (oxetan-2-yl) methyl, butyl, 3-methoxypropyl, (cyclobutyl) methyl, pentyl, and (bicyclo [1.1.1] pent-1-yl) methyl, wherein each R ¹ group is optionally substituted with one, two, three, or four substituents selected from fluoro, hydroxy, cyano, and difluoromethyl.

173. The compound of claim 164 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: methyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl.

174. The compound of claim 164 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl 1, 1-trifluoropropan-2-yl, 2-difluoroethyl, oxetan-3-yl.

175. The compound of claim 164 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: methyl, methyl-d ₃, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl-d ₅, isopropyl 2-methoxyethyl, (cyclopropyl) methyl-d ₂, 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl oxetan-3-yl, oxetan-3-ylmethyl, ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

176. The compound of claim 164 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from: methyl, 2-difluoropropyl, 2-trifluoroethyl, 3-trifluoropropyl, (1-fluorocyclopropyl) methyl, (R) -2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl 3-fluoropropyl, 2-fluoroethyl, 2- ((2-cyanoprop-2-yl) oxy) ethyl, 1-trifluoroprop-2-yl, 2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl ((R) -oxetan-2-yl) methyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 4-trifluorobutyl, 3-methoxypropyl, (3, 3-difluorocyclobutyl) methyl, (1- (difluoromethyl) cyclopropyl) methyl, 5-trifluoropentyl, (3-fluorocyclo [1.1.1] pent-1-yl) methyl, fluoromethyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

177. The compound of claim 1, wherein the compound is a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof,

Wherein:

178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₁-C₆ -alkyl, C ₃-C₇ -cycloalkyl, and C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene, wherein each group is optionally substituted by one, two, or three halo substituents.

179. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₂-C₃ -alkyl, cyclopropyl, C ₃-C₄ -cycloalkyl-CD ₂ -and C ₃-C₄ -cycloalkyl-CH ₂ -, wherein each group is optionally substituted by one, two or three halo substituents.

180. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of C ₂-C₃ -alkyl, cyclopropyl, and C ₃-C₄ -cycloalkyl-CH ₂ -, wherein each group is optionally substituted by one, two, or three halo substituents.

181. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, each of which is optionally substituted by one, two or three halo substituents.

182. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl, and (cyclobutyl) methyl, wherein each group is optionally substituted by one, two, or three halo substituents.

183. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, each of which is optionally substituted by one, two or three fluoro substituents.

184. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl) methyl, and (cyclobutyl) methyl, wherein each group is optionally substituted by one, two, or three fluoro substituents.

185. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl and (2, 2-difluorocyclopropyl) methyl.

186. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl and (2, 2-difluorocyclopropyl) methyl.

187. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

188. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl and ((R) -2, 2-difluorocyclopropyl) methyl.

189. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl-C ₁-C₄ -alkylene optionally substituted with one or two halo substituents.

190. The compound of claim 189 or pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, wherein each group is optionally substituted by one or two halo substituents.

191. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cyclopropyl) methyl or (cyclobutyl) methyl, wherein each group is optionally substituted by one or two halo substituents.

192. The compound of claim 189 or pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, and (cyclobutyl) methyl, wherein each group is optionally substituted by one or two fluoro substituents.

193. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cyclopropyl) methyl or (cyclobutyl) methyl, wherein each group is optionally substituted by one or two fluoro substituents.

194. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl and (2, 2-difluorocyclopropyl) methyl.

195. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl and (2, 2-difluorocyclopropyl) methyl.

196. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (cyclopropyl) methyl-d ₂, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

197. The compound of claim 189 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl) methyl, (3, 3-difluorocyclobutyl) methyl, ((S) -2, 2-difluorocyclopropyl) methyl, and ((R) -2, 2-difluorocyclopropyl) methyl.

198. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁-C₆ -alkyl optionally substituted with one, two or three halo substituents.

199. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is ethyl or propyl, wherein each group is optionally substituted with one, two, or three halo substituents.

200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is ethyl or propyl, wherein each group is optionally substituted with one, two, or three fluoro substituents.

201. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of 2, 2-trifluoroethyl, 3-trifluoropropyl and ethyl.

202. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃-C₇ -cycloalkyl.

203. The compound of claim 202, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cyclopropyl.

204. The compound of claim 1, selected from the following compounds:

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 1);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-isobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 2);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 3);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclobutylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 4);

2- (1- ((((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) methyl) cyclopropyl) acetonitrile (compound 5);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (isopentyloxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 6);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1-fluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 7);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclobutoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 8);

2- (2- (((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) ethoxy) -2-cyclopropylacetonitrile (compound 9);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-butoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 10);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9-propoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 11);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1-hydroxycyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 12);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-cyclopropyloxyethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 13);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-fluoro-2-methylpropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 14);

(2R, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 15);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2, 2-difluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 16);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2, 2-trifluoroethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 17);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3, 3-trifluoropropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 18);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-cyclopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 19);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 20);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((R) -2-hydroxypropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 21);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-ethoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 22);

(2R, 3R,11 bR) -3- (tert-butoxy) -9-isopropoxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 23);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2-methoxyethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 24);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 25);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (3-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 26);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-fluoroethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 27);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2-fluoroethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 28);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1, 1-trifluoropropan-2-yl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 29);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (ethoxy-d ₅) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 30);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (2, 2-difluoroethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 31);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (oxetan-3-yloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 32);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (oxetan-3-ylmethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 33);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (((R) -oxetan-2-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 34);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((S) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 35);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (4, 4-trifluorobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 36);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3-methoxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 37);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 38);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1- (difluoromethyl) cyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 39);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((5, 5-trifluoropentyl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 40);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3-fluoro-bicyclo [1.1.1] pent-1-yl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 41);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (fluoromethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 42);

(2 r,3r,11 br) -3- (tert-butoxy) -9- (((S) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 43);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((R) -2, 2-difluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 44);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2- (trifluoromethoxy) ethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 45);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (neopentyloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 46);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylcyclobutyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 47);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((2-methylcyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 48);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 49);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((3-fluorocyclobut-2-en-1-yl) oxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 50);

(2R, 3R,11 bR) -9- ((2-oxaspiro [3.3] hept-6-yl) oxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 51);

(1 r,3 r) -3- (((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) cyclobutane-1-carbonitrile (compound 52);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 r, 3R) -3-fluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 53);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 s, 3S) -3-fluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 54);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (3, 3-dimethylcyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 55);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (spiro [3.3] hept-2-yloxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 56);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylpyrrolidin-3-yl) oxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 57);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((3-methyloxetan-3-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 58);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1-methylcyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 59);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (1-methylcyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 60);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 2S) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 61);

(2 r,3r,11 br) -3- (tert-butoxy) -9- (((1 s,2 r) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 62);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1S, 3R) -2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 63);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 3S) -2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 64);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((S) -1-cyclobutylethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 65);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((R) -1-cyclobutylethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 66);

(2 r,3r,11 br) -3- (tert-butoxy) -9- (((1 s,2 s) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 67);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (((1R, 2R) -2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 68);

(2 r,3r,11 br) -3- (tert-butoxy) -9- (((S) -2, 2-dimethylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 69);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((3, 3-difluorocyclopentyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 70);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 s, 3S) -3- (trifluoromethyl) cyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 71);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((R) -2-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 72);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((S) -2-fluoropropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 73);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 s, 3S) -3-methoxycyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 74);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 s, 3S) -3- (dimethylamino) cyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 75);

(2S, 3R,11 bR) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 76);

(2S, 3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 77);

(2R, 3S,11 bS) -3- (tert-butoxy) -9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 78);

2- (((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) acetonitrile (compound 79);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (methoxy-d ₃) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 80);

1- ((((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) methyl) cyclobutane-1-carbonitrile (compound 81);

1- ((((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) methyl) cyclopropane-1-carbonitrile (compound 82);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((R) -3, 3-trifluoro-2-hydroxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 83);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((S) -2-hydroxypropoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 84);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((R) -2-methoxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (Compound 85);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((S) -2-methoxypropoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 86);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1- (methylsulfonyl) cyclopropyl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 87);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (3- (methylsulfonyl) propoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 88);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- (2- (methylsulfonyl) ethoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 89);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (3, 3-difluorocyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 90);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluorocyclobutyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 91);

(1 s,3 s) -3- (((2 r,3r,11 br) -3- (tert-butoxy) -2-hydroxy-10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-9-yl) oxy) cyclobutane-1-carbonitrile (compound 92);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 r, 3R) -3- (trifluoromethyl) cyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 93);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 r, 3R) -3-methoxycyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 94);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1 r, 3R) -3- (dimethylamino) cyclobutoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 95);

trans- (2 r,3r,11 br) -3- (tert-butoxy) -9- ((2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 96);

Trans- (2R, 3R,11 bR) -3- (tert-butoxy) -9- ((2, 2-difluoro-3-methylcyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 97), and

Cis- (2 r,3r,11 br) -3- (tert-butoxy) -9- ((2-fluorocyclopropyl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 98);

Or a pharmaceutically acceptable salt thereof.

205. The compound of claim 1, selected from the following compounds:

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((1 r, 3R) -3- (trifluoromethyl) cyclobutoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 93), and

Or a pharmaceutically acceptable salt thereof.

206. The compound of claim 1, selected from the following compounds:

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cyclopropylmethoxy-d ₂) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 99);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- (cuban-1-ylmethoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 100);

(2R, 3R,11 bR) -9- (bicyclo [1.1.1] pent-1-ylmethoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 101);

(2R, 3R,11 bR) -9- (bicyclo [2.1.1] hex-1-ylmethoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 102);

(2R, 3R,11 bR) -3- (tert-butoxy) -9- ((1, 1-dimethylsiloxane-3-yl) methoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 103);

(2R, 3R,11 bR) -3- (tert-butoxy) -10-methoxy-9- ((3- (trifluoromethyl) bicyclo [1.1.1] pent-1-yl) methoxy) -1,3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 104);

(2R, 3R,11 bR) -9- ((2-oxabicyclo [2.1.1] hex-1-yl) methoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 105), and

(2R, 3R,11 bR) -9- ((2-oxabicyclo [2.1.1] hex-4-yl) methoxy) -3- (tert-butoxy) -10-methoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (compound 106);

Or a pharmaceutically acceptable salt thereof.

207. A pharmaceutical product selected from the group consisting of a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof.

208. A pharmaceutical product selected from the group consisting of a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

209. A pharmaceutical composition comprising a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

210. A process for preparing a pharmaceutical composition comprising the step of mixing a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

211. A method of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder in a subject in need thereof, comprising administering to said subject a compound of any one of claims 1-206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product of claim 207 or 208, or a pharmaceutical composition of claim 209.

212. A method of treating a vesicular monoamine transporter-2 (VMAT 2) disease or disorder in a subject in need thereof, comprising administering to said subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 206, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein said VMAT2 disease or disorder is selected from ataxia or spinal muscular atrophy, chorea, congenital malformation, deformation or abnormality, dementia, oral, salivary gland or jaw disease, dyskinesia, dystonia, endocrine, nutritional or metabolic diseases, epilepsy, habit or impulse disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative diseases of the basal ganglia, extrapyramidal and movement disorders, neurological or psychiatric diseases or disorders, neurological or movement dysfunction, parkinson's/parkinsonism, stage pathogenic behavior and mood disorders, generalized developmental disorders, and substance abuse or dependence disorders.

213. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 206, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209.

214. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 206, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinesia, schizophrenia, schizoaffective disorder, mood disorder, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with alzheimer's disease, fragile X syndrome, or fragile X-related tremor-ataxia syndrome, autism spectrum disorder, rett syndrome, and chorea-acanthocytosis.

215. A method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 206, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein the neurological or psychiatric disease or disorder is hyperkinesia.

216. A method of treating hyperkinesia in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1-206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein the hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, huntington's disease-associated chorea, ataxia, chorea, dystonia, hemifacial spasms, myoclonus, restless leg syndrome, and tremors.

217. A method of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein the hyperkinesia is tardive dyskinesia.

218. A method of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-206, or a pharmaceutically acceptable salt thereof, the pharmaceutical product of claim 207 or 208, or the pharmaceutical composition of claim 209, wherein the hyperkinesia is huntington's disease.

219. A method of treating hyperkinesia in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, wherein the hyperkinesia is chorea associated with huntington's disease.

220. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of schizophrenia and schizoaffective disorder.

221. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is schizophrenia.

222. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is a schizoaffective disorder.

223. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

224. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

225. The method of claim 213 or 214, wherein the neurological or psychiatric disease or disorder is an autism spectrum disorder.

226. The method of any one of claims 211-225, wherein the method comprises using the compound, salt, product, or composition in adjuvant therapy.

227. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 in the manufacture of a medicament for the treatment of a vesicle monoamine transporter-2 (VMAT 2) disease or disorder.

228. The compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 for use in the manufacture of a medicament for the treatment of a vesicular monoamine transporter-2 (VMAT 2) disease or disorder selected from ataxia or spinal muscular atrophy, chorea, congenital malformations, deformities or abnormalities, dementia, oral, salivary gland or jaw diseases, dyskinesia, dystonia, endocrine, nutritional or metabolic disorders, epilepsy, habit or impulse disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative diseases of the basal ganglia, extrapyramidal and dyskinesias, neurological or psychiatric diseases or disorders, neurological or movement dysfunction, parkinson's/parkinsonism, childhood onset behavioural and mood disorders, pervasive developmental disorders, and substance abuse or dependency disorders.

229. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder.

230. The compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder selected from hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological disorders associated with Lesch-Nyhan syndrome, agitation associated with alzheimer's disease, fragile X syndrome or fragile X-related ataxia syndrome, autism spectrum disorders, reth syndrome and chorea-acanthocytosis.

231. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 in the manufacture of a medicament for the treatment of hyperkinesia.

232. The compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in the manufacture of a medicament for the treatment of hyperkinesia, wherein said hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea associated with huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors.

233. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 in the manufacture of a medicament for the treatment of tardive dyskinesia.

234. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209 in the manufacture of a medicament for the treatment of huntington's disease.

235. The use of a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, in the manufacture of a medicament for the treatment of chorea associated with huntington's disease.

236. The use of claim 228 or 229, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder.

237. The use according to claim 228 or 229, wherein the neurological or psychiatric disease or disorder is schizophrenia.

238. The use according to claim 228 or 229, wherein said neurological or psychiatric disease or disorder is a schizoaffective disorder.

239. The use according to claim 228 or 229, wherein said neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

240. The use according to claim 228 or 229, wherein said neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

241. The use of claim 228 or 229 wherein the neurological or psychiatric disease or disorder is an autism spectrum disorder.

242. The use of a compound, salt, product, or composition of any one of claims 227-241, wherein treatment comprises use of the compound, salt, product, or composition in adjuvant therapy.

243. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treatment of the human or animal body by therapy.

244. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder.

245. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating a vesicle monoamine transporter-2 (VMAT 2) disease or disorder selected from ataxia or spinal muscular atrophy, chorea, congenital malformations, deformations or abnormalities, dementia, oral, salivary gland or jaw diseases, dyskinesia, dystonia, endocrine, nutritional or metabolic disorders, epilepsy, habit or impulse disorders, huntington's disease or related disorders, mood or psychotic disorders, neurological disorders, stress-related disorders and body-form disorders, degenerative diseases of the basal ganglia, extrapyramidal and dyskinesia, neurological or psychiatric disorders, neurological or movement disorders, parkinson's/parkinsonism, childhood onset behavioural and mood disorders, pervasive developmental disorders, and substance abuse or dependency disorders.

246. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating a neurological or psychiatric disease or disorder.

247. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating a neurological or psychiatric disease or disorder selected from hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological disorders associated with Lesch-Nyhan syndrome, agitation associated with alzheimer's disease, fragile X syndrome or fragile X-related ataxia syndrome, autism spectrum disorders, rett syndrome and chorea-acanthocytosis.

248. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, for use in a method of treating hyperkinesia, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209.

249. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating hyperkinesia, wherein the hyperkinesia is selected from tardive dyskinesia, tourette's syndrome, huntington's disease, tics, chorea associated with huntington's disease, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome and tremors.

250. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating tardive dyskinesia.

251. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating huntington's disease.

252. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treating chorea associated with huntington's disease.

253. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder.

254. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is schizophrenia.

255. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is schizoaffective disorder.

256. The compound, salt, product, or composition for use of claim 245 or 246, wherein the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

257. The compound, salt, product, or composition for use of claim 245 or 246, wherein the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

258. The compound, salt, product, or composition for use of claim 245 or 246, wherein the neurological or psychiatric disease or disorder is autism spectrum disorder.

259. The compound, salt, product, or composition for use of any one of claims 244-258, wherein the method for treatment comprises using the compound, salt, product, or composition in adjuvant therapy.