JP2025531352A - Hexahydro-2H-pyrido[2,1-A]isoquinoline VMAT2 inhibitors and methods of use - Google Patents

Abstract

The present disclosure relates, inter alia, to certain compounds, compositions, and pharmaceutical compositions thereof that modulate the activity of the transporter protein vesicular monoamine transporter 2 (VMAT2), and is directed to methods useful for treating transporter protein vesicular monoamine transporter 2-mediated disorders, e.g., neurological or psychiatric diseases or disorders, including, but not limited to, hyperkinetic movement disorders (e.g., tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, ataxia, chorea (e.g., chorea associated with Huntington's disease), dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor). The disclosure further relates to synthetic methods and intermediates useful for preparing the compounds.
[Selected Figure] Figure 1A

Description

BACKGROUND ART [0002] The present disclosure relates, inter alia, to certain compounds, compositions, and pharmaceutical compositions thereof that modulate the activity of the transporter protein vesicular monoamine transporter 2 (VMAT2), and to methods useful for treating neurological or psychiatric diseases or disorders, including, but not limited to, transporter protein vesicular monoamine transporter 2-mediated disorders, such as hyperkinetic movement disorders (e.g., tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, ataxia, chorea (e.g., chorea associated with Huntington's disease), dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor). The present disclosure further relates to synthetic methods and intermediates useful for preparing the compounds.

2. Description of Related Art Dysregulation of the dopaminergic system is essential for several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinetic movement disorders and conditions such as schizophrenia and mood disorders. The transporter protein vesicular monoamine transporter 2 (VMAT2) plays a key role in presynaptic dopamine release, regulating the uptake of monoamines from the cytoplasm into synaptic vesicles for storage and release.

(±)-Tetrabenazine ((±)-TBZ) has been used as a drug for several decades. (±)-TBZ has been reported as a potent, reversible inhibitor of catecholamine uptake by VMAT2 (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 various hyperactivity disorders. Inhibition of VMAT2 by (±)-TBZ results in brain monoamine depletion 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). (±)-TBZ exhibits extensive first-pass metabolism after oral administration to humans, with little or no (±)-TBZ observed in the systemic circulation. Therefore, the pharmacological activity of (±)-TBZ is thought to be mediated primarily by active metabolites. (±)-TBZ has two chiral centers and is a racemic mixture of two stereoisomers. (±)-TBZ has been found to be rapidly and extensively metabolized in vivo by carbonyl reductase to four metabolic stereoisomers of 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (also known as dihydrotetrabenazine (DHTBZ)). The inhibition constants of these four metabolites against VMAT2 are reported, for example, in WO 2008/058261, Example 7. As shown, only two of the four DHTBZ isomers ([+]-alpha-DHTBZ and [+]-beta-DHTBZ) exhibit significant potency as inhibitors of VMAT2.

In patients receiving (±)-DHTBZ, [-]-alpha-DHTBZ (2S,3S,11bS-DHTBZ) and [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) were the most abundant DHTBZ isomers, while [-]-beta-DHTBZ (2R,3S,11bS-DHTBZ) and [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) were present as minor metabolites. The [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) isomer was found to be present in the smallest amount of all four isomers. Thus, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) appears to be the primary DHTBZ isomer responsible for the pharmacological activity of (±)-TBZ. Once formed, the half-life of [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) is relatively short (approximately 5 hours), necessitating a suboptimal (TID) dosing regimen for (±)-TBZ.

(±)-TBZ has a narrow therapeutic window, and its clinical use requires careful dosing. Side effects associated with (±)-TBZ and/or its metabolites include neuroleptic malignant syndrome, somnolence, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia, and parkinsonism. Generally speaking, the probability of observing side effects is a function of the plasma concentration achieved from a given dosing regimen. Compounds with longer half-lives (t _1/2 ) and lower clearance will experience smaller peak-to-trough fluctuations in plasma exposure given comparable dosing intervals. These long half-life compounds may exhibit improved tolerability by maintaining drug concentrations at levels required for efficacy, yet below levels that may induce side effects.

A fundamental and effective strategy for improving drug half-life is to reduce clearance. The term clearance describes the process of drug elimination from the body or from a single organ and is defined as the volume of drug fluid eliminated from the body per time unit. Clearance is a fundamental pharmacokinetic parameter that is commonly measured in drug research and development because it influences drug characteristics, such as half-life and ultimately dosing regimens. When compound and dose selection are optimized, the benefits of the smaller plasma concentration fluctuations seen in compounds with low clearance include potentially reduced steady-state peak concentrations, increased trough concentrations, and the prospect of improved medication adherence due to a potentially improved risk-benefit profile.

Although some progress has been made in this field, there remains a need in the art for improved VMAT2 inhibitors (including compounds, compositions, and related methods). Identification of VMAT2 small molecule inhibitors with long half-lives/low clearance is advantageous for drug discovery, especially when developed for long-term administration. In certain disease populations where patient compliance and pill burden continue to be a challenge, reduced dosing frequency is highly desirable and provides greater patient benefit.
The present disclosure meets these needs, for example, improved in vitro VMAT2 potency or improved pharmacokinetics, or both, as well as other needs, as will become apparent in conjunction with the disclosure below.

International Publication No. 2008/058261

SUMMARY One aspect of the present disclosure is, among others, a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to ₇ -membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C ₅ -C ₁₁ -spiro-cycloalkyl, cubanyl-C ₁ -C ₄ -alkylene, and 4- to 8-membered heterobicyclyl-C ₁ -C ₄ - alkylene,
each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.
Includes.

Also provided herein are pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each of which comprises a compound described herein, or a pharmaceutically acceptable salt thereof.

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

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

Also provided herein is a method for preparing a pharmaceutical composition, comprising admixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Also provided herein is a method for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein.

A method of treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder in a subject in need of such treatment, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the VMAT2 disease or disorder is selected from the group consisting of ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder. Also provided herein are methods for treating a condition selected from: a neurological disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependent disorders.

Also provided herein is a method for treating a neurological or neurological disorder or a psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein.

Also provided herein is a method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxis syndrome, autism spectrum disorder, Rett syndrome, and acanthocytosis.

Also provided herein is a method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder.

Also provided herein is a method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor.

Also provided herein is a method for treating a hyperkinetic movement disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the hyperkinetic movement disorder is tardive dyskinesia.

Also provided herein is a method for treating a hyperkinetic movement disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the hyperkinetic movement disorder is Huntington's disease.

Also provided herein is a method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

Also provided herein is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition 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 treatment-resistant obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the method comprises using the compound, salt, product, or composition in adjunctive therapy.

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder.

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder selected from ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary gland, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

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

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocyocytosis.

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating hyperkinetic movement disorder.

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a hyperkinetic movement disorder, wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor.

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

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

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

Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein, in the manufacture of a medicament for treating 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 treatment-resistant 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 adjunctive therapy.

Also provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods of treatment of the human or animal body by therapy.

Also provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods for treating vesicular monoamine transporter 2 (VMAT2) diseases or disorders.

Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder selected from ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary gland, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

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

Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and chorea acanthocytosis.

Also provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods for treating hyperkinetic movement disorders.

Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a hyperkinetic movement disorder selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor.

Also provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods for treating tardive dyskinesia.

Also provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods for treating Huntington's disease.

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

Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a neurological or psychiatric disease or disorder 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 treatment-resistant obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is an autism spectrum disorder. In some embodiments, the method of treatment comprises using the compound, salt, product, or composition in adjunctive therapy.

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

Figure 1A shows a general synthetic scheme for the preparation of certain compounds of formula (Ia) and related intermediates where ^R1 is methyl. In this representative example, ^R1 is methyl and is incorporated into compound 2-3.

1B shows a general synthetic scheme for the preparation of certain compounds of Formula (Ia) and related intermediates where ^R1 is methyl. In this representative example, the 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 preparing (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22), i.e., utilizing intermediate (±)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one (Compound 2-17) to afford (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4, A general synthetic scheme is shown that utilizes a resolution step of 6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19) with (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) to give (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21), which is subsequently deprotected to give compound 2-22.

FIG. 2B shows a general synthetic scheme for preparing (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22), i.e., utilizing intermediates 1-(tert-butoxy)propan-2-one (Compound 2-25) and 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (Compound 2-26) to form (±)-9-(benzoyl)-2-(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol. [0039] Figure 2 shows a general synthetic scheme for obtaining (±)-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 obtain (±)-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). A resolution step of compound (±)-2-19 with (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) is utilized to provide (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21), which is subsequently deprotected to provide compound 2-22.

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

FIG. 4 shows a general synthetic scheme for the preparation of compounds of formula (Ie), i.e., (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22), and different alkylating agents [wherein R ¹ has the same meaning as described herein, LG ¹ is a leaving group, R ^3a is H or C ₁ -C ₄ -alkyl (cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkoxy, and C ₂ -C _{4 -alkoxy]} . -dialkylamino). It is understood that LG ¹ can be a variety of leaving groups, such as those described herein and known in the art.

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

DETAILED DESCRIPTION Definitions For clarity and consistency, the following definitions are used throughout this patent document.

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

The terms "adjunctive treatment," "adjunctive therapy," "co-therapy," "combination therapy," and "combined treatment," 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 drug therapies, administered by any suitable means, e.g., simultaneously, sequentially, separately, or in a single pharmaceutical formulation.

The terms "administering" and "administration," as used herein, refer to providing a compound or other therapy described herein to a subject in a form capable of introducing into the subject's body a therapeutically useful form and in a therapeutically useful amount, including, but not limited to, oral dosage forms, e.g., tablets, capsules, syrups, suspensions, etc.; injectable dosage forms, e.g., intravenous (IV), intramuscular (IM), subcutaneous (SC), etc.; transdermal dosage forms, including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, etc.; and rectal dosage forms, e.g., suppositories.

A healthcare professional can provide a compound described herein directly to a subject in the form of a sample, or can provide the compound indirectly to a subject by providing an oral or written prescription for the compound. Alternatively, for example, a subject can obtain the compound themselves, without the involvement of a healthcare professional. When a compound is administered to a subject, the body is transformed by the compound at some point. When a compound described herein is provided in combination with one or more other agents, "administering" and "administration" are intended to include administering the compound and at least one other agent at the same time or at different times. When agents in a combination are administered simultaneously, the agents can be administered together in a single composition or can be administered separately. The preferred method of administration can vary depending on various factors, such as the components 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, combined with at least one additional component, e.g., 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 variants of the structures depicted herein. This term is also intended to refer to the compounds described herein, regardless of their method of preparation, e.g., whether they are prepared synthetically, via biological processes (e.g., metabolic or enzymatic transformations), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, may be found together with or isolated from other substances, e.g., water and solvents (e.g., hydrates and solvates). When solid, the compounds described herein and their salts may occur in various forms, such as co-crystals or solvates, including hydrates. The compounds may be in any solid form, e.g., polymorphs or solvates, and unless expressly indicated otherwise, references to the compounds and their salts herein should be understood to encompass all solid forms of the compounds. In some embodiments, the compounds described herein, or salts thereof, are substantially isolated. "Substantially isolated" means that a compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in a compound described herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein, or a salt thereof.

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

The terms "in need of treatment" and "in need thereof," when referring to treatment, are used interchangeably and mean that a caregiver (e.g., in the case of humans, a doctor, nurse, nurse practitioner, etc.; in the case of animals, including non-human mammals, a veterinarian) has determined that the subject or animal needs or will benefit from treatment. This determination is within the caregiver's area of expertise and is made based on a variety of factors, including knowledge that the subject or animal is ill or will become ill as a result of a disease, condition, or disorder treatable by the compounds described herein. Thus, the compounds described herein can be used in a protective or preventative manner, or the compounds described herein can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

The term "subject" refers to any animal, including mammals, e.g., 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 experiment, a subject can be a healthy volunteer or participant without an underlying VMAT2-mediated disorder or condition, or a volunteer or participant who has been diagnosed with a disorder or condition requiring medical treatment, as determined by a health care professional. In the context of a non-clinical trial, a subject who has been diagnosed with a disorder or condition and is under the care of a health care professional is typically described as a subject.

The term "pediatric subject" refers to a subject under 21 years of age at the time of diagnosis or treatment. The term "pediatric subject" can be further divided into various subpopulations, including: neonates (birth to 1 month); infants (1 month to 2 years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age, but before their 22nd birthday). See, e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams &Wilkins; 1994.

The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions, and/or dosage forms that 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 specific composition containing at least one active ingredient, including, but not limited to, salts, solvates, and hydrates of the compounds described herein, whereby the composition is suitable for investigation into a specified, effective outcome in a mammal (e.g., without limitation, a human). Those of skill in the art will understand and appreciate appropriate techniques for determining whether an active ingredient provides a desired, effective outcome based on the needs of the artisan.

The terms "prevent," "preventing," and "prevention" 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 "prevent," "preventing," and "prevention" can refer to administering therapy on a preventative or prophylactic basis to a subject who may eventually, but has not yet, manifested at least one symptom of a disorder. Such subjects can be identified based on the presence of risk factors, e.g., biomarkers, known to correlate with subsequent development of the disease. Alternatively, prophylactic therapy can be administered as a preventative measure, without prior identification of risk factors. Delaying the onset of at least one episode and/or symptom of a disorder can also be considered prophylaxis or prevention. In some embodiments, the subject can be a pediatric subject.

The terms "treat," "treating," and "treatment" refer to the medical management of a disease, disorder, or condition in a subject (e.g., a subject) (see, e.g., Stedman's Medical Dictionary). Generally, an appropriate dose and treatment regimen provides a VMAT2 inhibitor in an amount sufficient to provide a therapeutic benefit. Therapeutic benefits for a subject to whom a VMAT2 inhibitor compound(s) described herein is administered include, for example, improved clinical outcomes, with the goal of preventing, slowing, or delaying (reducing) undesired physiological changes associated with a disease, or preventing, slowing, or delaying (reducing) the progression or severity of such a disease. The efficacy of one or more VMAT2 inhibitors can include beneficial or desired clinical outcomes, including, but not limited to, a reduction, lowering, or alleviation of symptoms resulting from or associated with the disease being treated; reduced incidence of symptoms; improved quality of life; a longer disease-free state (i.e., reducing the likelihood or tendency of a subject to exhibit symptoms that were the basis for diagnosing the disease); a decrease in the extent of disease; a stabilized (i.e., non-worsening) state of disease; a delay or slowing of disease progression; improvement or palliative status; and remission (whether partial or complete), whether detectable or not; 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 an amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, that elicits the biological or drug response in a tissue, system, animal, or human that is being sought by the subject, researcher, veterinarian, medical doctor, or other clinician or caregiver, which may include one or more of the following:
(1) Preventing a disorder, e.g., preventing a disease, condition, or disorder in a subject who is predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the associated pathology or symptomology;
(2) inhibiting the disorder, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and/or symptomology) in a subject experiencing or exhibiting the associated pathology or symptomology; and (3) ameliorating the disorder, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and/or symptomology) in a subject experiencing or exhibiting the associated pathology or symptomology.

The term "contacting" refers to bringing the indicated moieties together in an in vitro system or 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 a subject, e.g., a human, having a VMAT2 protein, as well as, for example, introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing a VMAT2 protein.

Chemical Group Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term herein, the definitions in this section shall prevail unless otherwise stated.

The term "a-membered" (where "a" is an integer) preceding a group name refers to the number of atoms in the group. For example, oxetanyl contains four atoms and is a 4-membered heterocyclyl, 2-oxaspiro[3.3]heptanyl is an example of a 7-membered spiro-heterocyclyl, and piperidinyl is an example of a 6-membered heterocyclyl ring. Similarly, the term "a- to b-membered" (where "a" and "b" are integers) preceding a group name refers to an inclusive range of atoms in the group. For example, a "3- to 7-membered heterocyclyl" group refers to all "heterocyclyl" groups having 3 to 7 atoms (i.e., 3, 4, 5, 6, and 7 atoms), as "heterocyclyl" is defined herein, and a "4- to 5-membered heterocyclyl" refers to all "heterocyclyl" groups having 4 to 5 atoms (i.e., 4 and 5 atoms). If no "a" or "b" is specified for a group, the broadest range described in those definitions is to be assumed.

For compounds described herein, or pharmaceutically acceptable salts 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, if a structure is described in which two R groups coexist, e.g., 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.

When a group is described as "substituted," the group may be substituted with one or more of the designated substituents. Similarly, when a group is described as "unsubstituted or substituted," the substituent(s), if substituted, may be selected from one or more of the designated substituents. It is understood that substitution at a given atom is limited by valence. Additionally, it is understood that "optionally substituted" refers to a group that is unsubstituted or substituted.

The term "C _a -C _b " (where "a" and "b" are integers) preceding a group name refers to an inclusive range of carbon atoms in that group. For example, a "C ₁ -C ₄ -alkyl" group refers to all alkyl groups having one to four carbons (i.e., 1, 2, 3, and 4 carbons), such as methyl (CH ₃ --), ethyl (CH ₃ CH ₂ --), n-propyl (CH ₃ CH ₂ CH 2 --), iso-propyl ((CH ₃ ) ₂ CH-), n-butyl (CH ₃ CH ₂ CH ₂ CH ₂ --), iso-butyl ((CH ₃ ) _{2 CHCH 2} --), sec-butyl (CH ₃ CH ₂ CH(CH ₃ )-), and tert-butyl ((CH ₃ ) ₃ C-). When no "a" or "b" is specified for a group, the broadest range described in those definitions is intended to be assumed.

In addition to the foregoing, when used in this specification and claims, the following terms have the meanings indicated unless specified to the contrary.

The terms "C ₁ -C ₄ -alkylene" and "C ₂ -C ₄ -alkylene" refer to a straight-chain or branched, saturated aliphatic divalent radical having the 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 ₂ CH ₂ - and -CH(CH ₃ )-), n-propylene, isopropylene, n-butylene, s-butylene, isobutylene, and t-butylene. When one or more substituents are present on an "alkylene" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, an "alkylene" group can be substituted or unsubstituted.

The term "C ₁ -C ₄ -alkyl-O-C ₂ -C ₄ -alkylene" refers to a radical group consisting of a "C ₁ -C ₄ -alkyl" group bonded to an oxygen atom, which oxygen atom is bonded to a "C ₂ -C ₄ alkylene" radical, where "C ₁ -C ₄ -alkyl" and "C ₂ -C ₄ alkylene" have the same definitions as described herein. Examples include, but are not limited to, 1-methoxyethyl (i.e., CH ₃ -O-CH(CH ₃ )-), 2-methoxyethyl (i.e., CH ₃ -O-CH ₂ CH ₂ -), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, and 3-isopropoxypropyl. In some embodiments, "C ₁ -C ₄ -alkyl-O-C ₂ -C ₄ -alkylene" refers to a group selected from 2-methoxyethyl (i.e., CH ₃ -O-CH ₂ CH ₂ -), 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 -C ₄ -alkyl-O-C ₂ -C ₄ -alkylene" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "C ₁ -C ₄ -alkyl-O-C ₂ -C ₄ -alkylene" group can be substituted or unsubstituted.

The term "alkoxy" refers to a radical containing an "alkyl" group bonded directly to an oxygen atom, where "alkyl" has the same definition as found herein. Some embodiments contain 1 to 4 carbons (i.e., "C ₁ -C ₄ -alkoxy"). Some embodiments contain 1 to 3 carbons (i.e., "C ₁ -C ₃ -alkoxy"). Some embodiments contain 1 or 2 carbons. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term "alkyl" refers to a fully saturated, straight-chain or branched hydrocarbon radical. In some embodiments, the alkyl group can have 1 to 6 carbons (i.e., "C ₁ -C ₆ -alkyl"). Some embodiments are 1 to 5 carbons (i.e., "C ₁ -C ₅ -alkyl"), some embodiments are 1 to 4 carbons (i.e., C 1 -C ₄ -alkyl), some embodiments are 1 to 3 carbons (i.e., "C ₁ -C 3 -alkyl"), and some embodiments are 1 or 2 carbons. By way of example only, "C _{1 -C 4} -alkyl" indicates that there are 1 to ₄ carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, iso- _propyl , n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH( _CH3 ) _CH2CH2CH3 ], 2- _methylbutyl [i.e., _-CH2CH ( _CH3 ) _CH2CH3 ], and n- _hexyl . When one or more substituents are present on an "alkyl" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, an "alkyl" group can be substituted or unsubstituted.

The term "alkylsulfonyl" refers to a radical consisting of an "alkyl" radical attached to the sulfur of a sulfone radical of the formula: -S(=O) ₂ -, where "alkyl" has the same definition as described herein. An "alkylsulfonyl" group can have from 1 to 4 carbon atoms (i.e., "C ₁ -C ₄ -alkylsulfonyl"). Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, and t-butylsulfonyl.

The term "amino" refers to the group _--NH2 .

The term "bicycloalkyl" refers to a radical containing 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]butanyl, bicyclo[1.1.1]pentanyl, 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 substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the "bicycloalkyl" group may be substituted or unsubstituted.

The term " _C4 - _C8 -bicycloalkyl- _C1 - _C4 -alkylene" refers to a radical group consisting of a " _C4 - _C8 -bicycloalkyl" group attached to a "C1- _C4 alkylene" radical, where " _{C4 - C8} -bicycloalkyl" and " _C1 - _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]hex-1-yl)methyl, (bicyclo[2.2.1]hept-1-yl)methyl, and (bicyclo[2.2.2]oct-1-yl)methyl. When one or more substituents are present on a “C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene” group, the substituent(s) may be attached 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 -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene" group can be substituted or unsubstituted.

The term "4- to 8-membered heterobicyclyl" refers to a radical containing two fused or bridged rings containing carbon atoms and at least one heteroatom. The heteroatom(s) include, but are not limited to, oxygen, sulfur, and nitrogen, and when more than one heteroatom is present in a ring, the heteroatoms can be the same or different. In some embodiments, the "4- to 8-membered heterobicyclyl" is a group selected from 2-oxabicyclo[2.1.1]hexan-1-yl and 2-oxabicyclo[2.1.1]hexan-4-yl. When one or more substituents are present on a "4- to 8-membered heterobicyclyl" group, the substituent(s) can be attached at any available ring atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the "4- to 8-membered heterobicyclyl" group can be substituted or unsubstituted.

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

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

The term "cubanyl- _{C 1} -C ₄ -alkylene" refers to a radical group consisting of a "cubanyl" group attached to a "C ₁ -C ₄ alkylene" radical, where "cubanyl" and "C ₁ -C ₄ alkylene" have the same definitions as described herein. An example includes, but is not limited to, (cubanyl)methyl. When one or more substituents are present on a "cubanyl-C ₁ -C ₄ -alkylene" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "cubanyl-C ₁ -C ₄ -alkylene" group can be substituted or unsubstituted.

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

The term "cyano- _{C 1} -C ₄ -alkylene" refers to a radical group consisting of a "cyano" group attached to a "C ₁ -C ₄ alkylene" radical, where "cyano" and "C ₁ -C ₄ alkylene" have the same definitions 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. A "cycloalkenyl" group can contain from 4 to 7 atoms in the ring (i.e., "C ₄ -C ₇ -cycloalkenyl"). Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. In some embodiments, a "cycloalkenyl" is selected from 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" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "cycloalkenyl" group can be substituted or unsubstituted.

The term "cycloalkyl" refers to a fully saturated, all-carbon monocyclic ring system. In some embodiments, a cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., " _C3 - _C7 -cycloalkyl"). Some embodiments contain 3 to 6 carbons (i.e., " _C3 - _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 substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "cycloalkyl" group can be substituted or unsubstituted.

The term "C3 _{- C7} -cycloalkyl- _C1 - _C4 -alkylene" refers to a radical group consisting of a " _C3 - _C7 -cycloalkyl" group attached to a "C1- _C4 alkylene" radical, where " _{C3 - C7} -cycloalkyl" and " _C1 - _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 ₂ CH ₂ —), 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-cyclopentylbutyl, 4-cyclohexylbutyl, and 4-cycloheptylbutyl. If one or more substituents are present on a "C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene" group, the substituent(s) may be attached at any available carbon atom. If more than one substituent is present, the substituents may be the same or different. In some embodiments, a "C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene" group may be substituted or unsubstituted.

The term " _C3 - _C7 -cycloalkyl-O- _C2 - _C4 -alkylene" refers to a radical group consisting of a " _C3 - _C7 -cycloalkyl" group bonded to an oxygen atom, which oxygen atom is bonded to a " _C2 - _C4 alkylene" radical, wherein " _C3 - _C7 -cycloalkyl" and " _C2 - _C4 alkylene" have the same definitions as described herein. Examples include, but are not limited to _, 2-cyclopropoxyethyl (i.e., cyclopropyl-O- _CH2CH2- ), 2-cyclobutoxyethyl, 2-cyclopentyloxyethyl, 2-cyclohexyloxyethyl, 2-cycloheptyloxyethyl, 1-cyclopropoxyethyl (i.e., cyclopropyl-O-CH( _CH3 )-), 1-cyclobutoxyethyl, 1-cyclopentyloxyethyl, 1-cyclohexyloxyethyl, 1-cycloheptyloxyethyl, 3-cyclopropoxypropyl, 3-cyclobutoxypropyl, 3-cyclopentyloxypropyl, 3-cyclohexyloxypropyl, and 3-cycloheptyloxypropyl. The chemical group "(cyclopropyl)methyl- _d2 " is understood to refer to a group in which a deuterium atom is attached to the methylene carbon (i.e., cyclopropyl- _CD2- ), see, for example, compound 99. If one or more substituents are present on the "C ₃ -C ₇ -cycloalkyl-O-C ₂ -C ₄ -alkylene" group, the substituent(s) may be attached at any available carbon atom. If more than one substituent is present, the substituents may be the same or different. In some embodiments, the "C ₃ -C ₇ -cycloalkyl-O-C ₂ -C ₄ -alkylene" group may be substituted or unsubstituted.

The term "dialkylamino" refers to an amino group (-NH ₂ ) in which the nitrogen is substituted with two "alkyl" groups. The two alkyl groups can be the same or different. The term "alkyl" has the same definition as provided herein. A "dialkylamino" group can have from 2 to 4 carbon atoms (i.e., "C ₂ -C ₄ -dialkylamino"), provided that the total number of carbon atoms between the two alkyl groups does not exceed 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, in which one or more hydrogen atoms of the alkyl group have been replaced with a halogen atom. In some embodiments, a haloalkyl group can have 1 to 6 carbons (i.e., "C ₁ -C ₆ -haloalkyl"). A haloC ₁ -C ₆ alkyl can also be fully substituted, in which case it can be represented by the formula C _n L _2n+1 (where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6). When more than one halogen is present, they can be the same or different and can be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl contains 1 to 5 carbons (i.e., "C ₁ -C ₅ -haloalkyl"). In some embodiments, a haloalkyl contains ₁ to 4 carbons (i.e., "C ₁ -C 4 -haloalkyl"). In some embodiments, a haloalkyl contains 1 to 3 carbons (i.e., "C ₁ -C ₃ -haloalkyl"). In some embodiments, haloalkyl contains 1 or 2 carbons. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and 4,4,4-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 ring system containing carbon atoms and at least one heteroatom. The heteroatom(s) include, but are not limited to, oxygen, sulfur, and nitrogen; when more than one heteroatom is present in a ring, the heteroatoms can be the same or different. In some embodiments, a "3- to 7-membered heterocyclyl" refers to a ring system containing 3 to 7 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, a "4- to 5-membered heterocyclyl" refers to a ring system containing 4 or 5 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, a "4- to 7-membered heterocyclyl" refers to a ring system containing 4 to 7 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, a "3- to 6-membered heterocyclyl" refers to a ring system containing 3 to 6 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclyl" refers to a ring system containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, one or two heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, the heterocyclyl can contain a carbonyl (C=O) group adjacent to the heteroatom, i.e., is substituted on the carbon adjacent to the heteroatom with oxo, and 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 substituent(s) can be attached at any available carbon atom and/or heteroatom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "heterocyclyl" group can be substituted or unsubstituted.

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

The term "3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene" refers to a radical group consisting of a "3- to 7-membered heterocyclyl" group attached to a "C ₁ -C ₄ alkylene" radical, where "3- to 7-membered heterocyclyl" and "C ₁ -C ₄ alkylene" have the same definitions 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 —), 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 2 CH ₂ —), 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl)CH ₂ CH ₂ —), and 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl)CH ₂ CH 2 _—) . -), imidazolidinylmethyl, piperazin-1-ylmethyl, piperazin-2-ylmethyl, pyrrolidin-3-ylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, and tetrahydrothiopyranylmethyl. In some embodiments, "3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene" is a group selected from: 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 ₂ CH ₂ -), and 2-oxetan- ₂ -ylethyl (i.e., (oxetan-2-yl)CH ₂ CH ₂ -). When one or more substituents are present on a "3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene" group can be substituted or unsubstituted.

The term "spiro-cycloalkyl" refers to a non-aromatic, all-carbon, bicyclic ring system in which both rings are bonded together at a single common ring carbon. In some embodiments, "C ₅ -C ₁₁ -spiro-cycloalkyl" refers to a spiro ring system containing 5 to 11 ring carbons. In some embodiments, "C ₅ -C ₈ -spiro-cycloalkyl" refers to a spiro ring system containing 5 to 8 ring carbons. In some embodiments, "C ₅ -C ₇ -spiro-cycloalkyl" refers to a spiro ring system containing 5 to 7 ring carbons. In some embodiments, "C ₇ -spiro-cycloalkyl" refers to a spiro ring system containing 7 ring carbons (i.e., spiro[3.3]heptanyl and spiro[2.4]heptanyl). Examples include, but are not limited to, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.7]decanyl, spiro[3.6]decanyl, and spiro[4.5]decanyl. When one or more substituents are present on a "spiro-cycloalkyl" group, the substituent(s) can be attached at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, a "spiro-cycloalkyl" group can be substituted or unsubstituted.

The term "spiro-heterocyclyl" refers to a bicyclic ring system containing carbon atoms and at least one heteroatom, where both rings are joined together by a single common ring carbon. In some embodiments, a "5- to 11-membered spiro-heterocyclyl" refers to a spiro ring system containing 5 to 11 ring atoms. In some embodiments, a "5- to 8-membered spiro-heterocyclyl" refers to a spiro ring system containing 5 to 8 ring atoms. In some embodiments, a "5- to 7-membered spiro-heterocyclyl" refers to a spiro ring system containing 5 to 7 ring atoms. Examples include, but are not limited to, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, oxaspiro[2.3]hexanyl, oxaspiro[3.3]heptanyl, azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, azaspiro[3.5]nonanyl, and oxaspiro[3.5]nonan-9-yl. When one or more substituents are present on a "spiro-heterocyclyl" group, the substituent(s) can be attached at any available carbon atom and/or heteroatom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the "spiro-heterocyclyl" group can be substituted or unsubstituted.

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

As used herein, "excipient" refers to a substance added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. "Diluent" is a type of excipient that refers to an ingredient in a pharmaceutical composition that has no pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. A diluent can also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, and inert material or ingredient that does 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, 5th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. Those skilled in the art can further formulate the compounds disclosed and described herein in a suitable manner and according to generally accepted practices, for example, as disclosed in Remington, supra.

As used herein, "dose" or "administration" refers to a measured amount of a drug substance to be taken by a subject at one time. In certain embodiments where the drug substance is neither a free base nor a free acid, this amount is the molar equivalent to the corresponding amount of the free base or free acid.

As used herein, "pharmaceutically acceptable salts" refers to salts of compounds having acidic or basic moieties that are not biologically or otherwise unsuitable for use in pharmaceutical products. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of 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 compounds having a basic moiety with inorganic and organic acids. 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 possess one or more stereocenters. All stereoisomers, e.g., enantiomers and diastereomers, are intended unless otherwise indicated. For any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be the (R)-configuration, the (S)-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. Preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by resolution of racemic mixtures, by using enantiomerically pure or enantiomerically enriched starting materials, or by stereoselective or stereospecific synthesis. Definitions of stereochemistry are available 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 where the compounds described herein are chiral or otherwise contain one or more stereocenters, the compounds can be prepared in enantiomeric 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 racemic mixtures of compounds can be accomplished by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving organic acids with racemates containing basic groups. Other chiral resolving agents suitable for fractional crystallization include stereomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using chiral resolving bases can be utilized with racemates containing basic groups.

Resolution of racemic mixtures can also be achieved by elution on a chiral column. Appropriate elution solvent compositions can be determined by one skilled in the art.

In some embodiments, the compounds described herein can be prepared to have 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 within a range defined by any of the preceding numbers. In some embodiments, the compounds described herein can be prepared to have 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 within a range defined by any of the preceding numbers.

In some embodiments, the compounds described herein can be prepared to have 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 within a range defined by any of the preceding figures. In some embodiments, the compounds described herein can be prepared to have 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 within a range defined by any of the preceding figures.

Additionally, when the compounds described herein contain one or more double bond(s) (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, and unless otherwise specified, it is understood that the compounds include both Z and E geometric isomers (e.g., cis or trans). Cis and trans geometric isomers of the compounds described herein can be isolated as a mixture of isomers or as separated isomeric forms.

The compounds described herein also include tautomeric forms. Tautomeric forms result from the simultaneous exchange of a single bond with an adjacent double bond and the migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions within a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

The compounds described herein, and their pharmaceutically acceptable salts, can be found together with other substances, such as water and solvents, for example, in the form of hydrates or solvates. When solid, the compounds described herein and their salts can occur in various forms, including solvates, including hydrates. The compounds can be in any solid form, such as crystalline, amorphous, solvated, etc., and unless expressly indicated otherwise, references herein to the compounds and their salts should be understood to refer to any solid form of the compound.

The compounds described herein can be used in neutral form, e.g., free acid or free base form. Alternatively, the compounds can be used in the form of a pharmaceutically acceptable salt, e.g., a pharmaceutically acceptable addition salt of an acid or base.

In some embodiments, the compounds described herein, or salts thereof, are substantially isolated. The phrase "substantially isolated" refers to compounds that are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched for 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 the compounds described herein, or salts thereof.

Isotopes. The compounds disclosed and described herein independently permit and include atoms at each position of the compound having: 1) an isotopic distribution for chemical elements in proportionate amounts to that normally found in nature, or 2) an isotopic distribution in proportionate amounts different from that normally found in nature, unless the context clearly dictates otherwise. A particular chemical element has an atomic number defined by the number of protons in the atom's nucleus. Each atomic number identifies a particular chemical element but not an isotope, and atoms of a given element can have a wide range of numbers of neutrons. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. A compound in which one or more atoms have an isotopic distribution for chemical elements in proportionate amounts different from that normally found in nature is generally referred to as being isotopically labeled. Each chemical element represented in a compound structure can include any isotopic distribution of that element. For example, in a compound structure, hydrogen atoms can be explicitly disclosed or considered to be present in the compound. At any position in a compound where a hydrogen atom can 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 proportions typically found in nature and in proportions different from those typically found in nature. Thus, reference to a compound herein encompasses all potential isotopic distributions for each atom, unless the context clearly dictates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those skilled in the art, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, the use of compounds disclosed and described herein in which one or more atoms have an isotopic distribution different from that typically found in nature, for example, compounds having a greater proportion of ² H or ³ H than found in nature, or compounds having a greater proportion of ¹¹ C, ¹³ C, or ¹⁴ C, is also contemplated. By way of general example, and without limitation, isotopes of hydrogen include protium ( ¹ H), deuterium ( ² H), and tritium ( ³ H). Isotopes of carbon include carbon-11 ( ¹¹ C), carbon-12 ( ¹² C), 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, atoms at all positions in the compound have an isotope distribution for each chemical element in amounts proportional to those normally found in nature. In some embodiments, an atom at one position of a compound has an isotope distribution for chemical elements in proportional amounts different from that normally found in nature (with the remaining atoms having an isotope distribution for chemical elements in proportional amounts different from that normally found in nature). In some embodiments, atoms at at least two positions of a compound independently have an isotope distribution for chemical elements in proportional amounts different from that normally found in nature (with the remaining atoms having an isotope distribution for chemical elements in proportional amounts different from that normally found in nature). In some embodiments, atoms at at least three positions of a compound independently have an isotope distribution for chemical elements in proportional amounts different from that normally found in nature (with the remaining atoms having an isotope distribution for chemical elements in proportional amounts different from that normally found in nature). In some embodiments, atoms at at least four positions of a compound independently have an isotope distribution for chemical elements in proportional amounts different from that normally found in nature (with the remaining atoms having an isotope distribution for chemical elements in proportional amounts different from that normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have isotope distributions for chemical elements in proportional amounts different from those normally found in nature (with the remaining atoms having isotope distributions for chemical elements in proportional amounts different from those normally found in nature), hi some embodiments, atoms at at least six positions of the compound independently have isotope distributions for chemical elements in proportional amounts different from those normally found in nature (with the remaining atoms having isotope distributions for chemical elements in proportional amounts different from those normally found in nature).

Certain compounds, for example, those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are also useful in drug or substrate tissue distribution assays. Tritium ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. Compounds having proportionally greater amounts of isotopes, such as deuterium ( ² H), than those normally found in nature can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by performing procedures routinely practiced in the chemical arts. Methods for measuring such isotopic perturbations or enrichments, e.g., mass spectrometry, are readily available, and for isotopes that are radioactive, additional methods, e.g., radiation detectors used in conjunction with HPLC or GC, are also available.

As used herein, "isotopic variant" means a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions 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), fluorine- ¹⁸ ( ¹⁸ F), phosphorus-31 ( ³¹ P), phosphorus-32 ( ³² P), phosphorus-33 ( Iodine- ¹²³ ( ¹²³ I), Iodine-125 ( ¹²⁵ I), Iodine-127 ( ¹²⁷ I), Iodine- ^{129 ( 129 I} ), and Iodine- ^{131 ( 131 I} ) ^{. In} certain embodiments ^, " ^isotopic variants" ^of a compound are stable ^, i.e., non- ^{radioactive .} In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( ¹ H), deuterium ( ² H), carbon-12 ( ¹² C), carbon-13 ( ¹³ C), 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 unnatural proportions 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 understood that in the compounds provided herein, any hydrogen can contain, as the major isotope form, e.g., ² H, or any carbon can contain, as the major isotope form, e.g., ¹³ C, or any nitrogen can contain, as the major isotope form, e.g., ¹⁵ N, and any oxygen can contain, as the major isotope form, e.g., ¹⁸ O. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium ( ² H).

With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of, in certain embodiments, 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). 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 substantially greater than the natural abundance of the isotope. 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, in certain embodiments.

Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds described herein and are well known in the art. These synthetic methods, for example, for incorporating activity levels of tritium into target molecules, are as follows:

A. Catalytic reduction with tritium gas: This procedure usually produces products with high specific activity and requires halogenated or unsaturated precursors.

B. Reduction with Sodium Borohydride [ ³ H]: This procedure is somewhat less expensive and requires precursors containing reducible functional groups (eg, aldehydes, ketones, lactones, esters, etc.).

C. Reduction with Lithium Aluminum Hydride [ ^3H ]: This procedure provides products at nearly theoretical specific activities and requires precursors containing reducible functional groups (e.g., aldehydes, ketones, lactones, esters, etc.).

D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

E. N-Methylation Using Methyl Iodide [ ³ H]: This procedure is typically 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 for higher specific activities, e.g., about 70-90 Ci/mmol.

Synthetic methods for incorporating active levels of ¹²⁵ I into target molecules include:
A. Sandmeyer and similar reactions: This procedure converts arylamines or heteroarylamines to diazonium salts, such as diazonium tetrafluoroborate salts, followed by conversion to ¹²⁵ I-labeled compounds using Na ¹²⁵ I. A representative procedure was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948.

B. Ortho- ¹²⁵ Iodination of Phenols: This procedure allows the incorporation of ¹²⁵ I at the ortho position of a phenol, as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.

C. Exchange of Aryl and Heteroaryl Bromides with ^125I : This method is generally a two-step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate in the presence of a tri-alkyltin halide or hexaalkylditin [e.g., ( _CH3 ) _3SnSn ( _CH3 ) ₃ ], for example, using Pd catalysis [i.e., Pd( _Ph3P ) ₄ ], or via an aryl or heteroaryl lithium. A representative procedure was reported by Le Bas, M.-D., and co-workers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

Radiolabeled forms of the compounds described herein can be used in screening assays to identify/evaluate compounds. Generally, 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 VMAT2. The ability of the test compound to compete with radiolabeled forms of the compounds described herein for binding to VMAT2 correlates with its binding affinity.

Compounds One aspect of the present disclosure is, among others, a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to ₇ -membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C ₅ -C ₁₁ -spiro-cycloalkyl, cubanyl-C ₁ -C ₄ -alkylene, and 4- to 8-membered heterobicyclyl-C ₁ -C ₄ - alkylene,
each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.

Another aspect of the present disclosure is, among others, a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, _3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl and C ₅ -C ₁₁ -spiro-cycloalkyl;
each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.

In some embodiments, the ^R1 group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents. In some embodiments, the ^R1 group is optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents. In some embodiments, the ^R1 group is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents. In some embodiments, the ^R1 group is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, ^{the R1 group} is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the ^R1 group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the R1 group is optionally substituted with 1 or 2 substituents. In some embodiments, the ^R1 group is optionally substituted with 1 substituent. In some embodiments, the ^R1 group is unsubstituted.

In some embodiments, the ^R1 group is substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents. In some embodiments, the ^R1 group is substituted with 1, 2, 3, 4, 5, 6, or 7 substituents. In some embodiments, ^{the R1} group is substituted with 1, 2, 3, 4, 5, or 6 substituents. In some embodiments, the ^R1 group is substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, the ^R1 group is substituted with 1, 2, 3, or 4 substituents. In some embodiments, the ^R1 group is substituted with 1, 2, or 3 substituents. In some embodiments, the R1 group is substituted with 1 or 2 substituents. In some embodiments, ^{the R1} group is substituted with 1 substituent.

Some embodiments include a compound of formula (Ic):
or a pharmaceutically acceptable salt thereof, wherein ^R1 has the same definition as described hereinabove and hereinafter. The stereochemistry for compounds of formula (Ic) is understood to include both the 2S,3R,11bR isomer and the 2R,3R,11bR isomer.

Some embodiments include compounds of formula (Ie):
or a pharmaceutically acceptable salt thereof, wherein ^R1 has the same definition as described hereinabove and hereinafter. The stereochemistry for the compound of formula (Ie) is the 2R,3R,11bR isomer.

Some embodiments include a compound of formula (Ig):
or a pharmaceutically acceptable salt thereof, wherein ^R1 has the same definition as described hereinabove and hereinafter. The stereochemistry for the compound of formula (Ig) is the 2S,3R,11bR isomer.

Some embodiments include compounds of formula (Ii):
or a pharmaceutically acceptable salt thereof, wherein ^R1 has the same definition as described hereinabove and hereinafter. The stereochemistry for the compound of formula (Ii) is the 2R,3S,11bS isomer.

Some embodiments include compounds of formula (Ik):
or a pharmaceutically acceptable salt thereof, wherein R ¹ has the same definition as described hereinabove and hereinafter. The stereochemistry for the compound of formula (Ik) is the 2S,3S,11bS isomer.

Some embodiments provide a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an excretion t _1/2 ≧420 minutes as determined using a human liver microsome (HLM) assay, such as the assay described in Example 17. In some embodiments, the compound has an excretion t _1/2 ≧400 minutes. In some embodiments, the compound has an excretion t _1/2 ≧375 minutes. In some embodiments, the compound has an excretion t 1/2 ≧350 minutes. In some embodiments, the compound has an excretion t _1/2 ≧325 minutes. In some embodiments, the compound has an excretion t _1/2 ≧300 minutes. In some embodiments, the compound has _{an excretion t 1/2 ≧} 275 minutes. In some embodiments, the compound has an excretion t _1/2 ≧250 minutes. In some embodiments, the compound has an excretion t _1/2 ≧225 minutes. In some embodiments, the compound has an excretion t _1/2 ≧200 minutes.

Some embodiments provide a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an _IC50 for CYP2D6 and CYP3A4 >6,000 nM when determined using an _IC50 method, for example, the method described in Example 18. In some embodiments, the compound has an _IC50 for CYP2D6 >5,000 nM. In some embodiments, the compound has an IC50 for CYP2D6 >4,000 nM. In some embodiments, the compound has an _IC50 for CYP2D6 >3,000 nM. In some embodiments, the compound has an _IC50 for CYP2D6 >2,000 nM. In some embodiments, the compound has _{an IC50 for} CYP3A4 >5,000 nM. In some embodiments, the compound has an _IC50 for CYP3A4 >4,000 nM. In some embodiments, the compound has an _IC50 > 3,000 nM against CYP3A4. In some embodiments, the compound has an _IC50 > 2,000 nM against CYP3A4. In some embodiments, the compound is substantially inactive against CYP2D6. In some embodiments, the compound is substantially inactive against CYP3A4.

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

Phrases such as "a compound described herein" or "compounds described herein" refer to any and all compounds and compounds described above and below in this disclosure. In some embodiments, the compound(s) are compounds of formula (Ia). In some embodiments, the compound(s) are compounds of formula (Ic). In some embodiments, the compound(s) are compounds of formula (Ie). In some embodiments, the compound(s) are compounds of formula (Ig). In some embodiments, the compound(s) are compounds of formula (Ii). In some embodiments, the compound(s) are compounds of formula (Ik).

In some embodiments, R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C _{4 -alkylene, C 1} -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl, _3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C 4 -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, _5- to 11-membered spiro-heterocyclyl, C ₅ -C ₁₁ -spiro-cycloalkyl, cubanyl-C ₁ -C ₄ -alkylene, and 4- to 8-membered heterobicyclyl-C _{1 -C 4} - alkylene,
Each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C _{4 -alkylene, C 1} -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl, _3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, and C ₅ -C ₁₁ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
Each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
Each R ¹ group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH _{2 CH 2} —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, _{C 1 -C 3 -alkyl-O—CH 2 CH 2 —, cyclopropyl-O—CH 2 CH 2 — , 4} -membered heterocyclyl, ( _{4-membered heterocyclyl)CH 2 —} , (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C 1 -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O— _{CH 2} CH ₂ —, 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, ₍ C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, ^R is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, ^R is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, ^R is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, ^R is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, 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, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, 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, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, and 1-(cyclobutyl)ethyl;
Each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, and 1-(cyclobutyl)ethyl;
Each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl.

In some embodiments, R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl) (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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclo propyl)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-( and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl.

In some embodiments, R ¹ is selected from the group consisting of (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, 2-hydroxypropyl, 2-methyl ... (1-(difluoromethyl)cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, (2,2-difluoro (fluorocyclopropyl)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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl and (2,2-difluorocyclobutyl)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, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

In some embodiments, R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3- fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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-methoxy and (2-oxabicyclo[2.1.1]hexan-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-cyclopropoxyethyl. In some embodiments, R ¹ is 2-fluoro-2-methylpropyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is methyl- _d3 . In some embodiments, R ¹ is 2,2-difluoropropyl. In some embodiments, R ¹ is 2,2,2-trifluoroethyl. In some embodiments, R ¹ is 3,3,3-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-cyanopropan-2-yl)oxy)ethyl. In some embodiments, R ¹ is 1,1,1-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 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R ¹ is 4,4,4-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 5,5,5-trifluoropentyl. In some embodiments, R ¹ is (3-fluorobicyclo[1.1.1]pentan-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]heptan-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] ^{heptan-2-yl. In some embodiments, R 1 is} 1-methylpyrrolidin-3-yl. In some embodiments, R ¹ is (3-methyloxetan-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]pentan-1-yl)methyl. In some embodiments, R ¹ is (bicyclo[2.1.1]hexan-1-yl)methyl. In some embodiments, R ¹ is (1,1-dimethylsilolan-3-yl)methyl. In some embodiments, R ¹ is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R ¹ is (2-oxabicyclo[2.1.1]hexan-1-yl)methyl. In some embodiments, R ¹ is (2-oxabicyclo[2.1.1]hexan-4-yl)methyl.

In some embodiments, R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (3-methyloxetan-3-yl)methyl, (1-methyl and (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, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

In some embodiments, R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, (1-(methylsulfonyl)cyclobutyl and (1,1-dimethylsilolane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl.

In some embodiments, ^R1 is selected from the group consisting of (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl ... Cetane-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluoro (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclopropyl, ((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]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluoro Cyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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-(trifluoro [0023] The aryl group is selected from (1-(methylsulfonyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (1s,3S)-3-methoxycyclobutyl, (1s,3S)-3-(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl, and (1r,3R)-3-(dimethylamino)cyclobutyl.

It is understood that the stereochemistry for the R ¹ groups provided herein is assigned based on the R ¹ group being attached to the oxygen as 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)-3,3,3-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 (1s,3S)-3-fluorocyclobutyl. In some embodiments, R ¹ is ((1R,2S)-2-fluorocyclopropyl)methyl. In some embodiments, R ¹ is ((1S,2R)-2-fluorocyclopropyl)methyl. In some embodiments, R ¹ is ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl. In some embodiments, R ¹ is ((1R,3S)-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 ((1S,2S)-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 (1s,3S)-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 (1s,3S)-3-methoxycyclobutyl. In some embodiments, R ¹ is (1s,3S)-3-(dimethylamino)cyclobutyl. In some embodiments, R ¹ is (R)-3,3,3-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 (1S,3s)-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 (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxpropyl and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl.

In some embodiments, R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropane- 2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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-ene- 1-yl, 2-oxaspiro[3.3]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluoro (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-fluoro and (1r,3R)-3-methoxycyclobutyl.

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene.

In some embodiments, R ¹ is C ₃ -C 7 -cycloalkyl-C _{1 -C 4} -alkylene optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C _{1 -C 4} -haloalkyl, cyano, C ₁ -C _{4 -alkylsulfonyl, C 3 -C 6 -cycloalkyl ,} hydroxyl, C _{1 -C 4} -alkoxy, and C 2 -C ₄ -dialkylamino.

In some embodiments, R ¹ is C 3 -C ₇ -cycloalkyl-C _{1 -C} 4 -alkylene optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, hydroxyl, C ₁ -C ₄ -haloalkyl, C _{1 -C 4 -alkyl} , cyano, and C _{1 -C 4} -alkylsulfonyl.

In some embodiments, R ¹ is C _{3 -C 7} -cycloalkyl-C ₁ -C 4 -alkylene optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, hydroxyl, C _{1 -C 4} -haloalkyl, C _{1 -C 4 -alkyl} , and cyano.

In some embodiments, R ¹ is C 3 -C ₇ -cycloalkyl-C _{1 -C 4} -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, hydroxyl, C _{1 -C 4} -haloalkyl, C _{1 -C 4 -alkyl} , and cyano.

In some embodiments, R ¹ is C 3 -C 5 -cycloalkyl-C ₁ -C 2 -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyanomethyl, _halogen , hydroxyl, C ₁ -haloalkyl, methyl, _cyano , _and methylsulfonyl.

In some embodiments, R ¹ is C 3 -C 5 -cycloalkyl-C ₁ -C 2 -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyanomethyl, halogen, hydroxyl, C _{1 -haloalkyl} , methyl, _{and cyano} .

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)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, (2,2-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, (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, (2,2-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 (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)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 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, (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, ( and (2,2-difluorocyclobutyl)methyl.

In some embodiments, R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)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- and (2,2-difluorocyclobutyl)methyl.

In some embodiments, R ¹ is (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 [0023] The fluorocyclopropyl group is selected from (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, (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 -C ₆ -alkyl.

In some embodiments, R ¹ is C ₁ -C ₆ -alkyl optionally substituted with one _or more substituents selected from cyano-C 1 -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C _{4 -alkoxy, and C 2 -C 4} -dialkylamino.

In some embodiments, R ¹ is C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C ₁ -C ₄ -alkoxy, and C _{1 -C 4} -alkylsulfonyl _.

In some embodiments, R ¹ is C ₁ -C 6 -alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, and C _{1 -C 4 -alkoxy} .

In some embodiments, R ¹ is C ₁ -C ₆ -alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is C ₁ -C ₅ -alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is C ₁ -C ₅ -alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and methoxy.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and methoxy.

In some embodiments, R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and methoxy.

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

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

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

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

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

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl.

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano-C 1 -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C 4 -alkoxy, and C _{2 -C 4} -dialkylamino.

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C 1 -C ₄ -alkyl, C _{1 -C 4} -haloalkyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C 1 -C ₄ -alkyl, C _{1 -C 4 -haloalkyl, and C 1 -C 4 -alkoxy} .

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with 1 or 2 substituents selected from cyano, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, and C ₁ -C ₄ -alkoxy.

In some embodiments, R ¹ is C ₃ -C ₅ -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 -C ₇ -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, each group 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, each group optionally substituted with 1 or 2 substituents selected from cyano, fluoro, methyl, trifluoromethyl, and methoxy.

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

In some embodiments, R ¹ is C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene.

In some embodiments, R ¹ is C ₁ -C ₄ -alkyl-O—C 2 -C ₄ -alkylene optionally substituted with one or more substituents selected from cyano-C _{1 -C 4} -alkylene, halogen, C ₁ -C _{4 -alkyl, C 1 -C 4 -haloalkyl ,} cyano, C ₁ -C ₄ -alkylsulfonyl, C _{3 -C 6} -cycloalkyl, hydroxyl, C ₁ -C _{4 -alkoxy, and C 2 -C 4 -dialkylamino} .

In some embodiments, R ¹ is C 1 -C 4 -alkyl-O—C ₂ -C ₄ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and C _{3 -C 6} -cycloalkyl _.

In some embodiments, R ¹ is C ₁ -C ₃ -alkyl-O—C 2 -C ₃ -alkylene optionally substituted with one or more substituents selected from cyano, _halogen , and cyclopropyl.

In some embodiments, R ¹ is C ₁ -C ₃ -alkyl-O—C 2 -C 3 -alkylene optionally substituted with 1, ₂ , or ₃ substituents selected from cyano, halogen, and cyclopropyl.

In some embodiments, R ¹ is selected from methoxyethyl, ((propyl)oxy)ethyl, and methoxypropyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, fluoro, and cyclopropyl.

In some embodiments, R ¹ is selected from 2-(methoxy)ethyl, 2-methoxyethyl, 2-((propan-2-yl)oxy)ethyl, and 3-methoxypropyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, fluoro, and cyclopropyl.

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

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene.

In some embodiments, R ¹ is _{C 3} -C 7 -cycloalkyl-O—C ₂ -C ₄ -alkylene optionally substituted with one or more substituents selected from cyano-C _{1 -C 4} -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.

In some embodiments, R ¹ is cyclopropoxyethyl.

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 -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C _{1 -C 4 -alkoxy, and C 2} -C ₄ -dialkylamino.

In some embodiments, R ¹ is a 3-7 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ -alkyl substituents.

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

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

In some embodiments, R ¹ is a 4-membered heterocyclyl.

In some embodiments, R ¹ is oxetan-3-yl or pyrrolidin-3-yl, each group 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 a 3-7 membered heterocyclyl-C ₁ -C ₄ -alkylene.

In some embodiments, R ¹ is a 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene _optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C 3 -C 6 -cycloalkyl, hydroxyl, C 1 -C ₄ -alkoxy, and C _{2 -C 4 -dialkylamino} .

In some embodiments, R ¹ is a 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene optionally substituted with one or more C ₁ -C ₄ -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 (silolanyl)methyl, each group 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 (silolan-3-yl)methyl, each group optionally substituted with one or two methyl substituents.

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

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

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

In some embodiments, R ¹ is C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene.

In some embodiments, R ¹ is C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or more substituents selected from halogen and C ₁ -C ₄ -haloalkyl.

In some embodiments, R ¹ is (C ₅ -C ₆ -bicycloalkyl)CH ₂ — optionally substituted with one or more substituents selected from fluoro and trifluoromethyl.

In some embodiments, R ¹ is (C ₅ -C ₆ -bicycloalkyl)CH ₂ — optionally substituted with one substituent selected from fluoro and trifluoromethyl.

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

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

In some embodiments, R ¹ is selected from (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, and (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl.

In some embodiments, R ¹ is C ₄ -C 8 -bicycloalkyl-C ₁ -C 4 -alkylene optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C _{1 -C 4} -haloalkyl, cyano, C ₁ -C _{4 -alkylsulfonyl, C 3 -C 6 -cycloalkyl} , hydroxyl, C _{1 -C 4} -alkoxy, and C ₂ -C ₄ -dialkylamino.

In some embodiments, R ¹ is C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or more halogen 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]pentanyl)methyl optionally substituted with one fluoro substituent.

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

In some embodiments, R ¹ is C ₄ -C ₇ -cycloalkenyl.

In some embodiments, R ¹ is C _{4 -C} 7 -cycloalkenyl optionally substituted with one or more substituents selected from cyano-C 1 -C ₄ -alkylene, halogen, C _{1 -C 4} -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino.

In some embodiments, R ¹ is C ₄ -C ₇ -cycloalkenyl optionally substituted with one or more halogen 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 spiro-heterocyclyl.

In some embodiments, R ¹ is a 5-11 membered spiro-heterocyclyl optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C _{1 -C 4} -alkylsulfonyl, C _{3 -C 6} -cycloalkyl, hydroxyl, C ₁ -C 4 -alkoxy, and C 2 -C ₄ -dialkylamino.

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

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

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

In some embodiments, R ¹ is C ₅ -C ₁₁ -spiro-cycloalkyl.

In some embodiments, R ¹ is C ₅ -C ₁₁ -spiro-cycloalkyl optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C _{4 -alkoxy, and C 2 -C 4} -dialkylamino.

In some embodiments, R ¹ is C ₅ -C ₁₁ -spiro-cycloalkyl.

In some embodiments, R ¹ is C ₇ -spiro-cycloalkyl.

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

In some embodiments, R ¹ is cubanyl-C ₁ -C ₄ -alkylene.

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

In some embodiments, R ¹ is a 4-8 membered heterobicyclyl-C ₁ -C ₄ -alkylene.

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

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

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

One aspect of the present disclosure is, among others, a compound of formula (Ie):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₅ -C ₁₁ -spiro-cycloalkyl and cubanyl-C ₁ -C ₄ -alkylene;
Each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, and hydroxyl.
Includes.
One embodiment is a compound of formula (Ie):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene and C ₅ -C ₁₁ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, and hydroxyl.
Related to.

In some embodiments, R ¹ is selected from: R ¹ is selected from (C ₃ -C ₅ -cycloalkyl)CD ₂ —, (C ₃ -C ₅ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O—C _{2 -C 3} -alkylene, (4-membered heterocyclyl)CH ₂ —, (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₇ -spiro-cycloalkyl, and (cubanyl)CH ₂ —;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

In some embodiments, R ¹ is selected from: R ¹ is selected from (C ₃ -C ₅ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—C ₂ -C ₃ -alkylene, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, and C ₇ -spiro-cycloalkyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, spiro[3.3]heptanyl, (cubanyl)methyl, and (bicyclo[2.1.1]hexanyl)methyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

In some embodiments, ^R 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]pentanyl)methyl, and spiro[3.3]heptanyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopropyl, 2-((propan-2-yl)oxy)ethyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, spiro[3.3]heptan-2-yl, (cuban-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

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]pentan-1-yl)methyl, 2-(methoxy)ethyl, and spiro[3.3]heptan-2-yl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

In some embodiments, R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl and (bicyclo[1.1.1]hexan-1-yl)methyl.

In some embodiments, R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclopropyl)methyl, 4,4,4-trifluorobutyl ... and wherein the alkyl group is selected from (1-methylcyclobutyl), (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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 (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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]pentan-1-yl)methyl.

In some embodiments, R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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 (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d _{2 .} , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl , (3-fluorobicyclo[1.1.1]pentan-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 yl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl.

In some embodiments, R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, ((S)-2,2-difluoro (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl) and (S)-2-fluoropropyl.

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

In some embodiments, R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, (1s,3S)-3-fluoro cyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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-fluoropropyl.

One embodiment is a compound of formula (Ie):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene and C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene;
Each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -haloalkyl, cyano, and hydroxyl.
Related to.

In some embodiments, R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₃ -C ₄ -cycloalkyl-CD ₂ —, C ₁ -C ₅ -alkyl, C 3 -C ₄ -cycloalkyl, C _{1 -C 3} -alkyl-O—C ₂ -C ₃ -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —;
Each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl.

In some embodiments, R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₄ -cycloalkyl, C ₁ -C 3 -alkyl-O—C _{2 -C 3 -alkylene} , 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —;
Each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl.

In some embodiments, R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₃ -C ₄ -cycloalkyl-CD ₂ —, C ₁ -C ₅ -alkyl, C 3 -C ₄ -cycloalkyl, C _{1 -C 3} -alkyl-O—C ₂ -C ₃ -alkylene, 4-membered heterocyclyl, and (4-membered heterocyclyl)CH ₂ —;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl.

In some embodiments, R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₄ -cycloalkyl, C ₁ -C 3 -alkyl-O—C _{2 -C 3 -alkylene} , 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl.

In some embodiments, R ¹ is selected from methyl, methyl-d ₃ , propyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, and pentyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

In some embodiments, ^R 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]pentanyl)methyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

In some embodiments, R ¹ is selected from methyl, methyl-d ₃ , propyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 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, and pentyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

In some embodiments, R ¹ is selected from 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]pentan-1-yl)methyl;
Each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

In some embodiments, R ¹ is methyl, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl.

In some embodiments, R ¹ is methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl , (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl.

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

In some embodiments, R ¹ is selected from the group consisting of methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ( and ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.

One embodiment is a compound of formula (Ie):
or a pharmaceutically acceptable salt thereof,
R ¹ is selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, and C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, each group optionally substituted with one or more halogen substituents.
Related to.

In some embodiments, R ¹ is selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, and C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, each group optionally substituted with 1, 2, or 3 halogen substituents.

In some embodiments, R ¹ is selected from C ₂ -C ₃ -alkyl, cyclopropyl, C ₃ -C ₄ -cycloalkyl-CD ₂ -, and C ₃ -C ₄ -cycloalkyl-CH ₂ -, each group optionally substituted with 1, 2, or 3 halogen substituents.

In some embodiments, R ¹ is selected from C ₂ -C ₃ -alkyl, cyclopropyl, and C ₃ -C ₄ -cycloalkyl-CH ₂ —, each group optionally substituted with 1, 2, or 3 halogen substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents.

In some embodiments, R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents.

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

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

In some embodiments, R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (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 2,2,2-trifluoroethyl, 3,3,3-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 -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or two halogen substituents.

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

In some embodiments, R ¹ is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with 1 or 2 halogen substituents.

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

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

In some embodiments, R ¹ is C ₁ -C ₆ -alkyl optionally substituted with 1, 2, or 3 halogen substituents. In some embodiments, R ¹ is ethyl or propyl, each group optionally substituted with 1, 2, or 3 halogen substituents. In some embodiments, R ¹ is ethyl or propyl, each group optionally substituted with 1, 2, or 3 fluoro substituents. In some embodiments, R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl.

In some embodiments, R ¹ is C ₃ -C ₇ -cycloalkyl.

In some embodiments, R ¹ is cyclopropyl.

Some embodiments include all combinations of one or more compounds selected from the following group of compounds shown in Table A, and pharmaceutically acceptable salts thereof: Some embodiments include all combinations of one or more compounds selected from the following group of compounds shown in Table A:

Some embodiments of the present invention relate to compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 1); (2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2 ,1-a]isoquinolin-2-ol (Compound 2); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro 2-(1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropyl)acetonitrile (Compound 5); (2R,3R,11bR)-3-(tert-butoxy)-9-(isopentyl) (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 6); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 7); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 8); 2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylazone (Compound 8); 2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylazone (Compound 9); Acetonitrile (Compound 9); (2R,3R,11bR)-3-(tert-butoxy)-9-butoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 10); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-propoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (2R,3R,11bR)-3-(tert-butoxy)-9-((1-hydroxycyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 12); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-cyclopropoxyethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 13); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoro-2-methylpropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 14); (2R,3R,11bR)-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,11bR)-3-(tert-butoxy)-9-(2,2-difluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 16); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2,2,2-difluoropropoxy)- (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 17); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 18); (2R,3R,11bR)-3-(tert (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 20); (2R ,3R,11bR)-3-(tert-butoxy)-9-((R)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 21); (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( Compound 22); (2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 23); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-methoxyethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline -2-ol (Compound 24); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 25); (2R,3R,11bR)-3-(tert-butoxy)-9-(3-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Do[2,1-a]isoquinolin-2-ol (Compound 26); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 27); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b- Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 28); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 29); (2R,3R,11bR)-3-(tert-butoxy)-9-(ethoxy-d ₅ )-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 30); (2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 31); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-yloxy)-1,3,4,6,7,11b-hexahydro-2H -pyrido[2,1-a]isoquinolin-2-ol (compound 32); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-ylmethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 33); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(((R)-oxetan-2-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound Compound 34); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 35); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 36); (2R,3R,1 (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 37); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 38); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-(difluoro (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 39); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((5,5,5-trifluoropentyl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 40); (2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorobicyclo[1.1.1]pentyl)oxy) (2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 41); (2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 42); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3 ,4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 43); (2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 44); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(trifluoromethoxy)ethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 45) 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 45); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(neopentyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 46); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclobutyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 47)

); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((2-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 48); (2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 49); ( 2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorocyclobut-2-en-1-yl)oxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 50); (2R,3R,11bR)-9-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 51); (1R,3r)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (Compound 52); (2R,3R,11bR)-3-(tert-butoxy)-9-((1r,3R)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy ]isoquinolin-2-ol (compound 53); (2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 54); (2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-dimethylcyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline- 2-ol (Compound 55); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(spiro[3.3]heptan-2-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 56); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylpyrrolidin-3-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-methyloxetan-3-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 57); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 58); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound Compound 59); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(1-methylcyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 60); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 61); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 62); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 63); Isoquinolin-2-ol (Compound 63); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 64); (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 65); Do[2,1-a]isoquinolin-2-ol (Compound 65); (2R,3R,11bR)-3-(tert-butoxy)-9-((R)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 66); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-ol (Compound 67); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 68); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-dimethylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 69); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 70); (2R,3R,11bR)-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); (2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 72); (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Pyrido[2,1-a]isoquinolin-2-ol (Compound 73); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 74); (2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-(dimethylamino)cyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 75) H-pyrido[2,1-a]isoquinolin-2-ol (Compound 75); (2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 76); (2S,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 77); (2R,3S,11bS)-3-( tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 78); 2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)acetonitrile (Compound 79); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(methoxy-d ₃ )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 80); 1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclobutane-1-carbonitrile (compound Compound 81); 1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropane-1-carbonitrile (Compound 82); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-3 (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 83); (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline -2-ol (Compound 84); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 85); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-2-methoxypropoxy) )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 86); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-(methylsulfonyl)cyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 87); ( 2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-(methylsulfonyl)propoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 88); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(methylsulfonyl)ethoxy)-1,3,4,6,7, 11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 89); (2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 90); (2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 91) (1S,3s)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 91); (1S,3s)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[

2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (Compound 92); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 93); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9 -((1r,3R)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 94); and (2R,3R,11bR)-3-(tert-butoxy)-9-((1r,3R)-3-(dimethylamino)cyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 95); ns-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 96); trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 97); and cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 98), or all combinations of pharmaceutically acceptable salts thereof.

Some embodiments of the present invention relate to compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 1); (2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2 ,1-a]isoquinolin-2-ol (Compound 2); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro 2-(1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropyl)acetonitrile (Compound 5); (2R,3R,11bR)-3-(tert-butoxy)-9-(isopentyl) (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 6); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 7); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 8); 2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylazone (Compound 8); 2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylazone (Compound 9); Acetonitrile (Compound 9); (2R,3R,11bR)-3-(tert-butoxy)-9-butoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 10); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-propoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (2R,3R,11bR)-3-(tert-butoxy)-9-((1-hydroxycyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 12); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-cyclopropoxyethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 13); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoro-2-methylpropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 14); (2R,3R,11bR)-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,11bR)-3-(tert-butoxy)-9-(2,2-difluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 16); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2,2,2-difluoropropoxy)- (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 17); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 18); (2R,3R,11bR)-3-(tert (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 20); (2R ,3R,11bR)-3-(tert-butoxy)-9-((R)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 21); (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( Compound 22); (2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 23); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-methoxyethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline -2-ol (Compound 24); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 25); (2R,3R,11bR)-3-(tert-butoxy)-9-(3-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Do[2,1-a]isoquinolin-2-ol (Compound 26); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 27); (2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b- Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 28); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 29); (2R,3R,11bR)-3-(tert-butoxy)-9-(ethoxy-d ₅ )-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 30); (2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 31); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-yloxy)-1,3,4,6,7,11b-hexahydro-2H -pyrido[2,1-a]isoquinolin-2-ol (compound 32); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-ylmethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 33); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(((R)-oxetan-2-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound Compound 34); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 35); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 36); (2R,3R,1 (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 37); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 38); (2R,3R,11bR)-3-(tert-butoxy)-9-((1-(difluoro (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 39); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((5,5,5-trifluoropentyl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 40); (2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorobicyclo[1.1.1]pentyl)oxy) (2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 41); (2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 42); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3 ,4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 43); (2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 44); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(trifluoromethoxy)ethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 45) 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 45); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(neopentyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 46); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclobutyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 47)

), (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((2-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 48); (2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2 ,1-a]isoquinolin-2-ol (Compound 49); (2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorocyclobut-2-en-1-yl)oxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 50); (2R,3R,11bR)-9-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(tert-butoxy)-10 -Methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 51); (1R,3r)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (Compound 52); (2R,3R,11bR)-3-( (2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 53); (2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 54); (2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-dimethylcyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 55); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(spiro[3.3]heptan-2-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[ 2,1-a]isoquinolin-2-ol (Compound 56); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-methyloxetan-3-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 58); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclopropyl)methoxy)-1,3,4,6 ,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 59); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(1-methylcyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 60); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2S)-2-fluorocyclopropyl ) methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 61); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 62); (2R,3R,11bR)-3-( (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 63); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 64); Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 64); (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 65); (2R,3R,11bR)-3-(tert-butoxy)-9-((R)-1-cyclobutylethoxy)-10-methoxy-1 ,3,4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 66); (2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 67); (2R,3R,11bR)-3-(tert-butoxy)-9-(( (1R,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 68); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-dimethylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 6 9); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 70); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro 2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 71); (2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 72); (2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-fluoropropoxy)-10-methoxy-1,3,4, 6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 73); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 74); (2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3, 4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 76); 2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)acetonitrile (Compound 79); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(methoxy-d ₃ )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 80); 1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclobutane-1-carbonitrile (Compound 81); 1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropane-1-carbonitrile (Compound 82); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 83); (2R,3R,11 (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-2-hydroxypropoxy)-11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 84); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 85); (2R,3R,11bR )-3-(tert-butoxy)-10-methoxy-9-((S)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 86); (2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 90); (2R,3R,11bR)- 3-(tert-butoxy)-9-((2,2-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 91); (1S,3s)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonyl tolyl (Compound 92); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 93); and (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H- Pyrido[2,1-a]isoquinolin-2-ol (Compound 94); trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 96); trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy and cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 97); and cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 98), or all combinations of pharmaceutically acceptable salts thereof.

Some embodiments of the present invention relate to compounds of the following group: (2R,3R,11bR)-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); (2R,3R,11bR)-3-(tert-butoxy)-9-(cuban-1-ylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 100); (2R,3R,11bR)-9-(bicyclo[1.1.1]pentan-1-ylmethoxy)-3-(tert-butoxy)-10-methoxy-1,3, 4,6,7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 101); (2R,3R,11bR)-9-(bicyclo[2.1.1]hexan-1-ylmethoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 102); (2R,3R,11bR)-3-(tert-butoxy)-9-((1,1-dimethylsilolan-3-yl)methoxy)-10-methoxy-1,3,4,6, 7,11b-Hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 103); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 104); (2R,3R,11bR)-9-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-3-(tert-butoxy) and (2R,3R,11bR)-9-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 105); and (2R,3R,11bR)-9-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 106), or all combinations of pharmaceutically acceptable salts thereof.

Useful Intermediates Certain intermediates described herein above and below are novel and useful in the preparation of compounds, for example, compounds of formula (Ia), (Ic), (Ie), (Ig), (Ii), and (Ik). Certain intermediates are shown in Figures 2A and 2B.

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

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

In some embodiments, the salt is (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt.
is.

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

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

It should be further appreciated that certain features that 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 Compositions, Formulations, and Dosage Forms The present disclosure further provides pharmaceutical products, e.g., pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound described herein, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in the methods described herein, for example, for treating hyperkinetic movement disorders. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, and inert material or ingredient that does not interfere with the activity of the drug substance; an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, ^5th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, ^21st Ed. Mack Pub. Co., Easton, PA (2005)).

The compositions can also be formulated as pills, capsules, granules, or tablets containing, in addition to the VMAT2 inhibitor, diluents, dispersants and surfactants, binders, and lubricants. Those skilled in the art can further formulate the VMAT2 inhibitor in an appropriate manner and according to generally accepted practices, for example, according to the practices 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. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules, as well as liquids, syrups, suspensions, and emulsions.

Pharmaceutical preparations for oral administration can be obtained by any suitable method, usually by uniformly mixing the compound(s) with a liquid or finely divided solid carrier, or both, in the required proportions, then, if necessary, after adding suitable auxiliaries, processing the mixture, and, if desired, shaping the resulting mixture into the desired shape to obtain tablets or dragee cores.

Conventional additives, such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants, and disintegrants, can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral preparations can be in the form of a dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filter-sterilizing the solution before lyophilization, or simply by filling into appropriate vials or ampoules and sealing.

Some embodiments provide a method for preparing a pharmaceutical composition, the method comprising admixing a compound 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 active ingredient, such carriers as are known in the art to be appropriate.

In preparing pharmaceutical compositions, a drug substance is typically mixed (i.e., blended) 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 serves as a diluent, the excipient can be a solid, semi-solid, or liquid material, acting as a vehicle, carrier, or medium for the drug substance. Thus, compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, injectable sterile solutions, and sterile-packaged powders.

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

For preparing suppositories, a low-melting wax, such as a blend of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents.

The pharmaceutical compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the pharmaceutical compositions can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Pharmaceutical compositions can be formulated as aqueous solutions, aqueous-alcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or freeze-dried powders for reconstitution. Such pharmaceutical compositions can be administered directly or as admixtures for further dilution/reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and drip.

Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active pharmaceutical ingredients in water along with viscous materials.

For topical administration to the epidermis, the compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated as gels, ointments, creams, or lotions, or as a transdermal patch. Formulations suitable for topical administration in the mouth also include lozenges containing the active pharmaceutical ingredient in a flavored base.

The solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example, by dropper, pipette, or spray. The formulations may be provided in single-dose or multi-dose form. In the latter case of a dropper or pipette, administration may be achieved by administering an appropriate, predetermined volume of the solution or suspension to the patient. In the case of a spray, administration may be achieved, for example, by means of a metering atomizing spray pump.

Administration to the respiratory tract can also be achieved by means of an aerosol formulation provided in a pressurized pack with a suitable propellant. When 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, administration can be achieved using, for example, a spray, nebulizer, pump nebulizer, inhaler, 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 mix of the compound in a suitable powder base such as lactose, starch or starch derivatives. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of gelatin or blister packs from which the powder may be administered by means of an inhaler.

The compounds described herein, or pharmaceutically acceptable salts thereof, can also be administered via fast dissolving or slow release compositions, which include a biodegradable fast dissolving or slow release carrier.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. In some embodiments, the pharmaceutical preparation is a tablet or capsule for oral administration. In some embodiments, the pharmaceutical preparation is a liquid formulated for intravenous administration.

The compositions can be formulated as unit dosage forms, each dosage containing the active ingredient or an equivalent mass of the active ingredient. The term "unit dosage form" refers to a physically discrete unit of formulation suitable as a single dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, in association with suitable excipients as described herein.

Liquid forms containing the active ingredient that can be incorporated for oral administration or for administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils.

The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques, or sterile filtered. Aqueous solutions can be packaged for ready use or lyophilized, the lyophilized preparation 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, and powders. Liquid or solid compositions may contain suitable additives as described herein. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

Compositions may, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active pharmaceutical ingredient. The pack may, for example, comprise metal or plastic foil, e.g., a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice, affixed to the container, in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting agency approval of the drug form for human or veterinary administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that may comprise a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

To prepare solid compositions, e.g., tablets, the drug substance can be mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of the components. When these preformulation compositions are referred to as homogeneous, the drug substance is usually dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, e.g., tablets and capsules.

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

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

The amount of compound or composition administered to a subject will also vary depending on what is being administered, the purpose of the administration, e.g., prophylaxis or therapy, the condition of the subject, the mode of administration, etc. In therapeutic applications, compositions can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptomology and/or pathology of the disease and its complications. The therapeutically effective amount will depend on the condition being treated and the judgment of the attending physician depending on factors such as the severity of the disease, the age, weight, and general condition of the subject, etc.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more sub-doses per day. The sub-doses themselves may be further divided, for example, into several loosely spaced separate administrations. The daily dose may be divided into several, for example, two, three or four separate administrations, particularly when relatively large amounts are administered as deemed appropriate. It may also be necessary to deviate upwards or downwards from the daily dose indicated, if appropriate, depending on individual behavior.

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

Preparation As used herein, a "preparation" is the product of a process used to make or isolate a compound disclosed and described herein, and the preparation contains at least one other component in addition to the compound. In some embodiments, the preparation comprises a chemical entity.

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

Some embodiments provide preparations comprising a compound 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 disclosed and described herein. In some embodiments, the chemical entity is a (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt of a compound disclosed and described herein.

In some embodiments, the compounds of the preparation have 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 preceding numbers. In some embodiments, the compounds of the preparation have an enantiomeric excess of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%, or an enantiomeric excess within a range defined by any of the preceding numbers.

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

In some embodiments, the preparation comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 93% by weight of the compound, or a weight percentage of the compound within a range defined by any of the preceding numbers. In some embodiments, the preparation comprises at least 50%, 60%, 70%, 80%, 90%, or 93% by weight of the compound, or a weight percentage of the compound within a range defined by any of the preceding numbers. In some embodiments, the preparation comprises at most 50%, 60%, 70%, 80%, 90%, 93%, or 95% by weight of the compound, or a weight percentage of the compound within a range defined by any of the preceding numbers.

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

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

The VMAT2 inhibitors described herein can reduce monoamine levels in the central nervous system. Accordingly, the present disclosure includes a method for reducing monoamine levels in the central nervous system of a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the monoamine levels relative to pre-administration levels.

The VMAT2 inhibitors disclosed and described herein are believed to have utility across a wide range of therapeutic applications and can be used to treat or prevent a variety of disorders caused by or associated with inhibition of human vesicular monoamine transporter isoform 2. These disorders include neurological and psychiatric disorders, such as hyperkinetic movement disorders, schizophrenia, and mood disorders. The compounds described herein, or pharmaceutically acceptable salts thereof, can be used in any of the methods of treatment disclosed and described herein.

Accordingly, various embodiments disclosed herein provide methods for treating or preventing a neurological disease or disorder and/or a psychiatric disease or disorder 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. The neurological disease or disorder and/or psychiatric disease or disorder can be, for example, hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated ataxia syndrome, autism spectrum disorder (e.g., restricted and repetitive behaviors associated with autism spectrum disorder (ASD)), Rett syndrome, or acanthocyocytosis.

In various other embodiments disclosed herein, methods are provided for treating or preventing a vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder 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. The VMAT2 disease or disorder can be, for example, ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependent disorders.

Accordingly, various embodiments disclosed herein provide methods for treating or preventing a hyperkinetic movement disorder 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 hyperkinetic movement disorder is tardive dyskinesia, Tourette's syndrome, Huntington's disease, Huntington's disease with chorea, or tics. In other embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs 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 a 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.

Some embodiments disclosed herein provide methods for treating or preventing schizophrenia or schizoaffective disorder in a subject in need thereof by administering to a 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 disease or disorder or psychiatric disease or disorder is a hyperkinetic movement disorder.

In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia.

In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome.

In some embodiments, the hyperkinetic movement disorder is Huntington's disease.

In some embodiments, the hyperkinetic movement disorder is a tic.

In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease.

In some embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

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

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

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

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

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

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

In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is restricted and repetitive behaviors associated with autism spectrum disorder (ASD).

In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is obsessive-compulsive behaviors in partial responders and non-responders (or completely refractory) with obsessive-compulsive disorder (OCD). In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is obsessive-compulsive behaviors in partial responders and non-responders (or completely refractory) with obsessive-compulsive disorder (OCD), and the compounds described herein are administered as adjunctive therapy. In some embodiments, the compounds described herein are useful as adjunctive therapy or treatment for schizophrenia. In some embodiments, the compounds described herein are administered as adjunctive therapy, and the primary therapy is treatment with an antidepressant.

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

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat or prevent a disease or disorder selected from the following:
Ataxia or spinal muscular atrophy, e.g., spinocerebellar ataxia type 17 (SCA17)/HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia;
Chorea, e.g., benign hereditary chorea, chorea, mitochondrial/mitochondrial-related chorea, Wilson's disease-associated chorea, chorea of pregnancy, acanthocytosis, drug-induced chorea, hemiballismus, rheumatic/Sydenham chorea, and thyrotoxic/hyperthyroid chorea;
Congenital malformations, deformities, or abnormalities, such as Angelman syndrome, congenital neuropathy, Aicardi syndrome, neurofibromatosis, congenital facial nerve hypoplasia, Moebius type II syndrome, Cockayne syndrome, Sjogren-Larsson syndrome, Laurence-Moon-Bardet-Biedl syndrome, Fragile X syndrome, and Prader-Willi syndrome;
Dementia, such as AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, Lewy body dementia, microinfarct dementia, presenile dementia, senile dementia, and vascular dementia;
Diseases of the oral cavity, salivary glands, and jaw, such as glossalgia/burning mouth syndrome and temporomandibular joint disorders;
Dyskinesias, such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and respiratory dyskinesia;
Dystonias such as blepharospasm, buccoglossal syndrome, acute drug-induced dystonia, dystonia, juvenile-onset primary dystonia, genetic torsion dystonia, hand dystonia/writer's cramp, idiopathic non-familial dystonia, idiopathic orofacial dystonia/Meige disease, laryngeal dystonia, oromandibular dystonia, and spasmodic torticollis/cervical dystonia;
Endocrine, nutritional, and metabolic diseases, such as Wilson's disease, diabetes mellitus, obesity, Syndrome X, and Lesch-Nyhan syndrome;
Epilepsy, such as Baltic myoclonic epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, Lafora myoclonic epilepsy, severe myoclonic epilepsy of infancy, and convulsions;
Addiction and impulse disorders, such as binge eating disorder, kleptomania, impulse control disorders, trichotillomania, intermittent explosive disorder, pathological gambling, and pyromania;
Huntington's disease or related disorders, such as Huntington's disease, Huntington-like syndromes 1-3, Huntington's chorea, and X-linked McLeod neuroacanthocytosis;
Mood or psychiatric disorders, such as schizophrenia, psychosis, mania, bipolar disorder, depression, and mood disorders;
Other diseases or disorders, such as fumbling, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit mouth syndrome, spasticity, up and down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders, and rheumatoid arthritis;
Neurotic, stress-related, and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and psychogenic movement disorder;
Other degenerative diseases of the basal ganglia, such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglia degeneration, and neuroferritinopathy;
Other extrapyramidal and movement disorders, such as hemiballismus, extrapyramidal disorders, essential tremor, geniospasm, hyperalgesia, akathisia, ballismus/hemiballismus, myoclonus, and restless legs syndrome/Willis-Ekbom syndrome;
Other nervous system or motor functions, e.g., sleep-related bruxism, abnormal involuntary movement disorders, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, chronic hemifacial spasm, olfactory agenesis, congenital cranial nerve palsy, exercise ataxia syndrome, familial periodic paralysis, congenital hemiplegia hemiparesis), fine motor development delay, fine motor skill dysfunction, gross motor development delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, alternating hemiplegia of childhood, motor developmental delay, cerebral palsy, athetoid cerebral palsy, malocclusion, pseudoparesis, psychomotor hyperactivity, bradykinesia, synkinesia, akinesia, Riley-Day syndrome, and athetosis;
Parkinsonism/Parkinsonism, e.g., Parkinsonism, drug-induced parkinsonism, micrographia, and Parkinson's disease;
Childhood-onset behavioral and emotional disorders, such as attention deficit hyperactivity disorder, attention deficit disorder, hyperkinesia, hyperkinesia (neonatal), oppositional defiant disorder, transient tic disorder, persistent (chronic) motor or vocal tic disorder, stereotypic movement disorder, stereotypies, and Tourette's syndrome;
Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger's syndrome, pervasive developmental disorder NOS, and dyslexia; and Substance abuse or dependence, such as addictive disorders, alcohol dependence, cocaine dependence, illicit drug abuse, methamphetamine abuse, methamphetamine addiction/dependence, methamphetamine use disorder, morphine abuse, morphine-like substance abuse, nicotine dependence, polysubstance abuse, and prescription drug abuse.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat or prevent motor paralysis. In some embodiments, the motor paralysis is selected from spastic cerebral palsy (including, but not limited to, spastic hemiplegia cerebral palsy, spastic diplegia cerebral palsy, and spastic quadriplegia cerebral palsy), dyskinetic cerebral palsy, ataxic cerebral palsy, and "mixed" cerebral palsy.

In some embodiments, the motor paralysis is spastic cerebral palsy.

In some embodiments, the motor paralysis is dyskinetic cerebral palsy.

In some embodiments, the motor paralysis is ataxic cerebral palsy.

In some embodiments, the motor paralysis is "mixed" cerebral palsy.

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

In some embodiments, the patient to be treated has been determined to have 22q11.2 deletion syndrome. In some embodiments, because the patient has 22q11.2 deletion syndrome, the patient is predisposed to developing a psychiatric disorder. In some embodiments, the patient has been determined to have COMT haploinsufficiency. In some embodiments, because the patient has COMT haploinsufficiency, the patient is predisposed to developing a psychiatric disorder.

In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in a mammal to compounds capable of inhibiting human vesicular monoamine transporter isoform 2. Thus, these VMAT2 inhibitors can have additional utility in modifying the in vivo properties of metabolites, e.g., maximum concentration or duration of action, in a mammal.

Characterization of any of the VMAT2 inhibitors described herein can be determined using methods described herein and methods in the art. For example, dopamine depletion can be determined using the locomotor activity (LMA) assay. Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has been shown to be a valid and reliable preclinical model for evaluating the antipsychotic activity of compounds.

Combination therapy The compounds of the present disclosure and their pharmaceutically acceptable salts can be used as monotherapy or in combination with one or more other pharmaceutical agents.In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are administered together (simultaneously or sequentially) with one or more pharmaceutical agents selected from antidepressants, antipsychotics (typical or atypical), antiepileptics, antibacterial agents, antiarrhythmic agents, mood stabilizers, and gastrointestinal drugs.In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are used in adjunctive therapy, and adjunctive therapy refers to a treatment that is used in conjunction with a primary treatment and its purpose is to support the primary treatment.Adjunctive therapy is typically a co-administered therapy.As an example of adjunctive therapy, when treating obsessive-compulsive disorder, the primary treatment may be, for example, an antidepressant, and co-administration of the compounds described herein is considered adjunctive therapy.

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

In general, the compounds used in the reactions described herein can be made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. Methods known to those skilled in the art can be identified through various references and databases. Suitable references and treatises detailing the synthesis of reactants useful in preparing the compounds of the present disclosure, or providing references to articles describing the preparation, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions," 2nd Ed., W. A. Benjamin, Inc., Menlo Park, Calif., 1972; T. L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992.

Specific and similar reactants can also be identified through the index of known chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which is available at most public and university libraries and through online databases (further details can be contacted from the American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in catalogs can be prepared according to known methods by custom chemical synthesis companies; many standard chemical supply companies (e.g., those listed above) offer custom synthesis services.

The following examples are included to demonstrate embodiments of the present disclosure. However, one of ordinary skill in the art will, in light of this disclosure, recognize that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure. Additional illustrated syntheses for compounds of the present invention are shown in the accompanying drawings, in which symbols have the same definitions as those used throughout this disclosure.

Analytical HPLC analysis was performed on an LC-MS system equipped with a UV detector (Dionex™ UVD 170u UV/VIS Detector), a Corona array detector (Thermo™ Veo™ RS), and a mass analyzer (Dionex MSQ Plus™). Reverse-phase preparative HPLC purification was performed on a Phenomenex C ₁₈ Kinetix 5μ 100A 150 x 21.2 mm column liquid chromatography mass spectrometry (LCMS) system using an ACN/water gradient containing 0.05% TFA. Supercritical fluid chromatography (SFC) purification was performed on a Waters™ Prep 100q™ system equipped with a UV detector (Waters™ 2998 Photodiode Array Detector™) and a mass analyzer (Waters™ Acquity QDa Detector™). A Waters™ Viridis™ BEH2-Ethylpyridine 130 Å 5 μm, 30 mm × 100 mm column was used with a CO ₂ and 0.3% NH ₄ OH gradient in MeOH, run at 100 mL/min, 40°C, and a backpressure regulator of 105 bar. All final compounds were analyzed by analytical HPLC, and peaks were monitored for purity at 210, 254, and 280 nm. ¹ H was recorded in an appropriate NMR solvent, e.g., dimethyl sulfoxide-d ₆ (DMSO-d ₆ ), on a Bruker 400 MHz spectrometer equipped with a broadband NMR probe or a Bruker 500 MHz spectrometer equipped with a 5 mm QNP probe with a Z-gradient. ¹ H chemical signals are given in parts per million (ppm), using the residual solvent signal as the reference. Chemical shifts are expressed in ppm (δ), and coupling constants (J) are reported in Hertz (Hz). Reactions were performed under a dry nitrogen atmosphere unless otherwise noted.

Example 1
(2R,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 15); (2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 76); (2S Preparation of (2R,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 77); and (2R,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 78).
Step 1: Preparation of N,N,N-trimethyl-3-oxobutan-1-aminium iodide (compound 2-2).

To a solution of 4-(dimethylamino)butan-2-one (compound 2-1, 15.0 g, 130 mmol, 1.0 equiv.) in EtOAc (260 mL) was added methyl iodide (55.4 g, 390 mmol, 3.0 equiv.), and the mixture was stirred overnight at room temperature (RT). The mixture was concentrated in vacuo to give crude N,N,N-trimethyl-3-oxobutan-1-aminium iodide (compound 2-2, 31.51 g, 123 mmol, 94%) as a pale red solid, which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 3.50 (t, J = 7.5 Hz, 2H), 3.12 - 3.09 (t, J = 7.0 Hz, 2H), 3.04 (s, 9H), 2.18 (s, 3H).

Step 2: Preparation of (±)-9,10-dimethoxy-1,3,4,6,7,11b-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, 6.60 g, 34.5 mmol, 1.0 equiv.) in MeOH (66 mL) was added N,N,N-trimethyl-3-oxobutan-1-aminium iodide (compound 2-2, 13.3 g, 51.8 mmol, 1.5 equiv.) and the mixture was stirred at reflux for 1 h. The mixture was cooled to RT and stirred for 1 h. The mixture was concentrated in vacuo, suspended in water, and extracted three times with DCM. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: a silica gel column (220 g) was loaded with DCM and run with an increasing gradient of MeOH in DCM (0-5% over 20 min), and a silica gel column (40 g) was loaded with DCM and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min) to further purify the mixed fractions to give (±)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-4, 6.89 g, 26.4 mmol, 77%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.71 (s, 1H), 6.70 (s, 1H), 3.72 (s, 6H), 3.46 (br d, J = 11.1 Hz, 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, 14.2 Hz, 1H), 2.23 (br d, J = 11.2 Hz, 1H).

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

To a solution of (±)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-4, 4.40 g, 16.8 mmol, 1.0 equiv.) in THF (44 mL) was added 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (3.52 g, 20.2 mmol, 1.2 equiv.), and the mixture was stirred at reflux overnight. The mixture was cooled to RT, diluted with water (40 mL) and aqueous HCl (1 M, 50.5 mL, 50.5 mmol, 3.0 equiv.), and stirred for 1 h. 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 placed under vacuum overnight to afford (±)-3-((dimethylamino)methylene)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-5, 4.39 g, 13.9 mmol, 83%) as a sticky yellow solid, which was carried forward without further purification.

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

To a solution of (±)-3-((dimethylamino)methylene)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-5, 4.19 g, 13.2 mmol, 1.0 equiv.) in water (80 mL) was added aqueous HCl (12.1 M, 2.7 mL, 33.0 mmol, 2.5 equiv.) at 0° C. and stirred for 30 minutes. 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 extracts were discarded. The aqueous layer was basified to pH=11 with aqueous NaOH (6 M). The aqueous layer was concentrated. The crude material was slurried in MeOH (50 mL). The solid precipitate was collected by vacuum filtration over Celite. The filtrate was concentrated to give crude (±)-sodium (9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3(4H)-ylidene)methanolate (Compound 2-6, 5.61 g) as a solid, of which 2.10 g was carried directly to the next step (i.e., synthesis of (±)-3-diazo-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (Compound 2-7)).

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

To a solution of crude sodium (±)-(9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3(4H)-ylidene)methanolate (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 °C before adding tosyl azide (1.27 g, 6.42 mmol). The reaction was stirred at 0 °C for 1 h, then warmed to RT and stirred for 2 h. Aqueous KOH (1.4 M, 4.81 mL, 6.74 mL) was added and the reaction was stirred for an additional 15 min. The mixture was extracted three times with DCM. The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated in vacuo. DCM was used to pack a silica gel column (24 g) and run with an increasing gradient of EtOAc in hexanes (0-100% over 12 min) to give (±)-3-diazo-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-7, 0.337 g, 1.17 mmol, 24% over two steps) as a brown solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.75 (s, 1H), 6.68 (s, 1H), 4.01 (d, J = 12.6 Hz, 1H), 3.76 - 3.69 (m, 2H), 3.71 (s, 6H), 3.05 (td, J = 4.6, 11.1 Hz, 1H), 2.97 (dd, J = 4.1, 17.5 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.68 (td, J = 4.0, 15.9 Hz, 1H), 2.53 (m, 1H), 2.14 (dd, J = 11.2, 17.5 Hz, 1H).

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

To a solution of (±)-3-diazo-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-7, 0.140 g, 0.487 mmol, 1.0 equiv.) in tert-butanol (1.0 mL) was added dirhodium tetraacetate (10.8 mg, 0.0244 mmol, 0.050 equiv.). The mixture was heated with stirring at 80° C. for 2 h. The mixture was cooled to RT, filtered over Celite, and concentrated in vacuo. DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexanes (0-50% over 20 min) to give (±)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound (±)-2-8, 0.027 g, 0.0810 mmol, 17%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.72 (s, 1H), 6.69 (s, 1H), 4.37 (dd, J = 6.8, 11.0 Hz, 1H), 3.72 (s, 6H), 3.46 (br d, J = 11.0 Hz, 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-1,3,4,6,7,11b-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-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound (±)-2-8, 27 mg, 0.0810 mmol, 1.0 equiv.) in MeOH (2.0 mL) at 0° C. was added NaBH ₄ (4.6 mg, 0.121 mmol, 1.5 equiv.). 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. DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min) to give (±)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-9, 22 mg, 0.066 mmol, 81%) as a mixture of diastereomers. Separation of the four resulting isomers was achieved by preparing solutions in a minimal volume of MeOH and subjecting them to preparative chiral SFC. Chiral compound separation was performed using a Pic Solution™ SFC-PICLAB-Prep200™ supercritical fluid chromatography (SFC) system equipped with a UV detector and an Advion™ mass analyzer. A Chiral Technologies Inc™ ChiralPak™ IG/SFC 5 μm, 20 mm x 250 mm column was used with an isocratic gradient of 0.5% DMEA in 85% _CO and 15% MeOH at 150 mL/min, 55°C, and a backpressure regulator of 110 bar.

The following amounts of Compound 15, Compound 76, Compound 77, and Compound 78 were obtained:
(2R,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 15, 6 mg, 0.0179 mmol, 22%, slowest retention time of the four isomers);
(2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 76, 3 mg, 0.00894 mmol, 11%, earliest retention time of the four isomers);
(2S,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 77, 6 mg, 0.0179 mmol, 22%, second earliest retention time of the four isomers);
(2R,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 78, 4 mg, 0.0119 mmol, 15%, second slowest retention time of the four isomers).

Example 2
Preparation of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2-21).
Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15).

To a mixture of ethyl 4-(tert-butoxy)-3-oxobutanoate (compound 2-14, 39.4 g, 195 mmol, 1.0 equiv.) and water (600 mL), aqueous NaOH (6 N, 68.3 mL, 410 mmol, 2.1 equiv.) was added, and the resulting mixture was stirred at RT overnight. The mixture was cooled to 0 °C and then acidified to pH 1-2 with concentrated H ₂ SO _4. The aqueous layer was extracted five times with MTBE. The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated in vacuo to afford crude 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15, 33.1 g 190 mmol, 97%) as a clear brown oil, which was carried forward without any further purification. ^1H NMR (400 MHz, DMSO-d ₆ ): δ (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-1,3,4,6,7,11b-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, 28.9 g, 95 mmol, 1.0 equiv.) in water (289 mL) was added NaOAc (0.779 g, 9.50 mmol, 0.1 equiv.) at 50° C. A solution of 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15, 33.1 g, 190 mmol, 2.0 equiv.) was added dropwise, and the mixture was stirred at 50° C. for 3 h. 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 _MgSO4 , filtered, and concentrated in vacuo to yield 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, 95 mmol, 1.0 equiv.) and 37% (w/w) aqueous formaldehyde (6.6 mL, 80.8 mmol, 0.85 equiv.). The mixture was stirred at 40 °C overnight. The mixture was cooled to RT, quenched _with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo. Two silica gel columns (330 g) were packed using DCM and run with an increasing gradient of EtOAc in hexanes (0-50% over 20 min) 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, 13.1 g, 32.0 mmol, 34% over two steps) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 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, 10.9 Hz, 1H), 3.74 (s, 3H), 3.46 (br d, J = 11.9 Hz, 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)
Step 3A: 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).
To a solution of 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, 10.9 g, 26.6 mmol, 1.0 equiv) in MeOH (110 mL) at 0° C. was added NaBH ₄ (2.01 g, 53.2 mmol, 2.0 equiv) in portions. The mixture was stirred for 30 min, then warmed to RT and stirred for 1 h. The reaction mixture was diluted with water (100 mL) and aqueous NaOH (1 M, 100 mL) and then extracted three times with DCM. The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated in vacuo. DCM was used to pack a silica gel column (220 g) and run with an increasing gradient of EtOAc in hexanes (0-80% over 20 min) to give (±)-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) as a 1.4:1 mixture of diastereomers (8.64 g, 21.0 mmol, 79%).

(Reduction, Method B)
Step 3B: 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).
To a solution of 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, 11.7 g, 28.5 mmol, 1.0 equiv.) in THF (184 mL) at 0° C. was added DIBAL-H (1.0 M in hexanes, 42.8 mL, 42.8 mmol, 1.5 equiv.) dropwise. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with acetone. The mixture was diluted with aqueous Rochelle's salt (10% w/w) and stirred vigorously for 30 minutes. The mixture was extracted three times with DCM. The combined organic extracts were dried _over MgSO, filtered, and concentrated in vacuo to afford crude (±)-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) as a 6.5:1 mixture of diastereomers (11.70 g, 28.4 mmol, 99%), which was carried on directly to the next step (i.e., synthesis of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol).

Step 3C: 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 (±)-2-20).

Chromatography of compound (±)-2-19 (0.432 g, 1.05 mmol, 1.4:1 dr) afforded diastereomerically pure compound (±)-2-20. DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min) to give (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-20, 166 mg, 0.403 mmol, 38%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 = 4.7 Hz, 1H), 3.73 (s, 3H), 3.32 - 3.27 (m, 2H), 3.02 (br d, J = 11.0 Hz, 1H), 2.92 - 2.82 (m, 3H), 2.54 - 2.45 (m, 2H), 2.35 - 2.29 (m, 1H), 2.04 (br t, J = 10.3 Hz, 1H), 1.27 - 1.21 (m, 1H), 1.17 (s, 9H).

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

To a solution of crude (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19, 6.5:1dr, 11.70 g, 28.5 mmol, 1 equiv.) in EtOH (250 mL) was added (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA, 11.00 g, 28.5 mmol, 1.0 equiv.). The solution was heated to reflux with stirring, which became a suspension upon heating. After the addition of MeOH (60 mL), the mixture was held at reflux until a clear solution was obtained. The solution was cooled to 75°C, then seeded with compound 2-21·DPTTA (0.050 g, see Example 3 below) and held at a constant temperature for 1 hour and 30 minutes. The mixture was cooled to RT at a rate of 8°C per hour and then continuously stirred for 2 days. The resulting precipitate was collected by vacuum filtration and dried to give compound 2-21·DPTTA (7.357 g, 6.26 mmol, 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%. The chiral salt pair was suspended in DCM, and water was added. The mixture was basified with saturated aqueous NH ₄ OH until the pH was approximately 10. The mixture was extracted three times with DCM. The organic extract was dried over _MgSO4 , filtered, and concentrated in vacuo to provide the title compound (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21, 3.78 g, 6.12 mmol, 32% over two steps from compound (±)-2-18 prepared in Example 2, Step 2 above) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 = 4.7 Hz, 1H), 3.73 (s, 3H), 3.32 - 3.27 (m, 2H), 3.02 (br d, J = 11.0 Hz, 1H), 2.92 - 2.82 (m, 3H), 2.54 - 2.45 (m, 2H), 2.35 - 2.29 (m, 1H), 2.04 (br t, J = 10.3 Hz, 1H), 1.27 - 1.21 (m, 1H), 1.17 (s, 9H).

Example 3
Preparation of the salt of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol and (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (Compound 2-21•DPTTA).

To a solution of (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-20, 0.166 g, 0.403 mmol, 1.0 equiv.) in MeOH (2 mL) was added (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA, 0.156 g, 0.403 mmol, 1.0 equiv.). The mixture was heated to 50° C. with stirring and held at that temperature for 10 min. The mixture was cooled to rt and then concentrated in vacuo to give an off-white solid. The salt pair was suspended in EtOH (4 mL) and heated to 70° C. with stirring to give a suspension. MeOH (3 mL) was added and the mixture was stirred at 70° C., at which point it became a clear solution. The sample was allowed to cool to RT with stirring over 30 min and then stirred at RT overnight. The resulting precipitate was collected by vacuum filtration, rinsed with EtOH (0.5 mL), and dried to give compound 2-21·DPTTA (0.116 g, 0.145 mmol, 36%) as a white solid. Chiral purity analysis was performed using a Waters™ Ultra-Performance Convergence Chromatography (UPC2)™ supercritical fluid chromatography (SFC) system equipped with a UV detector (Waters™ Acquity UPC2 PDA Detector™) and a mass analyzer (Waters™ Acquity QDa Detector™). A Chiral Technologies Inc™ ChiralPak™ IBU/SFC 1.6 μm, 2.1 mm x 50 mm column was used with an isocratic gradient of 0.5% DMEA in 95% _CO2 and 5% MeOH at 1.5 mL/min, 40°C, and a backpressure regulator of 1500 psi. The extracted wavelength of 281 nm was used for %ee quantification and analysis. 100% ee optical purity as a single diastereomer was determined by chiral SFC analysis. The assigned structure was confirmed by single crystal x-ray structure.

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

(2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-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 approximately 50°C in a capped vial to obtain a clear solution, which was then cooled to RT. After 2 days, the solution remained clear at RT and was allowed to slowly evaporate. Within 3 days, the solution was observed to contain a single-crystal-quality block.

The crystal structure of compound 2-21·DPTTA was determined to be a mixed ethanol and methanol solvate with the formula C ₂₅ H ₃₄ NO ₄ ·C ₂₀ H ₁₇ O ₈ ·0.851 (C ₂ H ₆ O)·0.149 (CH ₄ O). The solvate was refined as being primarily ethanol with a minor amount of methanol disordered. The chiral centers at N1 (protonated), C2, C3, and C5 were all determined to have the R configuration. The chiral centers at C27 and C28 (O,O'-di-p-toluoyl-tartaric acid) both have the S configuration. The unit system and space group for compound 2-21·DPTTA are shown in Table 1. Data collection and refinement parameters for compound 2-21·DPTTA are shown in Table 2.

Example 4A
Preparation of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (compound 2-16).

To a solution of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (23.2 g, 86.6 mmol, 1.0 equiv) in 1:1 MTBE/THF (230 mL) was added HCl (4 M in dioxane, 22.7 mL, 91.0 mmol, 1.05 equiv) dropwise over 20 min at rt. The mixture was stirred at RT for 16 h. The precipitate was filtered and rinsed with MTBE (100 mL) to give 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (compound 2-16, 25.8 g, 84.9 mmol, 98%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 = 8.4 Hz, 2H).

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

Example 4C
Preparation of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22).
Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15).

To a suspension of ethyl 4-(tert-butoxy)-3-oxobutanoate (compound 2-14, 100 g, 494 mmol, 1.0 equiv.) in water (1 L) at 0° C. was added aqueous 6 N NaOH (173 mL, 1040 mmol, 2.1 equiv.) over 5 min, and the mixture was then stirred at RT for 16 h. The reaction mixture was acidified to pH 1-2 with aqueous H ₂ SO ₄ (18.1 M) and extracted five times with MTBE. The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated in vacuo to afford 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15, 83.8 g, 481 mmol, 97%) as a clear, light brown oil, which was used without further purification. ^1H NMR (500 MHz, DMSO-d ₆ ): δ (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, 83.8 g, 481 mmol) in DMSO (166 mL) was heated with stirring at 45° C. for 20 hours. The mixture was subjected to vacuum distillation to give 1-(tert-butoxy)propan-2-one (compound 2-25, 55.1 g, 423 mmol, 88%) as a clear, colorless oil having a boiling point of 50° C. at 12 mmHg. ¹ H NMR (400 MHz, CDCl ₃ ): δ (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, 55.1 g, 423.3 mmol, 1.0 equiv.) in EtOH (275 mL), dimethylamine hydrochloride (51.8 g, 635 mmol, 1.5 equiv.), paraformaldehyde (25.4 g, 847 mmol, 2.0 equiv.), and aqueous HCl (12.1 N, 1.75 mL, 21.2 mmol, 0.05 equiv.) were added, and the mixture was stirred at 75 °C for 22 h. The mixture was cooled to RT, diluted with water, basified with aqueous NaOH (1 M) to pH = 12, and extracted five times with MTBE. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was divided and subjected to two separate separations: DCM was used to pack a silica gel column (330 g) and run with an increasing gradient of MeOH in DCM (0-10% over 20 min), and DCM was used to pack a silica gel column (220 g) and run with an increasing gradient of MeOH in DCM (0-10% over 20 min) to give 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (compound 2-26, 25.1 g, 83% purity (w/w), 111 mmol, 26%) as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 3.94 (t, J = 6.6 Hz, 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-1,3,4,6,7,11b-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, 25.1 g, 83% purity (w/w), 111 mmol, 1.2 equiv.) in MeOH (110 mL) and water (58 mL) was added 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (compound 2-16, 28.3 g, 93.0 mmol, 1.0 equiv.), sodium acetate (9.27 g, 113 mmol, 1.2 equiv.), and acetic acid (6.5 mL, 113 mmol, 1.2 equiv.). The mixture was stirred at 45° C. for 40 hours, at which point a precipitate formed. The mixture was cooled to room temperature, and the precipitate was filtered. The solid was rinsed with 50% (v/v) MeOH in water (200 mL) and dried in vacuo for 16 hours 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, 20.6 g, 50.3 mmol, 54%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 10.9 Hz, 1H), 3.74 (s, 3H), 3.46 (br d, J = 11.9 Hz, 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-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19).

To a solution of 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound (±)-2-18, 20.6 g, 50.3 mmol, 1.0 equiv.) in THF (200 mL) at 0° C. was added DIBAL-H (1.0 M in hexanes, 75.4 mL, 75.4 mmol, 1.5 equiv.) dropwise. The mixture was stirred at 0° C. for 2 h. The mixture was warmed to RT, and then additional DIBAL-H (1.0 M in hexanes, 25.1 mL, 25.1 mmol, 0.5 equiv.) was added dropwise. The mixture was stirred at RT for 16 h. The reaction mixture was cooled to 0° C. and then quenched with acetone. The mixture was warmed to RT, diluted with DCM (200 mL) and aqueous Rochelle's salt (10% w/w), and stirred vigorously until the emulsion dissipated. The mixture was extracted three times with MTBE. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo to afford crude (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol as a mixture of diastereomers (compound (±)-2-19, 20.5 g, 49.8 mmol, 99%), which was carried on directly to the next step (synthesis of compound 2-21).

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

To a solution of crude (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19, 20.5 g, 49.8 mmol, 1.0 equiv.) in EtOH (440 mL) was added (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA, 19.2 g, 49.8 mmol, 1.0 equiv.). The solution was heated to reflux with stirring, and upon further heating it became a suspension. After the addition of MeOH (150 mL), the mixture was held at reflux until a clear solution was obtained. The solution was cooled to 75°C, then seeded with compound 2-21·DPTTA (0.070 g, see Example 1) and held at a constant temperature for 30 minutes. The mixture was cooled to RT at a rate of 8°C per hour and then continuously stirred for 16 hours. The resulting precipitate was collected by vacuum filtration, washed with MTBE (100 mL) and EtOH (40 mL), and dried in vacuo for 16 hours to give compound 2-21·DPTTA (16.1 g, 20.1 mmol, 40% 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%. The chiral salt pair was suspended in DCM, and water was added. The mixture was basified with saturated aqueous NH ₄ OH until the pH was approximately 10. The mixture was extracted three times with DCM. The organic extract was dried over _MgSO4 , filtered, and concentrated in vacuo to give (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21, 8.13 g, 19.8 mmol, 39% from compound (±)-2-18) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 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 = 4.7 Hz, 1H), 3.73 (s, 3H), 3.32 - 3.27 (m, 2H), 3.02 (br d, J = 11.0 Hz, 1H), 2.92 - 2.82 (m, 3H), 2.54 - 2.45 (m, 2H), 2.35 - 2.29 (m, 1H), 2.04 (br t, J = 10.3 Hz, 1H), 1.27 - 1.21 (m, 1H), 1.17 (s, 9H).

Step 6: Preparation of (2R,3R,11bR)-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 (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21, 8.13 g, 19.8 mmol, 1.0 equiv.) in 3:1 MeOH:H ₂ O (42 mL) was added aqueous HCl (12.1 M, 1.97 mL, 23.8 mmol, 1.2 equiv.) dropwise with stirring at 0° C. The mixture was stirred for 10 minutes. Palladium on carbon (10% w/w, 1.06 g, 0.994 mmol, 0.05 equiv.) and ammonium formate (12.5 g, 198 mmol, 10 equiv.) were added, and the mixture was stirred at 50° C. for 30 minutes. The mixture was cooled to 0°C and acidified to pH = 1 with aqueous HCl (12.1 M). The suspension was filtered, and the solid was rinsed with MeOH. The filtrate was transferred to a round-bottom flask equipped with a stir bar and basified with aqueous NaOH (6 M) to pH = 8, at which point a white solid precipitated. The solid was collected by vacuum filtration and dried in vacuo for 16 hours to give (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 5.74 g, 17.9 mmol, 90%) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.70 (s, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 4.58 (d, J = 4.9 Hz, 1H), 3.72 (s, 3H), 3.32 - 3.25 (m, 2H), 2.98 (br d, J = 11.0 Hz, 1H), 2.90 - 2.77 (m, 3H), 2.47 - 2.42 (m, 2H), 2.32 - 2.26 (m, 1H), 2.02 (t, J = 10.4 Hz, 1H), 1.23 (q, J = 11.6 Hz, 1H), 1.17 (s, 9H).

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

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.060 g, 0.187 mmol, 1.0 equiv.) in DMF (1.8 mL) was added cesium carbonate (0.183 g, 0.561 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.056 g, 0.243 mmol, 1.3 equiv.) was then added, and the mixture was stirred for 3 hours. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to three chromatographic separations: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-60% over 20 min), DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc (0-70% over 25 min), and DMSO was used to pack a reverse-phase C ₁₈ column (6 g) and run with an increasing gradient of ACN in water (10-50% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 17, 0.042 g, 0.104 mmol, 56%) as a white solid. Obs. Ion(m/z)=404.3[M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): 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 = 11.0 Hz, 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,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 18).

Batch A
To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, see Example 4B, 0.150 g, 0.467 mmol, 1.0 equiv) in MeOH (1.5 mL) was added cesium carbonate (0.456 g, 1.40 mmol, 3.0 equiv) and the resulting mixture was stirred at RT for 10 min. 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.149 g, 0.607 mmol, 1.3 equiv) was then added and the mixture was stirred at RT for 2 h, then a second portion was added (0.230 g, 0.934 mmol, 2.0 equiv) and the mixture was stirred for an additional 1 h. The mixture was diluted with water and extracted three times with DCM. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: DCM was used to load a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexanes (0-80% over 20 min), and DMSO was used to load a reverse-phase _C18 column (16 g) and run with an increasing gradient of ACN in water (10-40% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 18, 0.147 g, 0.352 mmol, 75%) as a white solid. Obs. Ion(m/z)=418.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.77 (s, 1H), 6.69 (s, 1H), 4.58 (d, J = 4.8 Hz, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.72 (s, 3H), 3.36 - 3.24 (m, 2H), 3.02 (br d, J = 10.9 Hz, 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 = 14.5 Hz, 1H), 1.17 (s, 9H).

Batch B
To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, see Example 4C, 0.450 g, 1.40 mmol, 1.0 equiv) in MeOH (4.5 mL) was added cesium carbonate (1.37 g, 4.20 mmol, 3.0 equiv) and the resulting mixture was stirred at RT for 10 minutes. 3,3,3-Trifluoropropyl trifluoromethanesulfonate (0.689 g, 2.80 mmol, 2.0 equiv) was then added and the mixture was stirred at RT for 16 hours, then a second portion was added (0.689 g, 2.80 mmol, 2.0 equiv) and the mixture was stirred for an additional 3 hours. The mixture was diluted with water and extracted three times with DCM. The combined organic extracts were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: DCM was used to load a silica gel column (12 g) and run with an increasing gradient of EtOAc in hexanes (0-60% over 20 min), and DMSO was used to load a reverse-phase _C18 column (16 g) and run with an increasing gradient of ACN in water (10-40% over 20 min) to yield (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 18, 0.446 g, 1.07 mmol, 76%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.77 (s, 1H), 6.69 (s, 1H), 4.58 (d, J = 4.8 Hz, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.72 (s, 3H), 3.36 - 3.24 (m, 2H), 3.02 (br d, J = 10.9 Hz, 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 = 14.5 Hz, 1H), 1.17 (s, 9H).

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

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.120 g, 0.373 mmol, 1.0 equiv.) in DMF (4 mL) was added cesium carbonate (0.365 g, 1.12 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. Cyclopropyl trifluoromethanesulfonate (0.106 g, 0.559 mmol, 1.5 equiv.) was then added, and the mixture was stirred overnight. An additional portion of cyclopropyl trifluoromethanesulfonate (0.071 g, 0.373 mmol, 1.0 equiv.) was added, and the mixture was stirred at 50° C. for 2 hours. 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. DCM was used to load a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexanes (0-100% over 25 min) to yield crude (2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19, 0.130 g, 0.360 mmol) as an off-white solid. To remove trace impurities, crude compound 19 (0.130 g, 0.360 mmol, 1.0 equiv) was dissolved in anhydrous THF (2.8 mL) with stirring under a nitrogen atmosphere at 0 °C. A solution of lithium aluminum hydride in THF (2 M, 0.40 mL, 0.810 mmol, 2.25 equiv) was added dropwise over 10 minutes. The temperature was raised to 60° C. and stirred for 3 hours. An additional portion of lithium aluminum hydride in THF (2 M, 0.18 mL, 0.360 mmol, 1.0 equiv) was added and the mixture was stirred at 60° C. overnight. The mixture was cooled to 0° C., then sodium sulfate decahydrate (0.116 g, 0.360 mmol, 1.0 equiv) was added over 10 minutes and then allowed to stir for 20 minutes. The mixture was filtered over Celite, the filter cake was rinsed with EtOAc, and the solvent was removed in vacuo. The crude material was chromatographed on a silica gel column (4 g) packed with DCM and run with an increasing gradient of EtOAc in hexanes (0-100% over 25 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19, 0.074 g, 0.205 mmol, 57%) as a white solid. Obs. Ion (m/z)=362.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.89 (s, 1H), 6.73 (s, 1H), 4.60 (d, J = 4.9 Hz, 1H), 3.75 (tt, J = 2.9, 6.0 Hz, 1H), 3.69 (s, 3H), 3.31 - 3.25 (m, 2H), 3.02 (br d, J = 11.5 Hz, 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,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 22).

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.150 g, 0.467 mmol, 1.0 equiv.) in DMF (1.5 mL) was added cesium carbonate (0.456 g, 1.40 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. Ethyl iodide (0.058 g, 0.375 mmol, 0.8 equiv.) was then added, and the mixture was stirred at RT for 1 hour. The mixture was diluted with EtOAc (100 mL) and rinsed five times with water (5 mL). The organic layer was dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min), and DMSO was used to pack a reversed-phase C ₁₈ column (16 g) and run with an increasing gradient of ACN in water (10-30% over 15 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 22, 0.123 g, 0.352 mmol, 75%) as a white solid. Obs. Ion (m/z) = 350.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.73 (s, 1H), 6.61 (s, 1H), 4.60 (d, J = 4.7 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.71 (s, 3H), 3.31 - 3.25 (m, 1H), 3.01 (br d, J = 10.7 Hz, 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 = 6.8 Hz, 3H), 1.23 - 1.23 (m, 1H), 1.24 (q, J = 11.7 Hz, 1H), 1.17 (s, 9H).

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

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.150 g, 0.467 mmol, 1.0 equiv.) in DMF (1.5 mL) was added cesium carbonate (0.456 g, 1.40 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. Then, (bromomethyl)cyclopropane (0.069 g, 0.514 mmol, 1.1 equiv.) was added, and the mixture was 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 _MgSO4 , filtered, and concentrated in vacuo. DCM was used to pack a silica gel column (12 g) and run with an increasing gradient of EtOAc in hexanes (0-100% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 25, 0.107 g, 0.285 mmol, 61%) as a white solid. Obs. Ion (m/z) = 376.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.73 (s, 1H), 6.59 (s, 1H), 4.57 (d, J = 4.8 Hz, 1H), 3.76 - 3.68 (m, 2H), 3.72 (s, 3H), 3.35 - 3.24 (m, 2H), 3.01 (br d, J = 11.1 Hz, 1H), 2.94 - 2.78 (m, 3H), 2.55 - 2.43 (m, 2H), 2.38 - 2.24 (m, 1H), 2.04 (br t, J = 10.3 Hz, 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,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 38).

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.150 g, 0.467 mmol, 1.0 equiv.) in DMF (4.5 mL) was added cesium carbonate (0.456 g, 1.40 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. 3-(bromomethyl)-1,1-difluorocyclobutane (0.173 g, 0.934 mmol, 2 equiv.) was then added, and the mixture was stirred at 50 °C for 3 hours. 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: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-70% over 20 min), and DMSO was used to pack two reverse-phase C18 columns (6 g) and run with an increasing gradient of MeCN in water (10-50% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 38, 0.120 g, 0.282 mmol, 60%) as a white solid. Obs. Ion (m/z) = 426.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.76 (s, 1H), 6.67 (s, 1H), 4.59 (d, J = 4.5 Hz, 1H), 3.96 (br d, J = 6.2 Hz, 2H), 3.73 (s, 3H), 3.36 - 3.25 (m, 4H), 3.02 (br d, J = 11.1 Hz, 1H), 2.94 - 2.81 (m, 3H), 2.76 - 2.63 (m, 2H), 2.60 - 2.28 (m, 4H), 2.05 (br t, J = 10.3 Hz, 1H), 1.30 - 1.20 (m, 1H), 1.18 (s, 9H).

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

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.088 g, 0.274 mmol, 1.0 equiv.) in DMF (2.5 mL) was added cesium carbonate (0.268 g, 0.822 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. Then, (2R)-2-(bromomethyl)-1,1-difluorocyclopropane (0.070 g, 0.411 mmol, 1.5 equiv.) was added, and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-70% over 12 min), and DMSO was used to pack a reversed-phase C ₁₈ column (6 g) and run with an increasing gradient of ACN in water (10-70% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 43, 0.023 g, 0.056 mmol, 20%) as a white solid. Obs. Ion (m/z)=412.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.76 (s, 1H), 6.65 (s, 1H), 4.61 (d, J = 4.7 Hz, 1H), 4.04 (ddd, J = 3.1, 6.8, 10.3 Hz, 1H), 3.90 (t, J = 9.6 Hz, 1H), 3.73 (s, 3H), 3.38 - 3.28 (m, 2H), 3.02 (br d, J = 11.0 Hz, 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 = 10.4 Hz, 1H), 1.70 (ddt, J = 4.8, 7.8, 12.0 Hz, 1H), 1.46 - 1.38 (m, 1H), 1.24 (q, J = 11.5 Hz, 1H), 1.17 (s, 9H).

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

Method A
To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.130 g, 0.404 mmol, 1.0 equiv.) in DMF (4.0 mL) was added cesium carbonate (0.394 g, 1.21 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. Then, (2S)-2-(bromomethyl)-1,1-difluorocyclopropane (0.104 g, 0.606 mmol, 1.5 equiv.) was added, and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-70% over 15 min), and DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-70% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 44, 0.131 g, 0.318 mmol, 79%) as a white solid. Obs. Ion (m/z)=412.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.76 (s, 1H), 6.65 (s, 1H), 4.60 (d, J = 4.9 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.89 (t, J = 9.7 Hz, 1H), 3.73 (s, 3H), 3.36 - 3.26 (m, 2H), 3.01 (br d, J = 11.2 Hz, 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, 12.0 Hz, 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,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.200 g, 0.622 mmol, 1.0 equiv.) in degassed toluene (4.0 mL) in a capped microwave vial was added (R)-(2,2-difluorocyclopropyl)methanol (0.134 g, 1.24 mmol, 2.0 equiv.) and (tributylphosphoranylidene)acetonitrile (0.299 g, 1.24 mmol, 2.0 equiv.). The headspace was evacuated and refilled with nitrogen three times. The resulting mixture was stirred under microwave irradiation at 100°C for 2 hours. The mixture was passed through a Celite filter and concentrated in vacuo. The crude material was subjected to three chromatographic separations: DCM was used to pack a silica gel column (4 g) and run with an increasing gradient of EtOAc in hexane (0-70% over 15 min), and DMSO was used to pack two reverse-phase C18 columns (6 g) and run with an increasing gradient of MeCN (10-50% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 44, 0.108 g, 0.262 mmol, 42%) as a white solid. Obs. Ion (m/z)=412.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 6.76 (s, 1H), 6.65 (s, 1H), 4.60 (d, J = 4.9 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.89 (t, J = 9.7 Hz, 1H), 3.73 (s, 3H), 3.36 - 3.26 (m, 2H), 3.01 (br d, J = 11.2 Hz, 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, 12.0 Hz, 1H), 1.46 - 1.38 (m, 1H), 1.30 - 1.20 (m, 1H), 1.17 (s, 9H).

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

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 0.300 g, 0.933 mmol, 1.0 equiv.) in DMF (10 mL) was added cesium carbonate (0.912 g, 2.80 mmol, 3.0 equiv.), and the resulting mixture was stirred at RT for 10 minutes. 2-Iodopropane (0.206 g, 1.21 mmol, 1.3 equiv.) was then 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 wash was extracted twice with EtOAc. The combined organic extracts were rinsed twice with 10% aqueous LiCl. The organic layer was dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was subjected to two chromatographic separations: a silica gel column (12 g) dry-packed with Celite with an increasing gradient of EtOAc in hexanes (0-55% over 15 min), and a reverse-phase _C18 column (16 g) packed with DMSO and run with an increasing gradient of ACN in water (0-55% over 20 min) to give (2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 23, 0.188 g, 0.517 mmol, 55%) as a white solid. Obs. Ion(m/z)=364.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 6.73 (s, 1H), 6.62 (s, 1H), 4.58 (d, J = 4.8 Hz, 1H), 4.45 (spt, J = 6.1 Hz, 1H), 3.70 (s, 3H), 3.31 - 3.25(m, 2H), 3.01 (br d, J = 11.0 Hz, 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, 1.8 Hz, 6H), 1.17 (s, 9H).

Example 12B
Preparation of (2R,3R,11bR)-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: Preparation of (iodomethyl-d ₂ )cyclopropane.

To a solution of triphenylphosphine (7.40 g, 28.2 mmol, 1.2 equiv.) in DCM (100 mL) was added I ₂ (6.57 g, 25.9 mmol, 1.1 equiv.) at RT. The reaction mixture was stirred at RT for 30 min. Imidazole (2.40 g, 35.3 mmol, 1.5 equiv.) and cyclopropylmethane-d ₂ -ol (1.74 g, 23.5 mmol, 1.0 equiv.) were added sequentially at RT. The reaction mixture was stirred at RT for 16 h. The mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ . The aqueous layer was extracted three times with diethyl ether. The combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Hexane was used to pack a silica gel column (24 g) and eluted with pentane to give (iodomethyl-d ₂ )cyclopropane (2.30 g, 12.5 mmol, 53% yield) as a colorless oil. ¹ H NMR (400 MHz, benzene-d ₆ ): δ (ppm) 0.87 (ddtdd, J = 9.1, 5.7, 4.7, 2.4, 1.0 Hz, 1H), 0.42 - 0.33 (m, 2H), -0.11 - -0.18 ppm (m, 2H).

Step 2: Preparation of (2R,3R,11bR)-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).

To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 2-22, 2.00 g, 6.22 mmol, 1.0 equiv.) in DMF (60 mL) was added cesium carbonate (5.05 g, 15.5 mmol, 2.5 equiv.), and the resulting mixture was stirred at 0° C. for 30 minutes. Then, (iodomethyl-d ₂ )cyclopropane (1.20 g, 6.53 mmol, 1.05 equiv.) was added, and the mixture was stirred at 0° C. overnight. The mixture was diluted with water (200 mL) and extracted with DCM (5×100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified on a silica gel column (24 g) packed with DCM and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min), followed by a C18 reverse-phase column (150 g) packed with DMSO and run with an increasing gradient of MeCN in H ₂ O (5-60% over 20 min), followed by recrystallization in hexane/ethyl acetate to give (2R,3R,11bR)-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, 1.80 g, 4.76 mmol, 77% yield, 97.6% as d ₂ ). 1.2% as ₁ and 1.2% non-deuterated, respectively, determined by MS (QTOF)) was obtained as a white solid. Obs. Ion (m/z)=378.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d): δ (ppm) 6.73 (s, 1H), 6.58 (s, 1H), 4.57 (d, J = 4.8 Hz, 1H), 3.72 (s, 3H), 3.31 - 3.22 (m, 2H), 3.01 (br d, J = 11.0 Hz, 1H), 2.94 - 2.78 (m, 3H), 2.56 - 2.51 (m, 1H), 2.46 (br d, J = 9.0 Hz, 1H), 2.36 - 2.25 (m, 1H), 2.04 (br t, J = 10.4 Hz, 1H), 1.30 - 1.20 (m, 1H), 1.20 - 1.06 (m, 10H), 0.58 - 0.49 (m, 2H), 0.31 - 0.23 ppm (m, 2H).

Example 13
Reagents used in the preparation of certain compounds listed in Table A.

Additional compounds shown in Table A were prepared using similar methods as described in the examples above and the following reagents shown in Table 3.
Table 3 also provides the observed (Obs) ion m/z ratios for the title compounds.

Example 14
Methods for determining the VMAT2 inhibitory activity of compounds.

An example of a technique for determining the ability of a compound to inhibit VMAT2 is provided below. The procedure was adapted from one previously described (see, e.g., Near, (1986), Mol. Pharmacol. 30: 252-57; Teng, et al., J. Neurochem. 71, 258-65, 1998). Homogenates from human platelets were prepared by homogenization and then washed by centrifugation as previously described (see, e.g., Hoare et al., (2003) Peptides 24:1881-97).

The following procedure was used to determine human VMAT2 K _i values for the compounds listed in Table A. Compound dilution series in DMSO were generated by either manual dilution from powder stocks or direct dilution using an Echo 655 (Beckman). Twelve concentrations of test compound were competed against 10 nM 3H-dihydrotetrabenezine (American Radiolabeled Chemicals) in VMAT2 binding buffer (Dulbecco's phosphate-buffered saline, 1 mM EDTA, pH 7.4) against human platelet homogenate (30 μg membrane protein per well) in a total volume of 0.145 mL in low-binding 96 ^-well plates (Corning #3605). After a 90-minute incubation at 25°C, bound radioligand was collected by rapid filtration through GF/C glass fiber filters pretreated with 0.1% polyethyleneimine using a Microlab Star (Hamilton). After collection, filter plates were washed with 0.8 mL of VMAT2 binding buffer, and bound radioligand was quantified by scintillation counting using a Microplate Counter Microbeta (PerkinElmer). Data from 12-point concentration-response curves were analyzed to calculate _IC50 values using a four-parameter logistic regression algorithm, with an upper limit constrained to 100 and a lower limit constrained to 0. Using a _Kd of 4.06 nM for ^3H -dihydrotetrabenazine, _K values for each compound were calculated using the Cheng-Prusoff equation.

The K _i (nM) values of the compounds are provided in Table 4.

Example 15
VMAT2 inhibitor-induced reduction in open field hypolocomotor activity.

The effect of VMAT2 inhibitors on dopamine depletion was measured using a locomotor activity (LMA) assay. After a 60- or 120-minute pretreatment period, male Sprague-Dawley rats (250-350 g) were placed in a locomotor activity chamber surrounded by an infrared photobeam (Med Associates). The rats' locomotor activity was detected by automated counting of successive beam breaks, and activity was defined as the number of beam breaks in a 60-minute period. Data were analyzed by one-way analysis of variance (ANOVA; GraphPad Prism), followed by Dunnett's post-hoc test for significance. ED50s were calculated for (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compound 18 (0.036 mg/kg, see FIG. 5) and (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compound 22 (0.013 mg/kg, see FIG. ₅ ).

In a manner similar to that described in this example, _ED50 was calculated for the following compounds: (2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compound 19 (0.04 mg/kg); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compound 20 (0.04 mg/kg); pyrido[2,1-a]isoquinolin-2-ol compound 38 (0.06 mg/kg); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compound 43 (0.03 mg/kg); and (2R,3R,11bR)-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 (0.03 mg/kg).

Example 16
Conditioned avoidance response assay of antipsychotic activity.

The conditioned avoidance response (CAR) test has been shown to be a valid and reliable preclinical model for evaluating the antipsychotic activity of compounds. In the CAR paradigm, rats are trained to respond to a conditioned (auditory) stimulus in a two-chamber shuttle box through negative reinforcement. If the animal does not move to the other chamber upon presentation of the auditory stimulus, a mild foot shock is administered to the side where the rat is located. Rats learn to avoid the mild foot shock by moving to the other chamber at the onset of the auditory signal, which is called a conditioned avoidance response. Crossing to the other chamber during the shock is called an escape response. If the rat does not move to the other chamber despite the administration of the foot shock, the rat is considered to have an escape failure. Numerous studies have shown that typical and atypical antipsychotic drugs selectively inhibit the CAR, making the CAR an ideal assay for screening potential antipsychotic compounds (see, e.g., Wadenberg et al., Biobehav. Rev. (1999) 23: 851-62).

Male Wistar rats are trained daily for 3-4 weeks. During training sessions, rats are placed in the CAR bidirectional shuttle box, followed by a 20-trial training period. A trial consisted of a 10-second presentation of 80 dB white noise, followed by a scrambled 0.6 mA foot shock lasting up to 20 seconds. The interval between trials ranged from 20-60 seconds. Rats learn to avoid the shock by moving from one compartment to the other when the conditioned stimulus is presented (conditioned avoidance response). Rats are considered fully trained if they avoid the shock when the conditioned stimulus is presented in at least 19 out of 20 trials. Rats that do not meet these criteria are not used.

On the day of testing, trained animals are allowed to acclimate to the testing room for 30 minutes prior to testing. Then, animals are dosed with compound and placed in the CAR two-way shuttle box. Each rat undergoes 20 trials during testing. In each trial, a conditioned stimulus is administered (a 10-second presentation of 80 dB white noise), followed by a footshock (a scrambled 0.6 mA footshock lasting up to 20 seconds). If the animal moves to the other chamber upon presentation of the conditioned stimulus, this is scored as a conditioned avoidance response. If the animal moves upon presentation of the footshock, this is scored as an escape. If the animal does not move upon presentation of the footshock, this is scored as an escape failure. Antipsychotic efficacy is evidenced by an increase in the number of escapes. Data are analyzed by analysis of variance (ANOVA), followed by post-hoc comparisons using Bonferroni tests, where appropriate. Effects are considered significant if p<0.05. If outliers, defined as two standard deviations above or below the mean, are detected, they are excluded from all analyses.

(Example 17)
A method for determining the stability of a compound in human liver microsomes.

Test compounds (0.5 μM) were incubated with pooled, mixed-gender human liver microsomes (0.5 mg/mL total protein) at 37°C in the presence of an NADPH-generating system containing 50 mM pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 unit/mL glucose-6-phosphate dehydrogenase. All concentrations were relative to a final incubation volume of 125 μL. Incubations were performed in a water bath at 37°C for 0, 5, 10, 20, 40, and 60 minutes and terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing an internal standard. Precipitated proteins were removed by centrifugation prior to LC-MS/MS analysis. Aliquots of the resulting supernatant fractions were analyzed by LC-MS/MS monitoring for depletion of the parent compound. The resulting peak area ratio versus time data was fitted to a nonlinear regression using XLfit Scientific Curve Fitting software (IDBS Ltd., Surrey, UK), and the elimination half-life (t _1/2 , minutes) was calculated from the slope. 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 the elimination half-life data and then adjusted to represent the expected clearance in whole animals. See Table 5 (human). Additional values calculated included the predicted extraction rate and predicted maximum bioavailability.

For highly stable compounds, the in vitro half-life calculated from the HLM method is up to 420 minutes. Therefore, for these stable compounds, the in vitro half-life is at least 420 minutes, but could be longer. Furthermore, for these stable compounds, the predicted total body clearance and adjusted intrinsic clearance are at least 2.59 and 2.97, respectively, but could be lower. The predicted maximum bioavailability (%F) is at least 87, but could be higher.

(Example 18)
A method for determining the inhibition of cytochrome P450 2D6 3A4 (CYP3A4) and (CYP2D6) in expressed human enzymes using a fluorescent marker substrate.

Test compounds were incubated with individually expressed human recombinant CYP enzyme systems in the presence of NADPH and IC ₅₀ values for inhibition were determined using the marker substrate approach.

For CYP3A4, expressed human CYP3A4 (Gentest Supersomes, Corning, Woburn, MA) was incubated with test compounds, _{and IC50} values for inhibition were determined using the marker substrate 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC). This marker is dealkylated by CYP3A4 to form the fluorescent product, 7-hydroxy-4-(trifluoromethyl)-coumarin (7-HFC). The amount of 7-HFC formed during incubation was detected using a 96-well fluorescence plate reader (BioTek Synergy LX, Agilent, Santa Clara, CA) with an excitation λ of 400 nm and an emission λ of 528 nm.

For CYP2D6, expressed human CYP2D6 (Gentest Supersomes, Corning, Woburn, MA) was incubated with test compounds, and _IC50 values for inhibition were determined using a marker substrate, 3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (AMMC). This marker is O-demethylated by CYP2D6 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 in a 96-well fluorescence plate reader (BioTek Synergy LX, Agilent, Santa Clara, CA) at an excitation λ of 360 nm and an emission λ of 460 nm.

For each enzyme assay, four concentrations of test compound (ranging from 0.048 to 6 μM) were evaluated in duplicate at a single concentration of substrate (K _m ), 50 μM for BFC and 1.5 μM for AMMC, respectively. Reactions (200 μL total volume) contained 100 μL of an NADPH-generating system containing 75 mM, pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 unit/mL glucose-6-phosphate, starting with 100 μL of CYP enzyme solution (10 pmol), which was added immediately before incubating the samples at 37°C. Incubations were stopped after 30 min by the addition of 75 μL of stop solution (80% acetonitrile/20% 0.5 M Tris Base). Ketoconazole and quinidine were used as positive controls for CYP3A4 and CYP2D6, respectively.

For each CYP, the degree of inhibition, expressed as a percentage, was calculated and the data were then plotted on a semi-logarithmic plot [log (inhibitor) on the x-axis and percentage of control activity on the y-axis] and fitted with the Levenberg-Marquardt algorithm as follows:

(Where "A" is the lower plateau of the curve, typically equal to 0, "B" is the upper plateau of the curve, typically having a value of 100, "C" represents the "X" value at the midpoint of the curve, representing the concentration of inhibitor that causes 50% inhibition, and "D" is the slope coefficient.) _IC50 values were calculated using XLfit Scientific Curve Fitting software (IDBS Ltd., Surrey, UK). _IC50 values of certain compounds for CYP2D6 and CYP3A4 are provided in Table 6.

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

The purpose of these studies was to investigate the in vitro effects of compounds on hERG (human ether-a-go-go-related gene) channel current (a surrogate for I _Kr (rapidly activating delayed rectifier cardiac potassium current), see, e.g., Redfern et al., Cardiovascular Research (2003) 58(1):32-45). The concentration-response relationship of certain compounds on hERG potassium channel current was assessed at room temperature in stably transfected mammalian cells expressing a cloned hERG potassium channel encoded by the KCNH2 gene. The hERG potassium channel was expressed in Chinese hamster ovary (CHO) cells, which lack endogenous I _Kr .

The cardiac potassium channel hERG is responsible for the rapid delayed rectifier current (I _Kr ) in human ventricles. Inhibition of I _Kr is the most common cause of myocardial action potential prolongation by non-cardiac drugs (see, e.g., Brown and Rampe, Pharmaceutical News (2000) 7:15-20; Weirich and Antoni, Basic Res. Cardiol. (1998) 93 Suppl 1:125-132; Yap and Camm, Clin Exp. Allergy (1999) 29 Suppl 3:174-181). Increased action potential duration causes QT interval prolongation and is associated with torsades de pointes (see, e.g., Brown and Rampe, Pharmaceutical News (2000) 7:15-20).

hERG Positive Control: A stock solution of the positive control substance was prepared in DMSO and stored at room temperature.

CHO/hERG cell line:

CHO culture: CHO cells were stably transfected with hERG cDNA. Stable transfectants were maintained in culture medium with appropriate selection pressure and antibiotics.

Test method:
1. Cell treatment: All experiments were performed at room temperature. Each cell was treated as its own control. Full block was achieved by the addition of 20 μM verapamil.
For test substance treatment groups, a 6-point dose-response curve was generated. 1:4 serial dilutions were made from a top concentration of 12 μM.

2. Automated Patch Clamp Procedure a. Platform: For all hERG studies, a 384-well-based automated patch clamp system, SyncroPatch 384PE (Nanion Technologies), was used with PatchControl software (data acquisition) and DataControl software (data analysis). Recordings were performed at room temperature (22°C) on planar NPC-384 multihole chips with four holes per well at medium resistance.
b. Recordings were performed in whole-cell patch mode. The internal solution had the following composition: 10 mM EGTA, 10 mM HEPES, 10 mM KCl, 10 mM NaCl, and 110 mM KF, pH 7.2, mOsm = 285. The external solution had the following composition: 10 mM HEPES, 80 mM NaCl, 60 mM NMDG, 5 mM glucose, 4 mM KCl, 5 mM _CaCl2 , and ₁ mM MgCl2, pH 7.4, mOsm = 298.
c. Compound preparation: All compounds were solvated in 100% DMSO. On the day of the experiment, serial dilutions in DMSO were prepared manually. Pre-diluted compounds were further diluted into the external solution by a dilution factor of 1:500 (0.2% DMSO by volume).
d. Compound acquisition mode: A single application of compound was used across the chip using several concentrations. Each well received one concentration of compound, followed by a full block of verapamil to assess leak current. Different concentrations of each compound were diffused across the chip to generate individual dose-response relationships.
e. Onset and block of hERG currents were measured using a stimulation voltage pattern consisting of a 500 ms prepulse to -40 mV (to subtract leakage), a 2 s activation pulse to +40 mV, followed by a 2 s test pulse to -40 mV, followed by a 2 s test pulse to -40 mV. The pulse pattern was repeated consecutively at 6 s intervals from a holding potential of -80 mV. The peak tail current was calculated from the current amplitude evoked by the -40 mV prepulse and subtracted from the total membrane current recording. For quality control, a small hyperpolarizing voltage step from -80 to -90 mV was introduced during the holding potential to calculate resistance according to Ohm's law.

3. Data Analysis Data were stored on the Neurocrine Biosciences computer network for offline analysis. Data acquisition and analysis were performed using Nanion Data Control software. Steady state was defined by a limited, constant rate of change with time (linear time dependence). Steady state data before and after application of test substances were used to calculate the percentage of current inhibited at each concentration.

The IC ₅₀ values of certain compounds against hERG are provided in Table 7.

The various embodiments described above can 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 referenced herein 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 utilize concepts from various patents, applications, and publications to provide still 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, but rather the claims should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims (259)

Compounds of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to ₇ -membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C ₅ -C ₁₁ -spiro-cycloalkyl, cubanyl-C ₁ -C ₄ -alkylene, and 4- to 8-membered heterobicyclyl-C ₁ -C ₄ - alkylene,
each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C ₆ -cycloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, and C ₂ -C ₄ -dialkylamino;
The compound or a pharmaceutically acceptable salt thereof. Formula (Ic):
or a pharmaceutically acceptable salt thereof. Formula (Ie):
or a pharmaceutically acceptable salt thereof. Formula (Ig):
or a pharmaceutically acceptable salt thereof. Formula (Ii):
or a pharmaceutically acceptable salt thereof. Formula (Ik):
or a pharmaceutically acceptable salt thereof. R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, and C ₅ -C ₁₁ -spiro-cycloalkyl;
7. The compound of any one of _claims 1 to _{6, or a pharmaceutically acceptable salt thereof, wherein each R 1 group is optionally substituted with one or more substituents selected from cyano-C 1 -C 4 -alkylene, halogen, C 1 -C 4} ^-alkyl _{, C 1 -C 4 -haloalkyl ,} cyano, C ₁ -C ₄ -alkylsulfonyl, C ₃ -C 6 -cycloalkyl, hydroxyl, C 1 -C ₄ -alkoxy, and C 2 -C 4 -dialkylamino. R ¹ is C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C 4 -alkylene, _3- to ₇ -membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C ₅ -C ₁₁ -spiro-cycloalkyl, cubanyl-C ₁ -C ₄ -alkylene, and 4- to 8-membered heterobicyclyl-C ₁ -C ₄ - alkylene,
7. The compound of any one of _{claims 1} to ₆ , or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C 1 -C 4 -alkoxy. R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C 3 -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, _3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₄ -C ₇ -cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, and C ₅ -C ₁₁ -spiro-cycloalkyl;
7. The compound of any one of _{claims 1} to ₆ , or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C 1 -C 4 -alkoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
7. The compound of any one of _{claims 1} to ₆ , or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C 1 -C 4 -alkoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
7. The compound of any one of _{claims 1} to ₆ , or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, hydroxyl, and C 1 -C 4 -alkoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -C ₆ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, C ₇ -spiro-cycloalkyl, (cubanyl)CH ₂ —, and 6-membered heterobicyclyl-C ₁ -C ₄ -alkylene-CH ₂ —;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from C ₃ -C ₅ -cycloalkyl-C ₁ -C ₂ -alkylene, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C ₃ -alkyl-O—CH ₂ CH ₂ —, cyclopropyl-O—CH ₂ CH ₂ —, 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, C ₄ -cycloalkenyl, 7-membered spiro-heterocyclyl, and C ₇ -spiro-cycloalkyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C ₁ -haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy. R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. R ¹ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexanyl)methyl, (silolanyl)methyl, and (2-oxabicyclo[2.1.1]hexanyl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl, and cyclopropyl. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, and 1-(cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d ₃ , ethyl, 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (silolan-3-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3]heptan-2-yl, and 1-(cyclobutyl)ethyl;
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, cyano, hydroxyl, difluoromethyl, methyl, trifluoromethyl, methoxy, and cyclopropyl. R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoro Methyl, (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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl cyclopropyl, (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 7. The compound of claim 1, wherein the methyl group is selected from the group consisting of 3,3-difluorocyclobutyl(2,2-difluorocyclobutyl)methyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsiloran-3-yl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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-cyclobutyl 7. The compound of any one of claims 1 to 6, wherein the methyl group is selected from ethyl, (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, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1 1.1]pentan-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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (3-methyloxetan-3-yl)methyl cyclobutyl, (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, 3,3-difluorocyclobutyl, (2,2-difluoro- 7. The compound of any one of claims 1 to 6, wherein the compound is selected from (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, (1,1-dimethylsilane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-Methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentyl) (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]heptan-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (1-cyanocyclobutyl)methyl, (2,2-difluoro-3-methylcyclopropyl)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, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl. R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, 1-methylpyrrolidin-3-yl methyl, (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 cyclopropyl, (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)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2- (methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl, (1r,3R)-3-(dimethylamino)cyclobutyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo 7. The compound of any one of claims 1 to 6, wherein the compound is selected from (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsilolane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, methyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl Orocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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) (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) 7. The compound of any one of claims 1 to 6, wherein the hydroxyl group is selected from (1-(methylsulfonyl)cyclopropyl)methyl, (1s,3S)-3-fluoropropyl, (1s,3S)-3-methoxycyclobutyl, (1s,3S)-3-(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl, and (1r,3R)-3-(dimethylamino)cyclobutyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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]heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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, ((1 (R,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)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2- 7. The compound of any one of claims 1 to 6, wherein the compound is selected from methoxypropyl, 3,3-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]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsilolan-3-yl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[2.1.1]hexan-1-yl)methyl, and (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2- Difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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] Heptan-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R) (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 7. The compound of any one of claims 1 to 6, wherein the compound is selected from (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)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)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, and (1r,3R)-3-methoxycyclobutyl, or a pharmaceutically acceptable salt thereof. 7. The compound of any one of claims 1 to 6, wherein R ¹ is C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or more substituents selected from cyano-C ₁ -C ₄ -alkylene, halogen, hydroxyl, C ₁ -C ₄ -haloalkyl, C _{1 -C 4} -alkyl, cyano, and C 1 -C ₄ -alkylsulfonyl, or a pharmaceutically acceptable salt thereof. 43. The compound of claim 42, or _a pharmaceutically acceptable salt thereof, wherein ^R1 is C3 _{- C7} - _cycloalkyl - _C1 - _C4 -alkylene optionally substituted with one or more substituents selected from cyano- _C1 - _C4 -alkylene, halogen, hydroxyl, _C1 -C4-haloalkyl, C1- _C4 -alkyl, and cyano. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyano-C _{1 -C 4} -alkylene, halogen, hydroxyl, C _{1 -C} 4 -haloalkyl, C ₁ -C 4 -alkyl, and cyano. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₅ -cycloalkyl-C ₁ -C _{2 -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyanomethyl, halogen, hydroxyl, C 1 -haloalkyl} , methyl, cyano, and methylsulfonyl. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein ^R1 is C3- _C5 -cycloalkyl- _C1 - _C2 -alkylene optionally substituted with 1, ₂ , or 3 substituents selected from cyanomethyl, halogen, hydroxyl, C1- _haloalkyl , methyl, and cyano. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl. R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ 43. The compound of claim 42, wherein the aryl group is selected from (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, or a pharmaceutically acceptable salt thereof. R ¹ is (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 43. The compound of claim 42, wherein the compound is selected from 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, or a pharmaceutically acceptable salt thereof. R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ 43. The compound of claim 42, wherein the methyl group is selected from (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, or a pharmaceutically acceptable salt thereof. R 43. The compound of claim 42, wherein 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; or a pharmaceutically acceptable salt thereof. R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)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 43. The compound of claim 42, wherein the compound is selected from (3,3-difluorocyclopentyl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (1-(methylsulfonyl)cyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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 43. The compound of claim 42, wherein the compound is selected from (3,3-difluorocyclopentyl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)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, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (1-(methylsulfonyl)cyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)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, 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, selected from ((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, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl. R ¹ is (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, ((1 43. The compound of claim 42, wherein the compound is selected from (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, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl, or a pharmaceutically acceptable salt thereof. 43. The compound of claim 42, 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. 43. The compound of claim 42, 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. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _{1 -C 6} -alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C _{1 -C 4} -alkoxy, and C 1 -C 4 -alkylsulfonyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₆ -alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, and C ₁ -C ₄ -alkoxy. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein ^R1 is _C1 - _C6 -alkyl optionally substituted with 1, ₂ , 3, or 4 substituents selected from halogen, hydroxyl, cyano, and C1- _C4 -alkoxy. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₅ -alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, methoxy, and methylsulfonyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₅ -alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and methoxy. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d ₃ , ethyl, ethyl-d ₅ , isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and methoxy. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and methoxy. 62. 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, methyl-d ₃ , 2,2-difluoropropyl, _2,2,2 -trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, 2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)ethyl. 62. The compound of claim 61, wherein ^R1 is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, 2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)ethyl; or a pharmaceutically acceptable salt thereof. 62. 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, methyl-d ₃ , 2,2-difluoropropyl, _2,2,2 -trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, and 2-methoxypropyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, and 2-methoxypropyl. R ¹ is isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)ethyl, or a pharmaceutically acceptable salt thereof. R ¹ is isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutan-2-yl, 62. The compound of claim 61, wherein the hydroxyl group is selected from methyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)ethyl, or a pharmaceutically acceptable salt thereof. R ¹ is isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, and (S)-2-methoxypropyl; or a pharmaceutically acceptable salt thereof. 62. The compound of claim 61, wherein ^R1 is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, and (S)-2-methoxypropyl. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl, and ethyl-d ₅ . 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl. 7. The compound of any one of claims 1 to ₆ , or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C _{1 -C 4} -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C 4 -alkoxy, and C 2 -C ₄ -dialkylamino. 81. The compound of claim 80 _, or a pharmaceutically acceptable salt thereof, wherein ^R1 is _C3 - _C7 -cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C1 _{- C4} -alkyl, _C1 - _C4 -haloalkyl, and C1- _C4 -alkoxy. 81. The compound of claim 80 _, or a pharmaceutically acceptable salt thereof, wherein ^R1 is _C3 - _C7 -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, _C1 - _C4 -alkyl, _C1 - _C4 -haloalkyl, and C1- _C4 -alkoxy. 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₅ -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl, methoxy, and dimethylamino. 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₇ -cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C ₁ -haloalkyl, and methoxy. 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from cyclopentyl, cyclobutyl, and cyclopropyl, each group optionally substituted with one or two substituents selected from cyano, fluoro, methyl, trifluoromethyl, methoxy, and dimethylamino. 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from cyclopentyl, cyclobutyl, and cyclopropyl, each group optionally substituted with one or two substituents selected from cyano, fluoro, methyl, trifluoromethyl, and methoxy. 81. The compound of claim 80, wherein ^R1 is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, 3-(trifluoromethyl)cyclobutyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, and 3,3-difluorocyclobutyl, or a pharmaceutically acceptable salt thereof. 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, 3-(trifluoromethyl)cyclobutyl, 3-methoxycyclobutyl, and 3,3-difluorocyclobutyl. 81. The compound of claim 80, wherein ^R1 is selected from cyclopentyl, cyclobutyl, cyclopropyl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (1s,3S)-3-methoxycyclobutyl, (1s,3S)-3-(dimethylamino)cyclobutyl, 3,3-difluorocyclobutyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl, and (1r,3R)-3-(dimethylamino)cyclobutyl; or a pharmaceutically acceptable salt thereof. 81. The compound of claim 80, wherein ^R1 is selected from cyclopentyl, cyclobutyl, cyclopropyl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (1s,3S)-3-methoxycyclobutyl, 3,3-difluorocyclobutyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, and (1r,3R)-3-methoxycyclobutyl, or a pharmaceutically acceptable salt thereof. 7. The compound of any one of claims ₁ to ₆ , or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ -alkyl-O-C ₂ -C ₄ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and C 3 -C 6 -cycloalkyl. 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₃ -alkyl-O-C ₂ -C ₃ -alkylene optionally substituted with one or more substituents selected from cyano, halogen, and cyclopropyl. 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₃ -alkyl-O—C ₂ -C ₃ -alkylene optionally substituted with 1, 2, or 3 substituents selected from cyano, halogen, and cyclopropyl. 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from methoxyethyl, ((propyl)oxy)ethyl, and methoxypropyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, fluoro, and cyclopropyl. 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2-(methoxy)ethyl, 2-methoxyethyl, 2-((propan-2-yl)oxy)ethyl, and 3-methoxypropyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, fluoro, and cyclopropyl. 92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2-(cyano(cyclopropyl)methoxy)ethyl, 2-methoxyethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 3-methoxypropyl, and 2-(trifluoromethoxy)ethyl. 7. The compound of any one of claims 1 to 6, wherein R ¹ is C ₃ -C ₇ -cycloalkyl-O—C ₂ -C ₄ -alkylene, or a pharmaceutically acceptable salt thereof. 98. The compound of claim 97, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 2-cyclopropoxyethyl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 3- to 7-membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ -alkyl substituents. 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 4-5 membered heterocyclyl optionally substituted with one or more C ₁ -C ₄ -alkyl substituents. 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 4-5 membered heterocyclyl optionally substituted with one C ₁ -C ₄ -alkyl substituent. 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is 4-membered heterocyclyl. 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is oxetan-3-yl or pyrrolidin-3-yl, each group optionally substituted with one methyl substituent. 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R ¹ is oxetan-3-yl or 1-methylpyrrolidin-3-yl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene optionally substituted with one or more C ₁ -C ₄ -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. 106. 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. 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 methyl substituent. 106. 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. 106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein ^R1 is (oxetanyl)methyl or (silolanyl)methyl, each group optionally substituted with one or two methyl substituents. 106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, and (siloran-3-yl)methyl, each group optionally substituted with one or two methyl substituents. 106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein ^R1 is (oxetan-3-yl)methyl or (oxetan-2-yl)methyl, each group optionally substituted with one methyl substituent. 106. 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-methyloxetan-3-yl)methyl, and (1,1-dimethylsiloran-3-yl)methyl. 106. 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-methyloxetan-3-yl)methyl. 99. The compound of claim 98, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl, and (1,1-dimethylsiloran-3-yl)methyl. 106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _{4 -C 8} -bicycloalkyl-C _{1 -C} 4 -alkylene optionally substituted with one or more substituents selected from halogen and C 1 -C ₄ -haloalkyl. 118. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅ -C ₆ -bicycloalkyl)CH ₂ — optionally substituted with one or more substituents selected from fluoro and trifluoromethyl. 118. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (C ₅ -C ₆ -bicycloalkyl)CH ₂ — optionally substituted with one substituent selected from fluoro and trifluoromethyl. 118. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein ^R1 is (bicyclo[1.1.1]pentanyl)methyl or (bicyclo[2.1.1]hexanyl)methyl, each group optionally substituted with one substituent selected from fluoro and trifluoromethyl. 118. The compound of claim 117, or a pharmaceutically acceptable salt thereof, wherein ^R1 is (bicyclo[1.1.1]pentan-1-yl)methyl or (bicyclo[2.1.1]hexan-1-yl)methyl, each group optionally substituted with one substituent selected from fluoro and trifluoromethyl. 118. The compound of claim 117, wherein R ¹ is selected from (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, and (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, or a pharmaceutically acceptable salt thereof. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or more halogen 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. 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 fluoro substituent. 124. The compound of claim 123, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is (bicyclo[1.1.1]pentanyl)methyl optionally substituted with one fluoro substituent. 124. The compound of claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (bicyclo[1.1.1]pentan-1-yl)methyl optionally substituted with one fluoro substituent. 124. The compound of claim 123, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₄ -C ₇ -cycloalkenyl optionally substituted with one or more halogen 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. 130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is cyclobutenyl optionally substituted with one fluoro substituent. 130. 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. 130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 3-fluorocyclobut-2-en-1-yl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 5- to 11-membered spiro-heterocyclyl. 135. The compound of claim 134, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 7-membered spiro-heterocyclyl. 135. The compound of claim 134, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is oxaspiro[3.3]heptanyl. 135. The compound of claim 134, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 2-oxaspiro[3.3]heptan-6-yl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₅ -C ₁₁ -spiro-cycloalkyl. 139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₇ -spiro-cycloalkyl. 139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is spiro[3.3]heptanyl. 139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein R ¹ is spiro[3.3]heptan-2-yl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cubanyl-C ₁ -C ₄ -alkylene. 143. The compound of claim 142, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cuban-1-yl)methyl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 4-8 membered heterobicyclyl- _{C 1} -C ₄ -alkylene. 145. The compound of claim 144, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 6-membered heterobicyclyl-CH ₂ -. 145. The compound of claim 144, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (2-oxabicyclo[2.1.1]hexanyl)methyl. 145. The compound of claim 144, wherein R ¹ is (2-oxabicyclo[2.1.1]hexan-1-yl)methyl or (2-oxabicyclo[2.1.1]hexan-4-yl)methyl, or a pharmaceutically acceptable salt thereof. Formula (Ie):
10. The compound of claim 1, wherein:
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, C ₅ -C ₁₁ -spiro-cycloalkyl and cubanyl-C ₁ -C ₄ -alkylene;
each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, and hydroxyl;
compound. R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene, C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene, and C ₅ -C ₁₁ -spiro-cycloalkyl;
149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, cyano, C ₃ -C ₆ -cycloalkyl, and hydroxyl. 149. The compound of claim 148, or a pharmaceutically acceptable salt _thereof , wherein R ¹ is selected from (C ₃ -C ₅ -cycloalkyl)CD ₂ -, (C ₃ -C ₅ -cycloalkyl)CH ₂ -, C _{1 -C 5} -alkyl, C ₃ -C ₅ -cycloalkyl, C ₁ -C 3 -alkyl-O-C ₂ -C 3 -alkylene, (4-membered heterocyclyl)CH ₂ -, (C ₅ -C ₆ -bicycloalkyl)CH ₂ -, C ₇ -spiro-cycloalkyl, and (cubanyl)CH ₂ -, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃ -C ₅ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₅ -cycloalkyl, C _{1 -C 3 -alkyl} -O—C ₂ -C 3 -alkylene, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —, and C ₇ -spiro-cycloalkyl, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, ethyl _{- d5} , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl- ^d2 , isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, spiro[3.3]heptanyl, (cubanyl)methyl, and (bicyclo[2.1.1]hexanyl)methyl, and each R1 group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein ^R1 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]pentanyl)methyl, and spiro[3.3]heptanyl, and each ^R1 group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. 149. 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, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopropyl, 2-((propan-2-yl)oxy)ethyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, spiro[3.3]heptan-2-yl, (cuban-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein ^R1 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]pentan-1-yl)methyl, 2-(methoxy)ethyl, and spiro[3.3]heptan-2-yl, and each ^R1 group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclo 149. The compound of claim 148, wherein the compound is selected from (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]pentan-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl; or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoro) 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-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]pentan-1-yl)methyl; or a pharmaceutically acceptable salt thereof. 149. The compound of claim 148, wherein ^R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (1-methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-dimethylcyclopropyl)methyl, 3-(trifluoromethyl)cyclobutyl, and 2-fluoropropyl; or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluoropropyl) (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 2-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl yl, spiro[3.3]heptan-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) 149. The compound of claim 148, wherein the compound is selected from (R)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (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, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoro propyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-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, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopentyl 149. The compound of claim 148, wherein the compound is selected from (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; or a pharmaceutically acceptable salt thereof. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d ₅ , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl) 149. The compound of claim 148, wherein the compound is selected from 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-fluoropropyl, (cuban-1-yl)methyl, and (bicyclo[1.1.1]pentan-1-yl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethyl 149. The compound of claim 148, wherein the compound is selected from cyclobutyl, spiro[3.3]heptan-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-fluoropropyl; or a pharmaceutically acceptable salt thereof. Formula (Ie):
10. The compound of claim 1, wherein:
R ¹ is selected from C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkyl-O—C ₂ -C ₄ -alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C ₁ -C ₄ -alkylene and C ₄ -C ₈ -bicycloalkyl-C ₁ -C ₄ -alkylene;
each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₄ -haloalkyl, cyano, and hydroxyl;
compound. R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₃ -C ₄ -cycloalkyl-CD ₂ —, C ₁ -C ₅ -alkyl, C 3 -C ₄ -cycloalkyl, C ₁ -C ₃ -alkyl-O—C _{2 -C 3 -alkylene} , 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —;
165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl. R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₄ -cycloalkyl, C ₁ -C ₃ -alkyl-O—C ₂ -C 3 -alkylene, 4-membered heterocyclyl, ( ₄ -membered heterocyclyl)CH ₂ —, (C ₅ -bicycloalkyl)CH ₂ —;
165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with one or more substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl. R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ —, C ₃ -C ₄ -cycloalkyl-CD ₂ —, C ₁ -C ₅ -alkyl, C ₃ -C ₄ -cycloalkyl, C _{1 -C 3} -alkyl-O—C _{2 -C 3} -alkylene, 4-membered heterocyclyl, and (4-membered heterocyclyl)CH ₂ —;
165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl. 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (C ₃ -C ₄ -cycloalkyl)CH ₂ -, C ₁ -C ₅ -alkyl, C ₃ -C ₄ -cycloalkyl, C _{1 -C 3 -alkyl} -O-C ₂ -C 3 -alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH ₂ -, (C ₅ -bicycloalkyl)CH ₂ -, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C ₁ -haloalkyl, cyano, and hydroxyl. 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, methyl-d ₃ , propyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, and pentyl, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl. 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein ^R1 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]pentanyl)methyl, and each ^R1 group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl. 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from methyl, methyl- _{d 3} , propyl, ethyl, ethyl-d ₅ , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , 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, and pentyl, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl. 165. 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-((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]pentan-1-yl)methyl, and each R ¹ group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl. R ¹ is methyl, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, (oxetan-3-yl)methyl 165. The compound of claim 164, wherein the aryl group is selected from aryl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is methyl, methyl-d ₃ , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d ₅ , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof. R ¹ is methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl) 165. The compound of claim 164, wherein the compound is selected from methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof. Formula (Ie):
10. The compound of claim 1, wherein:
R ¹ is selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, and C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, each group optionally substituted with one or more halogen substituents;
compound. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, and C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene, each group optionally substituted with 1, 2, or 3 halogen substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C ₂ -C ₃ -alkyl, cyclopropyl, C ₃ -C ₄ -cycloalkyl-CD ₂ -, and C ₃ -C ₄ -cycloalkyl-CH ₂ -, each group optionally substituted with 1, 2, or 3 halogen substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C ₂ -C ₃ -alkyl, cyclopropyl, and C ₃ -C ₄ -cycloalkyl-CH ₂ -, each group optionally substituted with 1, 2, or 3 halogen substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl. 178. The compound of claim 177, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl; or a pharmaceutically acceptable salt thereof. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkylene optionally substituted with one or two halogen substituents. 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with one or two halogen substituents. 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with 1 or 2 halogen substituents. 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d ₂ , and (cyclobutyl)methyl, each group optionally substituted with one or two fluoro substituents. 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with 1 or 2 fluoro substituents. 190. 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. 190. 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. 190. 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. 190. 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. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₆ -alkyl optionally substituted with 1, 2, or 3 halogen substituents. 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is ethyl or propyl, each group optionally substituted with 1, 2, or 3 halogen substituents. 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is ethyl or propyl, each group optionally substituted with 1, 2, or 3 fluoro substituents. 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl. 178. The compound of claim 177, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₇ -cycloalkyl. 203. The compound of claim 202, or a pharmaceutically acceptable salt thereof, wherein R ^<1> is cyclopropyl. The following compounds:
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1);
(2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 3);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 4);
2-(1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropyl)acetonitrile (compound 5);
(2R,3R,11bR)-3-(tert-butoxy)-9-(isopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 6);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 7);
(2R,3R,11bR)-3-(tert-butoxy)-9-cyclobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 8);
2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylacetonitrile (compound 9);
(2R,3R,11bR)-3-(tert-butoxy)-9-butoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 10);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-propoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 11);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-hydroxycyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 12);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-cyclopropoxyethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 13);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoro-2-methylpropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 14);
(2R,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 15);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 16);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 17);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 18);
(2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 20);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 21);
(2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 22);
(2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 23);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-methoxyethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 24);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 25);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 26);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 27);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 28);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 29);
(2R,3R,11bR)-3-(tert-butoxy)-9-(ethoxy-d ₅ )-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 30);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 31);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 32);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-ylmethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 33);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(((R)-oxetan-2-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 34);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 35);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 36);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 37);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 38);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-(difluoromethyl)cyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 39);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((5,5,5-trifluoropentyl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 40);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorobicyclo[1.1.1]pentan-1-yl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 41);
(2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 42);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 43);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 44);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(trifluoromethoxy)ethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 45);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(neopentyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 46);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclobutyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 47);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((2-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 48);
(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 49);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorocyclobut-2-en-1-yl)oxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 50);
(2R,3R,11bR)-9-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 51);
(1R,3r)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (compound 52);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1r,3R)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 53);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 54);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-dimethylcyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 55);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(spiro[3.3]heptan-2-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 56);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylpyrrolidin-3-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 57);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-methyloxetan-3-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 58);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 59);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(1-methylcyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 60);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 61);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 62);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 63);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 64);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 65);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 66);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 67);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 68);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-dimethylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 69);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 70);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 71);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 72);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 73);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 74);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-(dimethylamino)cyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 75);
(2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 76);
(2S,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 77);
(2R,3S,11bS)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 78);
2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)acetonitrile (compound 79);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(methoxy-d ₃ )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 80);
1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclobutane-1-carbonitrile (compound 81);
1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropane-1-carbonitrile (compound 82);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 83);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 84);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 85);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 86);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-(methylsulfonyl)cyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 87);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-(methylsulfonyl)propoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 88);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(methylsulfonyl)ethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 89);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 90);
(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 91);
(1S,3s)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (compound 92);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 93);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 94);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1r,3R)-3-(dimethylamino)cyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 95);
trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 96);
trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 97); and cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 98);
or a pharmaceutically acceptable salt thereof. The following compounds:
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1);
(2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 3);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 4);
2-(1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropyl)acetonitrile (compound 5);
(2R,3R,11bR)-3-(tert-butoxy)-9-(isopentyloxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 6);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 7);
(2R,3R,11bR)-3-(tert-butoxy)-9-cyclobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 8);
2-(2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)ethoxy)-2-cyclopropylacetonitrile (compound 9);
(2R,3R,11bR)-3-(tert-butoxy)-9-butoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 10);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-propoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 11);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-hydroxycyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 12);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-cyclopropoxyethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 13);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoro-2-methylpropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 14);
(2R,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 15);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 16);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 17);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 18);
(2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 19);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 20);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 21);
(2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 22);
(2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 23);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-methoxyethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 24);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 25);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 26);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 27);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2-fluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 28);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 29);
(2R,3R,11bR)-3-(tert-butoxy)-9-(ethoxy-d ₅ )-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 30);
(2R,3R,11bR)-3-(tert-butoxy)-9-(2,2-difluoroethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 31);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 32);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(oxetan-3-ylmethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 33);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(((R)-oxetan-2-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 34);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 35);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 36);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 37);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 38);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1-(difluoromethyl)cyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 39);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((5,5,5-trifluoropentyl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 40);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorobicyclo[1.1.1]pentan-1-yl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 41);
(2R,3R,11bR)-3-(tert-butoxy)-9-(fluoromethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 42);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 43);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2-difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 44);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(2-(trifluoromethoxy)ethoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 45);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(neopentyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 46);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclobutyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 47);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((2-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 48);
(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 49);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3-fluorocyclobut-2-en-1-yl)oxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 50);
(2R,3R,11bR)-9-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 51);
(1R,3r)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (compound 52);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1r,3R)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 53);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1s,3S)-3-fluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 54);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-dimethylcyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 55);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(spiro[3.3]heptan-2-yloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 56);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-methyloxetan-3-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 58);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-methylcyclopropyl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 59);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(1-methylcyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 60);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 61);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 62);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 63);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 64);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 65);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-1-cyclobutylethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 66);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1S,2S)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 67);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((1R,2R)-2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 68);
(2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2-dimethylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 69);
(2R,3R,11bR)-3-(tert-butoxy)-9-((3,3-difluorocyclopentyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 70);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 71);
(2R,3R,11bR)-3-(tert-butoxy)-9-((R)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 72);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-fluoropropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 73);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1s,3S)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 74);
(2S,3R,11bR)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 76);
2-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)acetonitrile (compound 79);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(methoxy-d ₃ )-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 80);
1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclobutane-1-carbonitrile (compound 81);
1-((((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)methyl)cyclopropane-1-carbonitrile (compound 82);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-3,3,3-trifluoro-2-hydroxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 83);
(2R,3R,11bR)-3-(tert-butoxy)-9-((S)-2-hydroxypropoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 84);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((R)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 85);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((S)-2-methoxypropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 86);
(2R,3R,11bR)-3-(tert-butoxy)-9-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 90);
(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 91);
(1S,3s)-3-(((2R,3R,11bR)-3-(tert-butoxy)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)cyclobutane-1-carbonitrile (compound 92);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 93); and (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-methoxycyclobutoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 94);
trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 96);
trans-(2R,3R,11bR)-3-(tert-butoxy)-9-((2,2-difluoro-3-methylcyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 97); and cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 98);
or a pharmaceutically acceptable salt thereof. The following compounds:
(2R,3R,11bR)-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);
(2R,3R,11bR)-3-(tert-butoxy)-9-(cuban-1-ylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 100);
(2R,3R,11bR)-9-(bicyclo[1.1.1]pentan-1-ylmethoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 101);
(2R,3R,11bR)-9-(bicyclo[2.1.1]hexan-1-ylmethoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 102);
(2R,3R,11bR)-3-(tert-butoxy)-9-((1,1-dimethylsilolan-3-yl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 103);
(2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 104);
(2R,3R,11bR)-9-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 105); and (2R,3R,11bR)-9-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 106);
or a pharmaceutically acceptable salt thereof. A pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each of which comprises a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof. A pharmaceutical product selected from 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. 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. A method for preparing a pharmaceutical composition, comprising the step of admixing a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder in a subject in need of such treatment, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209. A method of treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product of claim 207 or 208, or a pharmaceutical composition of claim 209, wherein the VMAT2 disease or VMAT2 disorder is selected from the group consisting of ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; The method is selected from diseases of the cavities, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disorders; epilepsy; addictive or impulse disorders; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependent disorders. A method for treating a neurological or neurological disorder or a psychiatric disease or disorder in a subject in need of such treatment, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209. A method for treating a neurological or neurological disorder or a psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the neurological or neurological disorder or the psychiatric disease or disorder is selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and chorea acanthocytosis. A method for treating a neurological disease or disorder or a psychiatric disease or disorder in a subject in need of such treatment, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the neurological disease or disorder or the psychiatric disease or disorder is a hyperkinetic movement disorder. A method of treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor. A method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the hyperkinetic movement disorder is tardive dyskinesia. A method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the hyperkinetic movement disorder is Huntington's disease. A method for treating a hyperkinetic movement disorder in a subject in need thereof, comprising administering to the subject a compound described in any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product described in claim 207 or 208, or a pharmaceutical composition described in claim 209, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizophrenia. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizoaffective disorder. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is obsessive-compulsive disorder. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is an autism spectrum disorder. The method of any one of claims 211 to 225, comprising using the compound, salt, product, or composition in adjunctive therapy. 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 treating a vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder. Use of a compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product of claim 207 or 208, or a pharmaceutical composition of claim 209, in the manufacture of a medicament for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder selected from ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders. 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 treating a neurological disease or disorder or a psychiatric disease or disorder. 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 treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocyocytosis. 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 treating hyperkinetic movement disorder. 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 treating a hyperkinetic movement disorder, wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor. 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 treating tardive dyskinesia. 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 treating Huntington's disease. 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 treating chorea associated with Huntington's disease. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. The use described in claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizophrenia. The use described in claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizoaffective disorder. The use described in claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is obsessive-compulsive disorder. The use described in claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder. The use described in claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is an autism spectrum disorder. Use of the compound, salt, product, or composition described in any one of claims 227 to 241, wherein treating comprises using the compound, salt, product, or composition in adjunctive therapy. 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. 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 for treating a vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder. 209. 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 for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder selected from ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorders; mood or psychiatric disorders; neurotic, stress-related, and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson/parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders. 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 for treating a neurological disease or disorder or a psychiatric disease or disorder. 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 for treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, nervous system dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocyocytosis. 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 for treating hyperkinetic movement disorder. 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 for treating a hyperkinetic movement disorder, wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor. 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 for treating tardive dyskinesia. 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 for treating Huntington's disease. 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 for treating chorea associated with Huntington's disease. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizophrenia. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizoaffective disorder. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is obsessive-compulsive disorder. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder. The compound, salt, product, or composition for use according to claim 245 or 246, wherein the neurological disease or disorder or the psychiatric disease or disorder is an autism spectrum disorder. The compound, salt, product, or composition for use according to any one of claims 244 to 258, wherein the method of treatment comprises using the compound, salt, product, or composition in adjunctive therapy.