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

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, such as 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.

Description

[Technical Field]

[0001] background Technical Field 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. [Background technology]

[0002] 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 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.

[0003] (±)-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), which is currently used to treat various hyperactivity disorders. Inhibition of VMAT2 by (±)-TBZ results in depletion of brain monoamines 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 primarily mediated by active metabolites. (±)-TBZ has two chiral centers and is a racemic mixture of two stereoisomers. (±)-TBZ has been shown 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. [Table 8]

[0004] In patients receiving (±)-TBZ, [-]-alpha-DHTBZ (2S,3S,11bS-DHTBZ) and [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) were the most abundant DHTBZ isomers, whereas [-]-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 lowest amount of all four isomers. Therefore, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) appears to be the major DHTBZ isomer responsible for the pharmacological activity of (±)-TBZ. Once formed, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) has a relatively short half-life (approximately 5 hours), which necessitates that (±)-TBZ have a suboptimal (TID) dosing regimen.

[0005] (±)-TBZ has a narrow therapeutic window, and its clinical use requires careful dose titration. 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. The half-life (t 1 / 2 Compounds with longer half-lives and lower clearances result in smaller peak-to-trough fluctuations in plasma exposure given comparable dosing intervals. These long half-life compounds can exhibit improved tolerability by maintaining drug concentrations at levels required for efficacy, yet below levels that may induce side effects.

[0006] 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 unit of time. Clearance is a fundamental pharmacokinetic parameter and 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 small 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.

[0007] Although some progress has been made in this field, there is still a need in the art for improved VMAT2 inhibitors (including compounds, compositions and related methods).Identifying the VMAT2 small molecule inhibitor with long half-life / 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, reducing the frequency of dosing is highly desirable and brings more benefits to patients. 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. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2008 / 058261 Summary of the Invention [Means for solving the problem]

[0009] overview One embodiment of the present disclosure is, among others, a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C5-C 11 -spiro-cycloalkyl, cubanyl-C1-C4-alkylene, and 4- to 8-membered heterobicyclyl-C1-C4-alkylene; Each R 1 The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino. Includes.

[0010] Also provided herein is a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each of which comprises a compound described herein, or a pharmaceutically acceptable salt thereof.

[0011] Also provided herein is a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0012] Also provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] 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.

[0014] 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.

[0015] 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 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. 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 addictive disorders.

[0016] Also provided herein is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product described herein; or a pharmaceutical composition described herein.

[0017] 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 the group consisting of hyperactivity and 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.

[0018] 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 a hyperkinetic movement disorder.

[0019] Also provided herein is a method of 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.

[0020] Also provided herein is a method of 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 tardive dyskinesia.

[0021] Also provided herein is a method of 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 Huntington's disease.

[0022] Also provided herein is a method of 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.

[0023] 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 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 comprises using the compound, salt, product, or composition in adjunctive therapy.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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 hyperactivity and 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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, wherein 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 autism spectrum disorder. In some embodiments, the treatment comprises using the compound, salt, product, or composition in adjunctive therapy.

[0034] 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.

[0035] 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.

[0036] 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 malformations, deformities, or abnormalities; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic diseases; 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 dependence disorders.

[0037] Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a neurological disease or disorder or a psychiatric disease or disorder.

[0038] Also provided herein is a compound, as 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 hyperactivity and 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.

[0039] Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating hyperkinetic movement disorders.

[0040] Also provided herein is a compound, as 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.

[0041] Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating tardive dyskinesia.

[0042] Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating Huntington's disease.

[0043] Also provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating chorea associated with Huntington's disease.

[0044] 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 for treatment comprises using the compound, salt, product, or composition in adjunctive therapy.

[0045] These and other aspects of the invention disclosed herein will be described in more detail as the patent disclosure proceeds. [Brief explanation of the drawings]

[0046] [Figure 1A] Figure 1A shows a general synthetic scheme for the preparation of certain compounds of formula (Ia) and related intermediates where R is methyl. In this representative example, R is methyl and is incorporated into compound 2-3.

[0047] [Figure 1B] 1B shows a general synthetic scheme for the preparation of certain compounds of Formula (Ia) and related intermediates (wherein R 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.

[0048] [Figure 2A]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 the intermediate (±)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one (compound 2-17) to produce (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol. A general synthetic scheme is shown in which 6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19) is resolved 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.

[0049] [Figure 2B]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., (±)-9-(benzoyl)-1-(tert-butoxy)propan-2-one (Compound 2-25) and 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (Compound 2-26).

[0039] Figure 2 shows a general synthetic scheme for (±)-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 (±)-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). Compound (±)-2-19 is resolved using (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.

[0050] [Figure 3]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, where R1 has the same meaning as described herein, LG1 is a leaving group, and R3a can be H or C1-C4-alkyl (optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C2-C4-dialkylamino). It is understood that LG1 can be a variety of leaving groups, such as those described herein and known in the art.

[0051] [Figure 4] FIG. 4 shows a general synthetic scheme for preparing compounds of formula (Ie), i.e., utilizing (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, where R1 has the same meaning as described herein, LG1 is a leaving group, and R3a can be H or C1-C4-alkyl (optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, C1-C4-alkoxy, and C2-C4-dialkylamino). It is understood that LG1 can be a variety of leaving groups, such as those described herein and known in the art.

[0052] [Figure 5]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 OF THE INVENTION

[0053] Detailed Description definition For clarity and consistency, the following definitions will be used throughout this patent document.

[0054] 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.

[0055] 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.

[0056] The terms "administering" and "administration," as used herein, refer to providing a compound or other therapy described herein to a subject in a form that is capable of introducing into a 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, and the like; injectable dosage forms, e.g., intravenous (IV), intramuscular (IM), subcutaneous (SC), and the like; transdermal dosage forms, including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal dosage forms, e.g., suppositories.

[0057] A medical professional can provide the compound described herein directly to a subject in the form of a sample, or can indirectly provide the compound to a subject by providing an oral or written prescription for the compound. For example, a subject can also obtain the compound themselves without the involvement of a medical 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 drugs, "administering" and "administration" are considered to include the compound and at least one other drug being administered at the same time or at different times. When drugs in a combination are administered at the same time, these drugs 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 preparation, the site of the disease, and the severity of the disease.

[0058] The term "composition" refers to a compound or crystalline form thereof, including but not limited to salts, solvates, and hydrates of the compound described herein, in combination with at least one additional component, e.g., a composition obtained / prepared during synthesis, pre-formulation, in-process testing (e.g., TLC, HPLC, NMR sample), etc.

[0059] 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, for example, 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, can be found together with or isolated from other substances, such as water and solvents (e.g., hydrates and solvates). When solid, the compounds described herein and their salts can occur in various forms, such as cocrystals or solvates, including hydrates. The compounds can be in any solid form, e.g., polymorphs or solvates, and unless expressly indicated otherwise, references to 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.

[0060] 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.

[0061] 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.

[0062] The terms "in need of treatment" and "in need of," 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.

[0063] The term " subject " refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates and humans.In the context of clinical trial or screening or activity experiment, subject can be a healthy volunteer or healthy participant that does not have underlying VMAT2-mediated disorder or condition, or a volunteer or participant that has been diagnosed with disorder or condition that requires medical treatment, as determined by health care professionals.In the context outside of clinical trial, the subject that has been diagnosed with disorder or condition and is under the care of health care professionals is usually described as subject.

[0064] The term "pediatric subject" refers to a subject who is 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, for example, Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB 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.

[0065] The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions, and / or dosage forms that are within the scope of sound medical judgment and are 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.

[0066] The term "pharmaceutical composition" refers to a specific composition comprising 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 skilled in the art will understand and appreciate the appropriate techniques for determining whether an active ingredient will produce a desired, effective outcome based on the needs of the artisan.

[0067] 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 prophylactic or preventative. In some embodiments, the subject can be a pediatric subject.

[0068] The terms "treat", "treating" and "treatment" refer to the medical management of a subject's (e.g., subject's) disease, disorder, or condition (see, e.g., Stedman's Medical Dictionary). Generally, an appropriate dosage and treatment regimen provides a VMAT2 inhibitor in an amount sufficient to provide a therapeutic benefit. The therapeutic benefit to a subject to whom the VMAT2 inhibitor compound(s) described herein is administered includes, for example, improved clinical outcomes, with the purpose of preventing, slowing down, or delaying (reducing) undesired physiological changes associated with a disease, or preventing, slowing down, or delaying (reducing) the progression or severity of such a disease. The effectiveness of one or more VMAT2 inhibitors can include beneficial or desired clinical results, including but not limited to: reduction, reduction or alleviation of the symptoms resulting from or associated with the disease to be treated; reduced occurrence of symptoms; improved quality of life; longer disease-free period (i.e., reducing the possibility or tendency of the subject to show the symptoms that were the basis for diagnosing the disease); reduction in the extent of the disease; stabilized (i.e., not getting worse) state of the disease; slowing or slowing down disease progression; improvement or alleviation of disease state; and remission (whether partial remission or complete remission) (whether these are detectable or not); and / or overall survival.In some embodiments, the subject can be a pediatric subject.

[0069] 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 a 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 symptomatology) in a subject experiencing or exhibiting the associated pathology or symptomatology; and (3) Reversing a disorder, e.g., reversing a disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) in a subject experiencing or exhibiting the associated pathology or symptomology.

[0070] The term "contacting" refers to bringing together the indicated parts in an in vitro system or an in vivo system.For example, "contacting" VMAT2 protein with the compound provided herein includes administering the compound provided herein (or its pharmaceutically acceptable salt) to a subject, for example, a human having VMAT2 protein, as well as introducing the compound provided herein into a sample containing a cell preparation or purified preparation containing VMAT2 protein.

[0071] 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 terms herein, those in this section shall prevail unless otherwise stated.

[0072] 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 4 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), where "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 intended to be assumed.

[0073] For compounds described herein, or pharmaceutically acceptable salts thereof, in which a variable occurs more than once, each variable can be a different moiety independently selected from the groups defining the variable. For example, if a structure is depicted in which two R groups coexist, e.g., on the same compound, the two R groups can represent different moieties independently selected from the groups defined for R, or the two R groups can be the same.

[0074] 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," if substituted, the substituent(s) 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.

[0075] The "C" that precedes the group name a ~Cb The terms "a" and "b" (where "a" and "b" are integers) refer to an inclusive range of carbon atoms in that group. For example, a "C1-C4-alkyl" group refers to all alkyl groups having one to four carbons (i.e., one, two, three, and four carbons), such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), iso-propyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), iso-butyl ((CH3)2CHCH2-), sec-butyl (CH3CH2CH(CH3)-), and tert-butyl ((CH3)3C-). When no "a" or "b" is specified for a group, the broadest range described in those definitions is intended.

[0076] In addition to the foregoing, as used in the specification and claims, unless specified to the contrary, the following terms have the meaning indicated.

[0077] The terms "C1-C4-alkylene" and "C2-C4-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 carbon atoms. Some embodiments contain 1 to 3 carbon atoms. Some embodiments contain 1 carbon atom. Some embodiments contain 2 to 3 carbon atoms. Some embodiments contain 2 carbon atoms. Examples include, but are not limited to, methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2- and -CH(CH3)-), 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.

[0078] The term "C1-C4-alkyl-O-C2-C4-alkylene" refers to a radical group consisting of a "C1-C4-alkyl" group bonded to an oxygen atom, which oxygen atom is bonded to a "C2-C4 alkylene" radical, where "C1-C4-alkyl" and "C2-C4 alkylene" have the same definitions as described herein. Examples include, but are not limited to, 1-methoxyethyl (i.e., CH3-O-CH(CH3)-), 2-methoxyethyl (i.e., CH3-O-CH2CH2-), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, and 3-isopropoxypropyl. In some embodiments, "C-C-alkyl-O-C-C-alkylene" refers to a group selected from 2-methoxyethyl (i.e., CH-O-CHCH-), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, and 3-isopropoxypropyl. When one or more substituents are present on the "C-C-alkyl-O-C-C-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 "C-C-alkyl-O-C-C-alkylene" group can be substituted or unsubstituted.

[0079] 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., "C1-C4-alkoxy"). Some embodiments contain 1 to 3 carbons (i.e., "C1-C3-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.

[0080] 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., "C1-C6-alkyl"). Some embodiments are 1 to 5 carbons (i.e., "C1-C5-alkyl"), some are 1 to 4 carbons (i.e., C1-C4-alkyl), some are 1 to 3 carbons (i.e., "C1-C3-alkyl"), and some are 1 or 2 carbons. By way of example only, "C1-C4-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.

[0081] 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 1 to 4 carbon atoms (i.e., "C1-C4-alkylsulfonyl"). Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, and t-butylsulfonyl.

[0082] The term "amino" refers to the group --NH.sub.2.

[0083] 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, a "bicycloalkyl" group may be substituted or unsubstituted.

[0084] 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)CH2-), (bicyclo[1.1.1]pentan-1-yl)methyl (i.e., (bicyclo[1.1.1]pentan-1-yl)CH2-), (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 "C4-C8-bicycloalkyl-C1-C4-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 "C4-C8-bicycloalkyl-C1-C4-alkylene" group can be substituted or unsubstituted.

[0085] 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 the "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.

[0086] The term "carbonyl" refers to the group -C(=O)-.

[0087] The term "cubanyl" refers to a radical group having the following structure: [ka]

[0088] The term "cubanyl-C1-C4-alkylene" refers to a radical group consisting of a "cubanyl" group attached to a "C1-C4 alkylene" radical, where "cubanyl" and "C1-C4 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 the "cubanyl-C1-C4-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 "cubanyl-C1-C4-alkylene" group can be substituted or unsubstituted.

[0089] The term "cyano" refers to the group --CN.

[0090] The term "cyano-C1-C4-alkylene" refers to a radical group consisting of a "cyano" group attached to a "C1-C4 alkylene" radical, where "cyano" and "C1-C4 alkylene" have the same definitions as described herein. Examples include, but are not limited to, cyanomethyl (i.e., -CH2CN), 2-cyanoethyl, 1-cyanoethyl (i.e., -CH(CH3)-CN), and 3-cyanopropyl.

[0091] 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 4 to 7 atoms in the ring (i.e., "C4-C7-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.

[0092] 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.

[0093] 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-), cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl (cyclopropyl-CHCH-), 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclopropylethyl (cyclopropyl-CH(CH)-), 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. When one or more substituents are present on a "C-C-cycloalkyl-C-C-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 "C3-C7-cycloalkyl-C1-C4-alkylene" group can be substituted or unsubstituted.

[0094] The term "C3-C7-cycloalkyl-O-C2-C4-alkylene" refers to a radical group consisting of a "C3-C7-cycloalkyl" group attached to an oxygen atom, which oxygen atom is attached 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—CHCH—), 2-cyclobutoxyethyl, 2-cyclopentyloxyethyl, 2-cyclohexyloxyethyl, 2-cycloheptyloxyethyl, 1-cyclopropoxyethyl (i.e., cyclopropyl-O—CH(CH)—), 1-cyclobutoxyethyl, 1-cyclopentyloxyethyl, 1-cyclohexyloxyethyl, 1-cycloheptyloxyethyl, 3-cyclopropoxypropyl, 3-cyclobutoxypropyl, 3-cyclopentyloxypropyl, 3-cyclohexyloxypropyl, and 3-cycloheptyloxypropyl. The chemical group “(cyclopropyl)methyl-d” is understood to refer to a group in which a deuterium atom is attached to a methylene carbon (i.e., cyclopropyl-CD—), see, for example, compound 99. When one or more substituents are present on the "C3-C7-cycloalkyl-O-C2-C4-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 "C3-C7-cycloalkyl-O-C2-C4-alkylene" group can be substituted or unsubstituted.

[0095] The term "dialkylamino" refers to an amino group (-NH2) 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 described herein. A "dialkylamino" group can have 2 to 4 carbon atoms (i.e., "C2-C4-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)).

[0096] 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, the haloalkyl group can have 1 to 6 carbons (i.e., a "C1-C6-haloalkyl"). A haloC1-C6 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., a "C1-C5-haloalkyl"). In some embodiments, a haloalkyl contains 1 to 4 carbons (i.e., a "C1-C4-haloalkyl"). In some embodiments, a haloalkyl contains 1 to 3 carbons (i.e., a "C1-C3-haloalkyl"). In some embodiments, a 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.

[0097] 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.

[0098] 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 the following: 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.

[0099] The term "4- to 8-membered heterobicyclyl-C1-C4-alkylene" refers to a radical group consisting of a "4- to 8-membered heterobicyclyl" group attached to a "C1-C4 alkylene" radical, where "4- to 8-membered heterobicyclyl" and "C1-C4 alkylene" have the same definitions as described herein. In some embodiments, the "4- to 8-membered heterobicyclyl-C1-C4-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 the "4- to 8-membered heterobicyclyl-C1-C4-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 "4-8 membered heterobicyclyl-C1-C4-alkylene" group can be substituted or unsubstituted.

[0100] The term "3- to 7-membered heterocyclyl-C1-C4-alkylene" refers to a radical group consisting of a "3- to 7-membered heterocyclyl" group attached to a "C1-C4 alkylene" radical, where "3- to 7-membered heterocyclyl" and "C1-C4 alkylene" have the same definitions as described herein. Examples include, but are not limited to, aziridin-1-ylmethyl (i.e., (aziridin-1-yl)CH2-), aziridin-2-ylmethyl, azetidin-2-ylmethyl (i.e., (azetidin-2-yl)CH2-), azetidin-3-ylmethyl (i.e., (azetidin-3-yl)CH2-), piperidinylmethyl, morpholinyl, oxetan-3-ylmethyl (i.e., (oxetan-3-yl)CH2-), oxetan-2-ylmethyl (i.e., (azetidin-3-yl)CH2-), and oxetan-2-ylmethyl (i.e., (azetidin-3-yl)CH2-). That is, (oxetan-2-yl)CH—), 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl)CHCH—), 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl)CHCH—), imidazolidinylmethyl, piperazin-1-ylmethyl, piperazin-2-ylmethyl, pyrrolidin-3-ylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, and tetrahydrothiopyranylmethyl. In some embodiments, the "3- to 7-membered heterocyclyl-C1-C4-alkylene" is a group selected from the following: oxetan-3-ylmethyl (i.e., (oxetan-3-yl)CH2-), oxetan-2-ylmethyl (i.e., (oxetan-2-yl)CH2-), 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl)CH2CH2-), and 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl)CH2CH2-). When one or more substituents are present on the "3- to 7-membered heterocyclyl-C1-C4-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 "3- to 7-membered heterocyclyl-C1-C4-alkylene" group can be substituted or unsubstituted.

[0101] The term "spiro-cycloalkyl" refers to a non-aromatic, all-carbon, bicyclic ring system in which both rings are joined together at a single common ring carbon. In some embodiments, "C5-C 11 "C5-C8-spiro-cycloalkyl" refers to a spiro ring system containing 5 to 11 ring carbons. In some embodiments, "C5-C7-spiro-cycloalkyl" refers to a spiro ring system containing 5 to 8 ring carbons. In some embodiments, "C7-spiro-cycloalkyl" refers to a spiro ring system containing 5 to 7 ring carbons. In some embodiments, "C7-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.

[0102] 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, a "spiro-heterocyclyl" group can be substituted or unsubstituted.

[0103] The term "hydroxyl" refers to the group --OH.

[0104] 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 does not have 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 production 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 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)). Preservatives, stabilizers, dyes, buffers, etc. 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.

[0105] 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.

[0106] 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 due to 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.

[0107] The compounds described herein may have one or more stereocenters. All stereoisomers, e.g., enantiomers and diastereomers, are intended unless otherwise indicated. In 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 in 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. Stereochemical definitions 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%.

[0108] Resolution of racemic mixtures of compounds can be achieved by any of a number of methods known in the art. An exemplary method involves fractional recrystallization using a chiral resolving organic acid with a racemic compound containing a basic group. 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 a chiral resolving base can be utilized with a racemic compound containing a basic group.

[0109] 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.

[0110] 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 figures. 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 figures.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] The compounds described herein and their pharmaceutically acceptable salts can be found with other substances, for example, water and solvent, in the form of, for example, hydrate or solvate.When solid, the compounds described herein and their salts can occur in various forms, for example, can also take the form of solvate, including hydrate.Compounds can be in any solid form, for example, crystalline form, amorphous form, solvate form, etc., and unless otherwise clearly indicated, it should be understood that the references herein to compounds and their salts represent any solid form of compounds.

[0115] 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.

[0116] In some embodiments, the compounds described herein, or salts thereof, are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched for the compounds described herein. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein, or salts thereof.

[0117] 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. Compounds in which one or more atoms have an isotopic distribution for chemical elements in proportionate amounts different from that normally found in nature are commonly referred to as 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 the compound where a hydrogen atom can be present, the hydrogen atom may be present in proportion to that normally found in nature, including, but not limited to, protium ( 1 H) and deuterium ( 2The isotope distribution of hydrogen may be an isotope distribution of hydrogen, including H). Thus, reference to a compound herein encompasses all potential isotope 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 one of ordinary skill in the art will recognize, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, compounds disclosed and described herein in which one or more atoms have an isotope distribution that differs from the isotope distribution normally found in nature, e.g., in a proportion greater than that found in nature, may be used. 2 H or 3 Compounds with H, or in greater proportions 11 C. 13 C, or 14 The use of compounds having C is also contemplated. As a general example, and without limitation, protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C), and carbon-14 ( 14 C). Nitrogen isotopes include nitrogen-13 ( 13 N), nitrogen-14( 14 N), and nitrogen-15( 15 N). Oxygen isotopes include oxygen-14 ( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18( 18 O). Fluorine isotopes include fluorine-17( 17 F), fluorine-18( 18 F), and fluorine-19( 19 F). Phosphorus isotopes include phosphorus-31 ( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34P), phosphorus-35( 35 P), and phosphorus-36( 36 P). Sulfur isotopes 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). Chlorine isotopes include chlorine-35 ( 35 Cl), chlorine-36( 36 Cl), and chlorine-37( 37 Cl). Bromine isotopes 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). Iodine isotopes include iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I), and iodine-135( 135I). In some embodiments, atoms at all positions of the compound have an isotope distribution for each chemical element in proportionate amounts to that normally found in nature. In some embodiments, atoms at one position of the compound have an isotope distribution for each chemical element in proportionate amounts different from that normally found in nature (the remaining atoms have an isotope distribution for each chemical element in proportionate amounts to that normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotope distribution for each chemical element in proportionate amounts different from that normally found in nature (the remaining atoms have an isotope distribution for each chemical element in proportionate amounts to that normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotope distribution for each chemical element in proportionate amounts different from that normally found in nature (the remaining atoms have an isotope distribution for each chemical element in proportionate amounts to that normally found in nature). In some embodiments, atoms at at least four 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). 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). In 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).

[0118] Certain compounds, such as radioisotopes, e.g. 3 H and 14 Compounds incorporating C are also useful in drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2Compounds having proportionally greater amounts of isotopes, such as 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 carrying out procedures conventionally practiced in the chemical arts. Methods for measuring such isotopic perturbations or enrichments, such as mass spectrometry, are readily available, and for isotopes that are radioactive, additional methods are also available, such as radiation detectors used in conjunction with HPLC or GC.

[0119] As used herein, "isotopic variant" refers to 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( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36(36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is 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 In certain embodiments, an "isotopic variant" of a compound is 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 In the compounds provided herein, all hydrogen is represented in the form of the major isotope, e.g., 2 H or any carbon can be in the form of a major isotope, e.g. 13 C, or any nitrogen in the form of the major isotope, e.g. 15N, and any oxygen in the form of a major isotope, e.g. 18 It is understood that an "isotopic variant" of a compound can contain unnatural proportions of deuterium ( 2 H).

[0120] With reference 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.

[0121] 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 a target molecule, are as follows:

[0122] A. Catalytic Reduction with Tritium Gas: This procedure usually produces products of high specific activity and requires halogenated or unsaturated precursors.

[0123] B. Sodium borohydride [ 3 Reduction with [H]: This procedure is somewhat less expensive and requires precursors containing reducible functional groups (e.g., aldehydes, ketones, lactones, esters, etc.).

[0124] C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure provides products at nearly theoretical specific activities. It also requires precursors containing reducible functional groups (e.g., aldehydes, ketones, lactones, esters, etc.).

[0125] D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0126] E. Methyl iodide [ 3 N-methylation using [H]: This procedure is typically used to convert the appropriate precursor to high specific activity methyl iodide ( 3 H) to give O-methyl or N-methyl ( 3 H) Prepare the product. This method generally allows for higher specific activities, e.g., about 70-90 Ci / mmol.

[0127] Activity level 125 Synthetic methods for incorporating I into target molecules include: A. Sandmeyer and similar reactions: This procedure converts an arylamine or heteroarylamine into a diazonium salt, e.g., a diazonium tetrafluoroborate salt, followed by the addition of Na125 Using I, 125 I-labeled compounds. A representative procedure was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948.

[0128] B. Phenol ortho 125 Iodination: This procedure allows the ortho-position of phenols to be iodinated as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266. 125 Enables the incorporation of I.

[0129] C. Aryl and heteroaryl bromides 125 Exchange with I: This method is generally a two-step process. The first step is the conversion of an 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.

[0130] The radiolabeled form of the compounds described herein can be used in screening assays to identify / evaluate compounds.Generally speaking, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled form of the compounds disclosed herein to VMAT2.The ability of the test compound to compete with the radiolabeled form of the compounds described herein for binding to VMAT2 correlates with its binding affinity.

[0131] compound One embodiment of the present disclosure is, among others, a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C5-C 11 -spiro-cycloalkyl, cubanyl-C1-C4-alkylene, and 4- to 8-membered heterobicyclyl-C1-C4-alkylene; Each R 1 The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0132] Another aspect of the present disclosure is, among others, a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, R 1is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, and C5-C 11 -spiro-cycloalkyl, Each R 1 The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0133] In some embodiments, R 1 The group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents. 1 The group is optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents. 1 The group is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents. 1 The group is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, R 1 The group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, R 1 The group is optionally substituted with one or two substituents. In some embodiments, R 1 The group is optionally substituted with one substituent. In some embodiments, R 1 The group is unsubstituted.

[0134] In some embodiments, R 1 The group is substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents. 1 The group is substituted with 1, 2, 3, 4, 5, 6, or 7 substituents. 1 The group is substituted with 1, 2, 3, 4, 5, or 6 substituents. 1 The group is substituted with 1, 2, 3, 4, or 5 substituents. 1 The group is substituted with 1, 2, 3, or 4 substituents. 1 The group is substituted with 1, 2, or 3 substituents. In some embodiments, R 1 The group is substituted with one or two substituents. In some embodiments, R 1 The group is substituted with one substituent.

[0135] Some embodiments include a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof [wherein: R 1 has the same definition as described above 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.

[0136] Some embodiments include a compound of formula (Ie): [ka] 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 (Ie) is the 2R,3R,11bR isomer.

[0137] Some embodiments include a compound of formula (Ig): [ka] 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 (Ig) is the 2S,3R,11bR isomer.

[0138] Some embodiments include a compound of formula (Ii): [ka] 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 (Ii) is the 2R,3S,11bS isomer.

[0139] Some embodiments include a compound of formula (Ik): [ka] 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.

[0140] Some embodiments may involve compounds that are excreted at 100°C or less as determined using a human liver microsome (HLM) assay, such as the assay described in Example 17. 1 / 2 In some embodiments, the compound has an excretion time of ≥ 420 minutes, or a pharmaceutically acceptable salt thereof. 1 / 2 In some embodiments, the compound has an excretion time of ≥ 400 minutes. 1 / 2 In some embodiments, the compound has an excretion time of t 1 / 2 In some embodiments, the compound has an excretion time of t 1 / 2 In some embodiments, the compound has an excretion time t 1 / 2 In some embodiments, the compound has an excretion time of t 1 / 2 In some embodiments, the compound has an excretion time of t 1 / 2In some embodiments, the compound has an excretion time of t 1 / 2 In some embodiments, the compound has an excretion time of t 1 / 2 ≧200 min.

[0141] Some embodiments include an IC 50 The compound has an IC activity for CYP2D6 and CYP3A4 as determined using a method, e.g., the method described in Example 18. 50 In some embodiments, the compound has an IC value of >6,000 nM for CYP2D6, or a pharmaceutically acceptable salt thereof. 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 >2,000 nM. In some embodiments, the compounds are substantially inactive against CYP2D6. In some embodiments, the compounds are substantially inactive against CYP3A4.

[0142] Some embodiments include an IC 50 The compound has an IC50 activity against hERG (human ether-a-go-go-related gene) as determined using a method, for example, the method described in Example 19. 50 In some embodiments, the compound has an IC50 activity against hERG of >12,000 nM, or a pharmaceutically acceptable salt thereof. 50In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 In some embodiments, the compound has an IC 50 >7,000 nM. In some embodiments, the compound is substantially inactive against hERG.

[0143] Phrases such as "a compound described herein" or "compounds described herein" refer to any compound or compounds described herein 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).

[0144] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, C5-C 11 -spiro-cycloalkyl, cubanyl-C1-C4-alkylene, and 4- to 8-membered heterobicyclyl-C1-C4-alkylene; Each R 1The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl, and C1-C4-alkoxy.

[0145] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5- to 11-membered spiro-heterocyclyl, and C5-C 11 -spiro-cycloalkyl, Each R 1 The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl, and C1-C4-alkoxy.

[0146] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl, and C1-C4-alkoxy.

[0147] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2—, (C5-bicycloalkyl)CH2—, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, and C7-spiro-cycloalkyl; Each R 1 The group is optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl, and C1-C4-alkoxy.

[0148] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0149] In some embodiments, R 1is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2—, (C5-bicycloalkyl)CH2—, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, and C7-spiro-cycloalkyl; Each R 1 The group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0150] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0151] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4- to 5-membered heterocyclyl, (4-membered heterocyclyl)CH2—, (C5-bicycloalkyl)CH2—, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, and C7-spiro-cycloalkyl; Each R 1The group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0152] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0153] In some embodiments, R 1 is selected from C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—CH2CH2—, cyclopropyl-O—CH2CH2—, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2—, (C5-bicycloalkyl)CH2—, C4-cycloalkenyl, 7-membered spiro-heterocyclyl, and C7-spiro-cycloalkyl; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

[0154] In some embodiments, R 1is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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.

[0155] In some embodiments, R 1 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.

[0156] In some embodiments, R1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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.

[0157] In some embodiments, R 1 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.

[0158] In some embodiments, R 1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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.

[0159] In some embodiments, R 1 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.

[0160] In some embodiments, R 1is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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.

[0161] In some embodiments, R 1 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.

[0162] In some embodiments, R 1are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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] 1.1]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, (siloran-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.

[0163] In some embodiments, R 1is 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.

[0164] In some embodiments, R 1are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, 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] 1.1]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, (siloran-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.

[0165] In some embodiments, R 1is 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.

[0166] In some embodiments, R 1are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (biscuitryl) is selected from (2-oxabicyclo[2.1.1]hexan-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.

[0167] 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.

[0168] In some embodiments, R 1 are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (biscuitryl) is selected from (2-oxabicyclo[2.1.1]hexan-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.

[0169] In some embodiments, R 1is 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.

[0170] In some embodiments, R 1are (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-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl , (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-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-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.

[0171] In some embodiments, R 1are (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, oxy Cetane-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-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

[0172] In some embodiments, R 1are (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-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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-methoxypropyl, 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-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.

[0173] 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 1is (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-d5. 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-d2. 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 1is (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, R1 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, R1 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.

[0174] In some embodiments, R 1are (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, oxy Cetane-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-methoxypropyl, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

[0175] In some embodiments, R 1are (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-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3 ,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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-difluoro cyclopropyl)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, (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-cyanocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3- The aryl group is selected from methoxycyclobutyl, (1r,3R)-3-(dimethylamino)cyclobutyl, (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.

[0176] In some embodiments, R 1is (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) (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, (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)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.

[0177] R provided herein 1 The stereochemistry for the R group is as shown in the formulae provided herein (e.g., Formula (Ia), Formula (Ic), Formula (Ie), Formula (Ig), Formula (Ii), and Formula (Ik)). 1 It is understood that the groups are assigned based on their attachment to the oxygen.

[0178] 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 1is (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.

[0179] In some embodiments, R 1are (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-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3, 3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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-difluoro cyclopropyl)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-cyano (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclopropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl The silyl group is selected from cyclobutyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-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.

[0180] In some embodiments, R 1are (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) (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-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.

[0181] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene.

[0182] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0183] In some embodiments, R 1 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, cyano, and C1-C4-alkylsulfonyl.

[0184] In some embodiments, R 1 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.

[0185] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene optionally substituted with 1, 2 or 3 substituents selected from cyano-C1-C4-alkylene, halogen, hydroxyl, C1-C4-haloalkyl, C1-C4-alkyl and cyano.

[0186] In some embodiments, R 1 is a C3-C5-cycloalkyl-C1-C2-alkylene optionally substituted with 1, 2, or 3 substituents selected from cyanomethyl, halogen, hydroxyl, C1-haloalkyl, methyl, cyano, and methylsulfonyl.

[0187] In some embodiments, R 1 is a C3-C5-cycloalkyl-C1-C2-alkylene optionally substituted with 1, 2, or 3 substituents selected from cyanomethyl, halogen, hydroxyl, C1-haloalkyl, methyl, and cyano.

[0188] In some embodiments, R 1is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)ethyl, each group optionally substituted with one, two, or three substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl.

[0189] 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.

[0190] In some embodiments, R 1 is selected from (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)ethyl, each group optionally substituted with 1, 2, or 3 substituents selected from cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl.

[0191] 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.

[0192] In some embodiments, R 1are (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl and (2,2-difluorocyclobutyl)methyl.

[0193] 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.

[0194] 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-d2, (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.

[0195] 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.

[0196] In some embodiments, R 1 are (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (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 and (2,2-difluorocyclobutyl)methyl.

[0197] In some embodiments, R 1are (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, (( 1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl, (R)-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.

[0198] In some embodiments, R 1are (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (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) and (2,2-difluoro-3-methylcyclopropyl)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, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl.

[0199] In some embodiments, R 1are (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] In some embodiments, the aryl 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.

[0200] In some embodiments, R 1 is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.

[0201] 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.

[0202] In some embodiments, R 1 is C1-C6-alkyl.

[0203] In some embodiments, R 1 is C1-C6-alkyl optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0204] In some embodiments, R 1 is C1-C6-alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, C1-C4-alkoxy, and C1-C4-alkylsulfonyl.

[0205] In some embodiments, R 1 is C1-C6-alkyl optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, and C1-C4-alkoxy.

[0206] In some embodiments, R 1 is C1-C6-alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and C1-C4-alkoxy.

[0207] In some embodiments, R 1 is C1-C5-alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, methoxy, and methylsulfonyl.

[0208] In some embodiments, R 1 is C1-C5-alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and methoxy.

[0209] In some embodiments, R 1 is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl.

[0210] 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.

[0211] In some embodiments, R 1 is selected from isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl, and neopentyl, each group optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and methoxy.

[0212] 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.

[0213] In some embodiments, R 1is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, ethyl-d5, 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.

[0214] 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.

[0215] In some embodiments, R 1is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxypropyl, ethyl, ethyl-d5, 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.

[0216] 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.

[0217] In some embodiments, R 1is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, 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.

[0218] 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.

[0219] In some embodiments, R 1is selected from isobutyl, isopentyl, butyl, propyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, 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.

[0220] 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.

[0221] In some embodiments, R 1 is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl, and ethyl-d5.

[0222] In some embodiments, R1 is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl.

[0223] In some embodiments, R 1 is C3-C7-cycloalkyl.

[0224] In some embodiments, R 1 is C3-C7-cycloalkyl optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0225] In some embodiments, R 1 is C3-C7-cycloalkyl optionally substituted with one or more substituents selected from cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0226] In some embodiments, R 1 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.

[0227] In some embodiments, R 1 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.

[0228] In some embodiments, R 1is C3-C5-cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl, methoxy, and dimethylamino.

[0229] In some embodiments, R 1 is C3-C7-cycloalkyl optionally substituted with one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl, and methoxy.

[0230] 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.

[0231] 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, and methoxy.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] In some embodiments, R 1 is C1-C4-alkyl-O-C2-C4-alkylene.

[0237] In some embodiments, R 1is C1-C4-alkyl-O—C2-C4-alkylene optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0238] In some embodiments, R 1 is C1-C4-alkyl-O-C2-C4-alkylene optionally substituted with one or more substituents selected from cyano, halogen, and C3-C6-cycloalkyl.

[0239] In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene optionally substituted with one or more substituents selected from cyano, halogen, and cyclopropyl.

[0240] In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene optionally substituted with 1, 2 or 3 substituents selected from cyano, halogen and cyclopropyl.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] In some embodiments, R 1 is C3-C7-cycloalkyl-O-C2-C4-alkylene.

[0245] In some embodiments, R 1 is C3-C7-cycloalkyl-O—C2-C4-alkylene optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0246] In some embodiments, R 1 is cyclopropoxyethyl.

[0247] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl.

[0248] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0249] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl optionally substituted with one or more C1-C4-alkyl substituents.

[0250] In some embodiments, R 1 is a 4-5 membered heterocyclyl optionally substituted with one or more C1-C4-alkyl substituents.

[0251] In some embodiments, R 1 is a 4-5 membered heterocyclyl optionally substituted with one C1-C4-alkyl substituent.

[0252] In some embodiments, R 1 is a four-membered heterocyclyl.

[0253] In some embodiments, R 1 is oxetan-3-yl or pyrrolidin-3-yl, each group optionally substituted with one methyl substituent.

[0254] In some embodiments, R 1 is oxetan-3-yl or 1-methylpyrrolidin-3-yl.

[0255] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl-C1-C4-alkylene.

[0256] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl-C1-C4-alkylene optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0257] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl-C1-C4-alkylene optionally substituted with one or more C1-C4-alkyl substituents.

[0258] In some embodiments, R1 is (4-5 membered heterocyclyl)CH2- optionally substituted with one or more methyl substituents.

[0259] In some embodiments, R 1 is (4-membered heterocyclyl)CH2- optionally substituted with one or more methyl substituents.

[0260] In some embodiments, R 1 is (4-5 membered heterocyclyl)CH2- optionally substituted with one methyl substituent.

[0261] In some embodiments, R 1 is (4-membered heterocyclyl)CH2- optionally substituted with one methyl substituent.

[0262] In some embodiments, R 1 is (oxetanyl)methyl or (silolanyl)methyl, each group optionally substituted with one or two methyl substituents.

[0263] 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.

[0264] In some embodiments, R 1 is (oxetan-3-yl)methyl or (oxetan-2-yl)methyl, each group optionally substituted with one methyl substituent.

[0265] In some embodiments, 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.

[0266] In some embodiments, R 1 is selected from (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl.

[0267] 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.

[0268] In some embodiments, R 1 is selected from oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl.

[0269] In some embodiments, R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene.

[0270] In some embodiments, R 1 is a C4-C8-bicycloalkyl-C1-C4-alkylene optionally substituted with one or more substituents selected from halogen and C1-C4-haloalkyl.

[0271] In some embodiments, R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted with one or more substituents selected from fluoro and trifluoromethyl.

[0272] In some embodiments, R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted with one substituent selected from fluoro and trifluoromethyl.

[0273] In some embodiments, R 1is (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.

[0274] 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.

[0275] 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.

[0276] In some embodiments, R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0277] In some embodiments, R 1 is a C4-C8-bicycloalkyl-C1-C4-alkylene optionally substituted with one or more halogen substituents.

[0278] In some embodiments, R 1 is (C5-bicycloalkyl)CH2- optionally substituted with one or more fluoro substituents.

[0279] In some embodiments, R1 is (C5-bicycloalkyl)CH2- optionally substituted with one fluoro substituent.

[0280] In some embodiments, R 1 is (bicyclo[1.1.1]pentanyl)methyl optionally substituted with one fluoro substituent.

[0281] In some embodiments, R 1 is (bicyclo[1.1.1]pentan-1-yl)methyl optionally substituted with one fluoro substituent.

[0282] In some embodiments, R 1 is C4-C7-cycloalkenyl.

[0283] In some embodiments, R 1 is C4-C7-cycloalkenyl optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0284] In some embodiments, R 1 is a C4-C7-cycloalkenyl optionally substituted with one or more halogen substituents.

[0285] In some embodiments, R 1 is a C4-cycloalkenyl optionally substituted with one halogen substituent.

[0286] In some embodiments, R 1 is cyclobutenyl optionally substituted with one fluoro substituent.

[0287] In some embodiments, R 1is cyclobut-2-en-1-yl optionally substituted with one fluoro substituent.

[0288] In some embodiments, R 1 is a 5- to 11-membered spiro-heterocyclyl.

[0289] In some embodiments, R 1 is a 5- to 11-membered spiro-heterocyclyl optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.

[0290] In some embodiments, R 1 is a 5- to 11-membered spiro-heterocyclyl.

[0291] In some embodiments, R 1 is a seven-membered spiro-heterocyclyl.

[0292] In some embodiments, R 1 is oxaspiro[3.3]heptanyl.

[0293] In some embodiments, R 1 is C5~C 11 -spiro-cycloalkyl.

[0294] In some embodiments, R 1 is a C5-C alkyl group optionally substituted with one or more substituents selected from cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino; 11 -spiro-cycloalkyl.

[0295] In some embodiments, R 1 is C5~C 11 -spiro-cycloalkyl.

[0296] In some embodiments, R 1 is a C7-spiro-cycloalkyl.

[0297] In some embodiments, R 1 is spiro[3.3]heptanyl.

[0298] In some embodiments, R 1 is cubanyl-C1-C4-alkylene.

[0299] In some embodiments, R 1 is (cuban-1-yl)methyl.

[0300] In some embodiments, R 1 is a 4- to 8-membered heterobicyclyl-C1-C4-alkylene.

[0301] In some embodiments, R 1 is a six-membered heterobicyclyl-CH2-.

[0302] In some embodiments, R 1 is (2-oxabicyclo[2.1.1]hexanyl)methyl.

[0303] 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.

[0304] One embodiment of the present disclosure is, among others, a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C5-C 11 -spiro-cycloalkyl, and cubanyl-C1-C4-alkylene; Each R 1 The group is optionally substituted with one or more substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, and hydroxyl. Includes. One embodiment is a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3- to 7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, and C5-C 11 -spiro-cycloalkyl, Each R 1 The group is optionally substituted with one or more substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, and hydroxyl. Related to.

[0305] In some embodiments, R 1 is selected from: 1is selected from (C3-C5-cycloalkyl)CD2-, (C3-C5-cycloalkyl)CH2-, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O—C2-C3-alkylene, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C7-spiro-cycloalkyl, and (cubanyl)CH2-; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0306] In some embodiments, R 1 is selected from: 1 is selected from (C3-C5-cycloalkyl)CH2-, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, and C7-spiro-cycloalkyl; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0307] In some embodiments, R 1 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; Each R 1The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0308] In some embodiments, R 1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, and spiro[3.3]heptanyl; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0309] In some embodiments, R 1 is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0310] In some embodiments, R 1is 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 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

[0311] In some embodiments, R 1are (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-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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 (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 and (bicyclo[1.1.1]hexan-1-yl)methyl.

[0312] In some embodiments, R 1are (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-difluorocyclo butyl)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-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.

[0313] In some embodiments, R 1are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclo and (bicyclo[1.1.1]pentan-1-yl)methyl.

[0314] 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.

[0315] In some embodiments, R 1are (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-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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, 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-fluorocyclopropyl)methyl, ((S)-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.

[0316] In some embodiments, R 1are (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)methyl, (1-methylcyclobutyl)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 and (S)-2-fluoropropyl.

[0317] In some embodiments, R 1 are (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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)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.

[0318] In some embodiments, R 1are (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.

[0319] One embodiment is a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is selected from C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O—C2-C4-alkylene, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-C4-alkylene, and C4-C8-bicycloalkyl-C1-C4-alkylene, Each R 1The group is optionally substituted with one or more substituents selected from halogen, C1-C4-haloalkyl, cyano, and hydroxyl. Related to.

[0320] In some embodiments, R 1 is selected from (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-CD2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O—C2-C3-alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, Each R 1 Groups are optionally substituted with one or more substituents selected from halogen, C1-haloalkyl, cyano, and hydroxyl.

[0321] In some embodiments, R 1 is selected from (C3-C4-cycloalkyl)CH2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, Each R 1 Groups are optionally substituted with one or more substituents selected from halogen, C1-haloalkyl, cyano, and hydroxyl.

[0322] In some embodiments, R 1 is selected from (C-C-cycloalkyl)CH-, C-C-cycloalkyl-CD-, C-C-alkyl, C-C-cycloalkyl, C-C-alkyl-O-C-C-alkylene, 4-membered heterocyclyl, and (4-membered heterocyclyl)CH-, Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C1-haloalkyl, cyano, and hydroxyl.

[0323] In some embodiments, R1 is selected from (C3-C4-cycloalkyl)CH2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, C1-haloalkyl, cyano, and hydroxyl.

[0324] In some embodiments, R 1 is selected from methyl, methyl-d3, propyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, and pentyl; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

[0325] In some embodiments, R 1 is selected from methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, pentyl, and (bicyclo[1.1.1]pentanyl)methyl; Each R 1 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

[0326] In some embodiments, R 1is selected from methyl, methyl-d3, propyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 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 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

[0327] 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 The group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

[0328] In some embodiments, R 1are methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoropropyl and (2,2-difluorocyclopropyl)methyl.

[0329] 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.

[0330] In some embodiments, R 1 are methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, and selected from 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.

[0331] In some embodiments, R 1is 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.

[0332] One embodiment is a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is selected from C1-C6-alkyl, C3-C7-cycloalkyl, and C3-C7-cycloalkyl-C1-C4-alkylene, each group optionally substituted with one or more halogen substituents. Related to.

[0333] In some embodiments, R 1 is selected from C1-C6-alkyl, C3-C7-cycloalkyl, and C3-C7-cycloalkyl-C1-C4-alkylene, each group optionally substituted with 1, 2, or 3 halogen substituents.

[0334] In some embodiments, R 1is selected from C2-C3-alkyl, cyclopropyl, C3-C4-cycloalkyl-CD2-, and C3-C4-cycloalkyl-CH2-, each group optionally substituted with 1, 2, or 3 halogen substituents.

[0335] In some embodiments, R 1 is selected from C2-C3-alkyl, cyclopropyl, and C3-C4-cycloalkyl-CH2-, each group optionally substituted with 1, 2, or 3 halogen substituents.

[0336] In some embodiments, R 1 is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents.

[0337] 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.

[0338] In some embodiments, R 1 is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents.

[0339] 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.

[0340] In some embodiments, R 1is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.

[0341] 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.

[0342] In some embodiments, R 1 is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.

[0343] 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.

[0344] In some embodiments, R 1 is a C3-C7-cycloalkyl-C1-C4-alkylene optionally substituted with one or two halogen substituents.

[0345] In some embodiments, R 1is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl, each group optionally substituted with one or two halogen substituents.

[0346] In some embodiments, R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with one or two halogen substituents.

[0347] In some embodiments, R 1 is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl, each group optionally substituted with one or two fluoro substituents.

[0348] In some embodiments, R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with one or two fluoro substituents.

[0349] In some embodiments, R 1 is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.

[0350] In some embodiments, R 1 is selected from (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.

[0351] In some embodiments, R 1 is selected from (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl, each group optionally substituted with one or two halogen substituents.

[0352] In some embodiments, R 1is C1-C6-alkyl optionally substituted with 1, 2, or 3 halogen substituents. 1 is ethyl or propyl, each group optionally substituted with 1, 2, or 3 halogen substituents. 1 is ethyl or propyl, each group optionally substituted with 1, 2, or 3 fluoro substituents. 1 is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl.

[0353] In some embodiments, R 1 is C3-C7-cycloalkyl.

[0354] In some embodiments, R 1 is cyclopropyl.

[0355] 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: [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

[0356] 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-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (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-hydroxycyclobutyric acid) (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 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 (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- (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 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)-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)-9-(ethoxy-d5)-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)-1,3,4,6,7,11 b-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 (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,11b (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-(difluoromethyl)cyclopropyl)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, (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,11 bR)-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]isoquinoline-2- (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,3 (R,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-(t (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 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 6 5); (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-(t (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 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-((1s,3S)-3-(dimethylamino)cyclobutoxy)-10-methoxy-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 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-d3)-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)cyclopro Pan-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 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]isoquinoline-2-ol 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); 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 any combination of pharmaceutically acceptable salts thereof.

[0357] 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-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (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-hydroxycyclobutyric acid) (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 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 (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- (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 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)-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)-9-(ethoxy-d5)-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)-1,3,4,6,7,11 b-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 (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,11b (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1-(difluoromethyl)cyclopropyl)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, (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,11 bR)-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]isoquinoline-2- (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,1 1bR)-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,2R)-2-fluorocyclopropyl)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 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); (2 (R,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); (2 S,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)-2-hydroxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-9-yl)oxy)acetonitrile (Compound 79) 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)cyclobutane-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-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-(3,3-difluorocyclobutoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (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,11 bR)-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 any combination of pharmaceutically acceptable salts thereof.

[0358] Some embodiments of the present invention relate to compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy-d2)-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]isoquinoline-2-ol (compound 99); -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 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) (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 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.and (c)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 106), or any combination thereof.

[0359] Useful intermediates Certain intermediates described hereinabove and hereinafter are novel and useful in the preparation of compounds, for example, compounds of Formula (Ia), Formula (Ic), Formula (Ie), Formula (Ig), Formula (Ii), and Formula (Ik). Certain intermediates are shown in Figures 2A and 2B.

[0360] 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.

[0361] In some embodiments, the compound is 3-(tert-butoxy)-4-(dimethylamino)butan-2-one, or a salt thereof: [ka]

[0362] 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.

[0363] 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.

[0364] 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: [ka]

[0365] 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.

[0366] 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: [ka]

[0367] 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.

[0368] 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: [ka]

[0369] In some embodiments, the salt is (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt. [ka] is.

[0370] 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.

[0371] 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: [ka]

[0372] 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.

[0373] It will 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.

[0374] Pharmaceutical Compositions, Formulations, and Dosage Forms The present disclosure further provides pharmaceutical products, eg, pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound described herein, or a pharmaceutically acceptable salt thereof.

[0375] 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 can 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, 5 th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005).

[0376] Composition can also be formulated as pills, capsules, granules or tablets containing VMAT2 inhibitor, diluent, dispersant and surfactant, binder and lubricant.Those skilled in the art can further formulate VMAT2 inhibitor in suitable manner and according to generally accepted practice, for example according to the practice disclosed in Remington above.

[0377] The method of administration comprises the systemic administration of the VMAT2 inhibitor described herein, preferably in the form of pharmaceutical compositions discussed above.As used herein, systemic administration includes oral and parenteral administration methods.For oral administration, suitable pharmaceutical compositions include powder, granule, pill, tablet and capsule, as well as liquid, syrup, suspension and emulsion.

[0378] 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 give tablets or dragee cores.

[0379] 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.The liquid preparations for oral administration can be in the form of solution, emulsion, aqueous or oily suspension and syrup.Alternatively, oral preparations can be in the form of dry powder, which can be reconstituted with water or other suitable liquid vehicle before use.Non-oral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle, and sterilizing the solution by filtration before lyophilization, or by simply filling into suitable vials or ampoules and sealing them.

[0380] 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.

[0381] 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.

[0382] In preparing pharmaceutical compositions, the drug substance is usually mixed (i.e., blended) with an excipient, diluted with an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient can be a solid, semi-solid, or liquid material, and acts as a vehicle, carrier, or medium for the drug substance. Thus, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsule, suppository, injectable sterile solution, and sterile packaged powder.

[0383] For preparing solid-form pharmaceutical compositions, such as powder, tablet, capsule, cachet, suppository and dispersible granule, additives can be one or more substances that can also act as diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or encapsulating material.Also included are solid-form preparations that are intended to be converted into liquid-form preparations for oral administration immediately before use.Such liquid forms include solutions, suspensions and emulsions.These preparations can also contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. in addition to active ingredients.

[0384] 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, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0385] 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 dispersants or wetting agents and suspending agents.Sterile injectable preparations can also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents.

[0386] 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.

[0387] Pharmaceutical compositions can be formulated as aqueous solutions, aqueous-alcoholic solutions, solid suspensions, emulsions, liposome suspensions, or freeze-dried powders for reconstitution.Such pharmaceutical compositions can be administered directly or as admixtures for further dilution / reconstitution.Administration routes include intravenous bolus, intravenous infusion, irrigation, and drip infusion.

[0388] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents, as desired.

[0389] Aqueous suspensions suitable for oral use can be made by dispersing finely divided drug substance in water along with a viscous material.

[0390] 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.

[0391] The solution or suspension can be directly applied to the nasal cavity by conventional means, for example, a dropper, a pipette, or a spray.The formulation can be provided in the form of a single dose or multiple doses.In the latter case of a dropper or a pipette, administration can be achieved by administering an appropriate, predetermined volume of the solution or suspension to the patient.In the case of a spray, administration can be achieved, for example, by means of a metering atomizing spray pump.

[0392] 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, for example, as a nasal aerosol, or by inhalation, administration can be achieved using, for example, a spray, a nebulizer, a pump nebulizer, an inhalation device, a metered dose inhaler, or a dry powder inhaler.

[0393] 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, for example, lactose, starch, 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.

[0394] The compounds described herein, or pharmaceutically acceptable salts thereof, can also be administered via fast dissolving or slow release compositions, which comprise a biodegradable fast dissolving or slow release carrier.

[0395] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts 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 the unit dosage form can be the appropriate number of any of these packaged forms. 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.

[0396] The compositions can be formulated as unit dosage forms, each dosage containing the drug substance or an equivalent mass of the drug substance. 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 active material calculated to produce the desired therapeutic effect, in association with suitable excipients as described herein.

[0397] Liquid forms containing the drug substance 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 including edible oils.

[0398] 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, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0399] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable additives as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions can 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 a device that delivers the formulation in an appropriate manner.

[0400] The compositions can also be presented in a pack or dispenser device, if desired, which can contain one or more unit dosage forms containing the drug substance. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can 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, which notice reflects the agency's approval of the drug in this form for human or veterinary administration. Such notice can be, for example, a label approved by the US Food and Drug Administration for prescription drugs or an approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0401] 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 may be readily subdivided into equally effective unit dosage forms, e.g., tablets and capsules.

[0402] The kit with unit dose of one or more compounds described herein or its pharmaceutically acceptable salts is provided, usually in oral or injectable dose.Such kit can include a container that contains unit dose, an information package insert that describes the use of drug in treating the target pathological condition and its associated advantages, and optionally, the instrument or device for delivering the composition.

[0403] The compounds described herein, or their pharmaceutically acceptable salts, can be effective over a wide range of dosages and are generally administered in a therapeutically effective amount.However, it is understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound to be administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0404] 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, for example, the severity of the disease, the age, weight, and general condition of the subject, etc.

[0405] The desired dose can be conveniently presented in a single dose, or can be presented as a divided dose, which is administered at appropriate intervals, for example, 2, 3, 4 or more sub-doses per day.The sub-dose itself can be further divided, for example, into several separate administrations that are roughly spaced apart.The daily dose can be divided into several, for example, 2, 3 or 4 separate administrations, especially when a relatively large amount is administered as deemed appropriate.If appropriate, it may be necessary to deviate upward or downward from the indicated daily dose, depending on individual behavior.

[0406] It will be apparent to one of ordinary skill in the art that the dosage forms described herein can comprise a compound described herein or a pharmaceutically acceptable salt thereof.

[0407] 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.

[0408] 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 can be a co-crystal or salt of the compounds disclosed and described herein.

[0409] Some embodiments provide preparations comprising the compounds disclosed and described herein. In some embodiments, the compounds are components 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] How to use The compounds described herein are inhibitors of VMAT2. Thus, the present disclosure includes a method of inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing the 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, for example, where VMAT2 is located in a purified preparation, or in a cell outside of a living organism (e.g., a tissue sample or cell preparation). In some embodiments, contacting can occur in vivo, for example, where VMAT2 is located inside a living organism.

[0415] The VMAT2 inhibitors described herein can reduce the level of monoamines in the central nervous system.Accordingly, the present disclosure includes a method for reducing the level of monoamines 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 level of monoamines compared to the level before administration.

[0416] The VMAT2 inhibitors disclosed and described herein are believed to be useful across a wide range of therapeutic applications and can be used to treat or prevent a variety of disorders caused by or associated with the 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 therapeutic methods disclosed and described herein.

[0417] Therefore, various embodiments disclosed herein provide a method for treating or preventing a neurological disease or disorder and / or a psychiatric disease or disorder in a subject in need thereof by administering a pharmaceutically effective amount of a VMAT2 inhibitor described herein or a pharmaceutically acceptable salt thereof to the subject.The neurological disease or disorder and / or a psychiatric disease or disorder may 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 tremor ataxia syndrome, autism spectrum disorder (e.g., restricted and repetitive behaviors associated with autism spectrum disorder (ASD)), Rett syndrome, or acanthocyocytosis.

[0418] In various other embodiments disclosed herein, a method is provided for treating or preventing vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder in a subject in need thereof by administering a pharmaceutically effective amount of the VMAT2 inhibitor described herein or a pharmaceutically acceptable salt thereof to the subject.The VMAT2 disease or VMAT2 disorder can be, for example, ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity, or abnormality; dementia; oral cavity, salivary gland, or jaw disease; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; epilepsy; addictive or impulse disorder; Huntington's disease or related disorder; mood or psychiatric disorder; neurotic, stress-related, and somatoform disorder; degenerative disease of the basal ganglia; extrapyramidal and movement disorder; neurological or psychiatric disease or disorder; nervous system or motor dysfunction disorder; Parkinson's / parkinsonism disorder; childhood-onset behavioral and emotional disorder; pervasive developmental disorder; and substance abuse or dependency disorder.

[0419] Therefore, various embodiments disclosed herein provide a method for treating or preventing hyperkinetic movement disorder in a subject in need thereof by administering a pharmaceutically effective amount of the VMAT2 inhibitor described herein or a pharmaceutically acceptable salt thereof to the subject in need thereof.In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia, Tourette's syndrome, Huntington's disease, Huntington's disease with chorea, or tic.In other embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, or tremor.

[0420] In some embodiments, provided herein is a method for treating or preventing mood disorder in a subject in need thereof, by administering a pharmaceutically effective amount of the VMAT2 inhibitor described herein or its pharmaceutically acceptable salt to the subject in need thereof.In some embodiments, the mood disorder is bipolar disorder, major depressive disorder, mania in mood disorder, or depression in mood disorder.

[0421] In some embodiments disclosed herein, there is provided a method for treating or preventing schizophrenia or schizoaffective disorder in a subject in need thereof, by administering a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0422] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

[0423] In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia.

[0424] In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome.

[0425] In some embodiments, the hyperkinetic movement disorder is Huntington's disease.

[0426] In some embodiments, the hyperkinetic movement disorder is a tic.

[0427] In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0428] In some embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

[0429] In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder.

[0430] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.

[0431] In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is schizoaffective disorder.

[0432] In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.

[0433] In some embodiments, the neurological or psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder.

[0434] In some embodiments, the neurological or psychiatric disease or disorder is an autism spectrum disorder.

[0435] In some embodiments, the neurological or psychiatric disease or disorder is restricted and repetitive behaviors associated with autism spectrum disorder (ASD).

[0436] 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 adjunctive treatment for schizophrenia. In some embodiments, the compounds described herein are administered as adjunctive therapy, and the primary therapy is treatment with an antidepressant.

[0437] In some embodiments, the neurological disease or disorder or psychiatric disease or disorder is type I bipolar disorder.In some embodiments, the compound described herein is administered as monotherapy for the treatment of type I bipolar disorder.In some embodiments, the compound described herein is administered as maintenance therapy for the treatment of type I bipolar disorder.In some embodiments, the compound described herein is administered as monotherapy maintenance therapy for the treatment of type I bipolar disorder.

[0438] 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, rheumatoid / 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, Sjögren-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; Dyskinesia, for example, pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and respiratory dyskinesia; Dystonias, e.g., blepharospasm, buccoglossal syndrome, acute drug-induced dystonia, dystonia, early-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 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 such as sleep-related bruxism, abnormal involuntary movement disorders, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, chronic hemifacial spasm, olfactory nerve agenesis, congenital cranial nerve palsies, exercise ataxia syndrome, familial periodic paralysis, congenital 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, awkward posture, 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 syndrome, pervasive developmental disorder (NOS), and dyslexia; and Substance abuse or dependence, for example, 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.

[0439] In some embodiments, the 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.

[0440] In some embodiments, the motor paralysis is spastic cerebral palsy.

[0441] In some embodiments, the motor paralysis is dyskinetic cerebral palsy.

[0442] In some embodiments, the motor paralysis is ataxic cerebral palsy.

[0443] In some embodiments, the motor palsy is "mixed" cerebral palsy.

[0444] The phrase "mixed" cerebral palsy includes a mixture of symptoms associated with other types of cerebral palsy.

[0445] In some embodiments, the patient to be treated is determined to have 22q11.2 deletion syndrome.In some embodiments, because the patient has 22q11.2 deletion syndrome, the patient is predisposed to developing mental disorders.In some embodiments, the patient is determined to have COMT haploinsufficiency.In some embodiments, because the patient has COMT haploinsufficiency, the patient is predisposed to developing mental disorders.

[0446] In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in a mammalian body to compounds that can inhibit human vesicular monoamine transporter isoform 2. Thus, these VMAT2 inhibitors can have additional utility in modifying the in vivo properties of metabolites, such as maximum concentration or duration of action, in a mammal.

[0447] The characterization of any of the VMAT2 inhibitors described herein can be determined using the method described herein and the method in the art.For example, dopamine depletion can be determined using locomotor activity (LMA) assay.Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has been shown to be an effective and reliable preclinical model for evaluating the antipsychotic activity of compounds.

[0448] 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.

[0449] 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.

[0450] 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, which methods 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 treatises 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.

[0451] 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. [Example]

[0452] The following examples are included to demonstrate embodiments of the present disclosure. However, those skilled in the art will recognize in light of this disclosure 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 the symbols have the same definitions as those used throughout this disclosure.

[0453] 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 liquid chromatography mass spectrometry (LCMS) system C using an ACN / water gradient containing 0.05% TFA. 18Purification was performed on a Kinetix 5μ 100A 150 × 21.2 mm column (Phenomenex). 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 gradient of 0.3% NH4OH in CO2 and 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-d6 (DMSO-d6), on a Bruker 400 MHz spectrometer equipped with a broadband NMR probe or on a Bruker 500 MHz spectrometer equipped with a 5 mm QNP probe with Z-gradient. 1 H chemical signals are given in parts per million (ppm) using the residual solvent signal as reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Reactions were carried out under a dry nitrogen atmosphere unless otherwise stated.

[0454] 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). [ka] Step 1: Preparation of N,N,N-trimethyl-3-oxobutan-1-aminium iodide (compound 2-2). [ka]

[0455] 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. 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-d6): 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).

[0456] 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). [ka]

[0457] 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), N,N,N-trimethyl-3-oxobutan-1-aminium iodide (compound 2-2, 13.3 g, 51.8 mmol, 1.5 equiv.) was added, 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 packed 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 packed with DCM and run with an increasing gradient of EtOAc in hexane (0-100% over 20 min) to further purify the mixed fractions, affording (±)-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-d6): 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).

[0458] 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). [ka]

[0459] 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 NaHCO3 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 give (±)-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.

[0460] 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). [ka]

[0461] 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 min. The mixture was warmed to RT and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 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)).

[0462] 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). [ka]

[0463] 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, and then tosyl azide (1.27 g, 6.42 mmol) was added. 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 MgSO4, 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-d6): 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).

[0464] 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). [ka]

[0465] 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 at 80° C. with stirring for 2 hours. 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 to 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-d6): 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).

[0466] 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. [ka]

[0467] 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) was added NaBH (4.6 mg, 0.121 mmol, 1.5 equiv.) at 0 °C. The mixture was warmed to RT and stirred overnight. The reaction mixture was quenched with water and extracted three times with DCM. The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. A silica gel column (4 g) was packed with DCM 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% CO2 and 15% MeOH at 150 mL / min, 55°C, and a backpressure regulator of 110 bar.

[0468] 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 among 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).

[0469] 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). [ka] Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15). [ka]

[0470] 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 (6N, 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 H2SO4. The aqueous layer was extracted five times with MTBE. The combined organic extracts were dried over MgSO4, 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. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

[0471] 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). [ka]

[0472] 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. The aqueous layer was extracted three times with MTBE. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to produce 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 with 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. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.46 - 7.31 (m, 5H), 6.81 (s, 1H), 6.75 (s, 1H), 5.03 (s, 2H), 4.37 (dd, J = 7.0, 10.9 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).

[0473] (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). [ka] 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 (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, 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 to 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%).

[0474] (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) was added dropwise DIBAL-H (1.0 M in hexanes, 42.8 mL, 42.8 mmol, 1.5 equiv.) at 0° C. 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 give 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).

[0475] 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). [ka]

[0476] Chromatography of compound (±)-2-19 (0.432 g, 1.05 mmol, 1.4:1 dr) afforded diastereomerically pure compound (±)-2-20. A silica gel column (4 g) was packed with DCM 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-d6): δ (ppm) 7.45 - 7.41 (m, 2H), 7.41 - 7.37 (m, 2H), 7.34 - 7.31 (m, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 5.01 (s, 2H), 4.61 (d, J = 4.7 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).

[0477] 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). [ka]

[0478] 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, 6.5:1 dr, 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 NH4OH until the pH was approximately 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO, 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. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.45 - 7.41 (m, 2H), 7.41 - 7.37 (m, 2H), 7.34 - 7.31 (m, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 5.01 (s, 2H), 4.61 (d, J = 4.7 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).

[0479] 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). [ka]

[0480] 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 minutes. 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 cooled 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. An 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.

[0481] 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).

[0482] (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.

[0483] The crystal structure of compound 2-21·DPTTA is shown in formula C 25 H 34 NO4·C 20 H 17 The solvate was determined to be a mixed ethanol and methanol solvate with an NMR δ of O8 0.851 (C2H6O) 0.149 (C4O). The solvate was refined as being primarily ethanol and minorly 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. The data collection and refinement parameters for compound 2-21·DPTTA are shown in Table 2. [Table 1-1] [Table 1-2] [Table 2]

[0484] Example 4A Preparation of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (compound 2-16). [ka]

[0485] 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), HCl (4 M in dioxane, 22.7 mL, 91.0 mmol, 1.05 equiv.) was added 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-d6): δ (ppm) 12.94 (br s, 1H), 8.94 (s, 1H), 7.54 (s, 1H), 7.49 - 7.46 (m, 2H), 7.45 - 7.40 (m, 2H), 7.40 - 7.35 (m, 1H), 7.29 (s, 1H), 5.27 (s, 2H), 3.88 - 3.84 (m, 2H), 3.81 (s, 3H), 3.06 (t, J = 8.4 Hz, 2H).

[0486] 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). [ka]

[0487] 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:HO (20 mL), aqueous HCl (12.1 M, 0.47 mL, 5.69 mmol, 1.2 equiv.) was added dropwise with stirring at 0 °C. The mixture was stirred for 10 min. 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 min. 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-d6): 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).

[0488] 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). [ka] Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (compound 2-15). [ka]

[0489] 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, aqueous 6 N NaOH (173 mL, 1040 mmol, 2.1 equiv.) was added 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 H2SO4 (18.1 M) and extracted five times with MTBE. The combined organic extracts were dried over MgSO4, 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. 1 H NMR (500 MHz, DMSO-d6): δ (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

[0490] Step 2: Preparation of 1-(tert-butoxy)propan-2-one (compound 2-25). [ka]

[0491] 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 with a boiling point of 50° C. at 12 mmHg. 1 H NMR (400 MHz, CDCl3): δ (ppm) 3.96 (s, 2H), 2.20 (s, 3H), 1.25 (s, 9H).

[0492] Step 3: Preparation of 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (compound 2-26). [ka]

[0493] 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. 1H NMR (400 MHz, DMSO-d6): 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).

[0494] 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). [ka]

[0495] 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 h 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%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.46 - 7.31 (m, 5H), 6.81 (s, 1H), 6.75 (s, 1H), 5.03 (s, 2H), 4.37 (dd, J = 7.0, 10.9 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).

[0496] 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). [ka]

[0497] 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., DIBAL-H (1.0 M in hexanes, 75.4 mL, 75.4 mmol, 1.5 equiv) was added 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 vigorously stirred until the emulsion dissipated. The mixture was extracted three times with MTBE. The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give 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).

[0498] 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). [ka]

[0499] 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 further heating turned it into 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 min. The mixture was cooled to RT at a rate of 8 °C per hour and then continuously stirred for 16 h. The resulting precipitate was collected by vacuum filtration, washed with MTBE (100 mL) and EtOH (40 mL), and dried in vacuo for 16 h 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 NH4OH until the pH was approximately 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO, 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. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.45 - 7.41 (m, 2H), 7.41 - 7.37 (m, 2H), 7.34 - 7.31 (m, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 5.01 (s, 2H), 4.61 (d, J = 4.7 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).

[0500] 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). [ka]

[0501] 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:HO (42 mL), aqueous HCl (12.1 M, 1.97 mL, 23.8 mmol, 1.2 equiv.) was added dropwise with stirring at 0 °C. The mixture was stirred for 10 min. 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 min. 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 to pH = 8 with aqueous NaOH (6 M), 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-d6): 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).

[0502] 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). [ka]

[0503] 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), cesium carbonate (0.183 g, 0.561 mmol, 3.0 equiv.) was added, 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: a silica gel column (4 g) was packed using DCM and run with an increasing gradient of EtOAc in hexane (0-60% over 20 min), a silica gel column (4 g) was packed using DCM and run with an increasing gradient of EtOAc (0-70% over 25 min), and a reversed-phase C column was packed using DMSO. 18 A column (6 g) was packed 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] + . 1H NMR (500 MHz, DMSO-d6): δ (ppm) 6.83 (s, 1H), 6.78 (s, 1H), 4.66 - 4.58 (m, 3H), 3.76 (s, 3H), 3.38 - 3.26 (m, 2H), 3.04 (br d, J = 11.0 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). 【050...

Claims

1. Compounds of formula (Ia): 【Chemical 57】 or a pharmaceutically acceptable salt thereof, wherein: 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, Each R １ The group is 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.

2. Formula (Ic): 【Chemistry 58】 or a pharmaceutically acceptable salt thereof.

3. Formula (Ie): 【Chemical Formula 59】 or a pharmaceutically acceptable salt thereof.

4. Formula (Ig): 【Chemistry 60】 or a pharmaceutically acceptable salt thereof.

5. Formula (Ii): 【Hua 61】 or a pharmaceutically acceptable salt thereof.

6. Formula (Ik): 【Hua 62】 or a pharmaceutically acceptable salt thereof.

7. R １ But 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 The group is 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 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -dialkylamino.

8. R １ But 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 The group is 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 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -alkoxy.

9. R １ But 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 The group is 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 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -alkoxy.

10. R １ But 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 - is selected from, Each R １ The group is 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 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -alkoxy.

11. R １ But 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 The group is 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 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -alkoxy.

12. R １ But 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 - is selected from, Each R １ The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

13. R １ But 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 The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

14. R １ But 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 - is selected from, Each R １ The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

15. R １ But 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 The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

16. R １ But 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 - is selected from, Each R １ The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

17. R １ But 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 The group is cyanomethyl, fluoro, methyl, C １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.

18. R １ (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.

19. R １ 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.

20. R １ (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.

21. R １ 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.

22. R １ (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.

23. R １ 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.

24. R １ (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.

25. R １ 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.

26. R １ (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.

27. 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.

28. R １ (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.

29. 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.

30. R １ (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.

31. 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.

32. R １ (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.

33. 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.

34. R １ (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-trifluoro oropentyl, (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-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3 -(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-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,The compound according to any one of claims 1 to 6, wherein the compound is selected from (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.

35. R １ (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 propyl, (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-ene-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-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,The compound according to any one of claims 1 to 6, wherein the compound is selected from (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.

36. R １ (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]hepta cyclobutyl, 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-difluorocyclopentan-6-yl). (1-cyanocyclobutyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, 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,The compound according to any one of claims 1 to 6, wherein the compound is selected from (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.

37. R １ (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-trifluoro fluorobutyl, 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-fluoro Cyclobut-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,The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

38. R １ (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-trifluoro tetrafluoropentyl, (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-cyanocyclobutyric acid cyclobutyl, (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)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from (1r,3R)-3-methoxycyclobutyl, (1r,3R)-3-(dimethylamino)cyclobutyl, (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.

39. R １ (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) (R)-oxetan-2-yl)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-difluoro (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, (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-cyanocyclobutyl)methyl, 7. The compound of any one of claims 1 to 6, wherein the compound is selected from (1-(methylsulfonyl)cyclopropyl)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.

40. R １ (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-fluoro cyclobutyl, (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-cyclobutyl ethyl, (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-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]pentane-1 7. The compound according to 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, (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.

41. R １ (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, cyclopropyl)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-fluorocyclobutene ter-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 7. The compound of any one of claims 1 to 6, wherein the hydroxyl group is selected from 3,3,3-trifluoro-2-hydroxypropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3-difluorocyclobutyl ...

42. R １ But cyano-C １ ~C ４ -Alkylene, halogen, hydroxyl, C １ ~C ４ -haloalkyl, C １ ~C ４ - alkyl, cyano, and C １ ~C ４ -C optionally substituted with one or more substituents selected from alkylsulfonyl ３ ~C ７ -cycloalkyl-C １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

43. R １ But cyano-C １ ~C ４ -Alkylene, halogen, hydroxyl, C １ ~C ４ -haloalkyl, C １ ~C ４ C optionally substituted with one or more substituents selected from alkyl, and cyano ３ ~C ７ -cycloalkyl-C １ ~C ４ - alkylene, or a pharmaceutically acceptable salt thereof.

44. R １ But cyano-C １ ~C ４ -Alkylene, halogen, hydroxyl, C １ ~C ４ -haloalkyl, C １ ~C ４ C optionally substituted with 1, 2, or 3 substituents selected from alkyl, and cyano ３ ~C ７ -cycloalkyl-C １ ~C ４ - alkylene, or a pharmaceutically acceptable salt thereof.

45. R １ cyanomethyl, halogen, hydroxyl, C １ C optionally substituted with 1, 2, or 3 substituents selected from haloalkyl, methyl, cyano, and methylsulfonyl ３ ~C ５ -cycloalkyl-C １ ~C ２ - alkylene, or a pharmaceutically acceptable salt thereof.

46. R １ cyanomethyl, halogen, hydroxyl, C １ -C optionally substituted with 1, 2, or 3 substituents selected from haloalkyl, methyl, and cyano ３ ~C ５ -cycloalkyl-C １ ~C ２ - alkylene, or a pharmaceutically acceptable salt thereof.

47. R １ (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, or a pharmaceutically acceptable salt thereof.

48. 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, or a pharmaceutically acceptable salt thereof.

49. R １ (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, or a pharmaceutically acceptable salt thereof.

50. 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, or a pharmaceutically acceptable salt thereof.

51. R １ (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.

52. R １ are (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 aryl group is selected from aryl, (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.

53. R １ (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.

54. 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; or a pharmaceutically acceptable salt thereof.

55. R １ (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.

56. R １ However, (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.

57. R １ (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.

58. R １ are (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 43. The compound of claim 42, wherein the compound is selected from (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.

59. R １ (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ 43. The compound of claim 42, wherein the aryl group is selected from (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

60. R １ is selected from (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

61. R １ is halogen, hydroxyl, cyano, C １ ~C ４ -alkoxy, and C １ ~C ４ -C optionally substituted with one or more substituents selected from alkylsulfonyl １ ~C ６ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: - is - alkyl.

62. R １ is halogen, hydroxyl, cyano, and C １ ~C ４ -C optionally substituted with one or more substituents selected from -alkoxy １ ~C ６ - alkyl, or a pharmaceutically acceptable salt thereof.

63. R １ is halogen, hydroxyl, cyano, and C １ ~C ４ -C optionally substituted with 1, 2, 3, or 4 substituents selected from -alkoxy １ ~C ６ - alkyl, or a pharmaceutically acceptable salt thereof.

64. R １ is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, methoxy, and methylsulfonyl; １ ~C ５ - alkyl, or a pharmaceutically acceptable salt thereof.

65. R １ is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxyl, cyano, and methoxy; １ ~C ５ - alkyl, or a pharmaceutically acceptable salt thereof.

66. R １ 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, or a pharmaceutically acceptable salt thereof.

67. 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, or a pharmaceutically acceptable salt thereof.

68. R １ 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, or a pharmaceutically acceptable salt thereof.

69. 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, or a pharmaceutically acceptable salt thereof.

70. R １ 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, or a pharmaceutically acceptable salt thereof.

71. 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; or a pharmaceutically acceptable salt thereof.

72. R １ 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, or a pharmaceutically acceptable salt thereof.

73. 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; or a pharmaceutically acceptable salt thereof.

74. R １ 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.

75. R １ 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 62. The compound of claim 61, wherein the aryl group is selected from aryl, 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.

76. R １ 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.

77. 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.

78. R １ 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl, and ethyl-d ５ 62. The compound of claim 61 selected from:

79. R １ 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl.

80. R １ But cyano, halogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, C １ ~C ４ -alkoxy, and C ２ ~C ４ -C optionally substituted with one or more substituents selected from dialkylamino ３ ~C ７ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: -cycloalkyl.

81. R １ But cyano, halogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, and C １ ~C ４ -C optionally substituted with one or more substituents selected from -alkoxy ３ ~C ７ -cycloalkyl; or a pharmaceutically acceptable salt thereof.

82. R １ But cyano, halogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, and C １ ~C ４ -C optionally substituted with 1 or 2 substituents selected from -alkoxy ３ ~C ７ -cycloalkyl; or a pharmaceutically acceptable salt thereof.

83. R １ But cyano, halogen, methyl, C １ C optionally substituted with 1 or 2 substituents selected from haloalkyl, methoxy, and dimethylamino ３ ~C ５ -cycloalkyl; or a pharmaceutically acceptable salt thereof.

84. R １ But cyano, halogen, methyl, C １ C optionally substituted with 1 or 2 substituents selected from haloalkyl, and methoxy ３ ~C ７ -cycloalkyl; or a pharmaceutically acceptable salt thereof.

85. 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, or a pharmaceutically acceptable salt thereof.

86. R １ is selected from cyclopentyl, cyclobutyl, and cyclopropyl, each group optionally substituted with one or two substituents selected from cyano, fluoro, methyl, trifluoromethyl, and methoxy, or a pharmaceutically acceptable salt thereof.

87. 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, or a pharmaceutically acceptable salt thereof.

88. 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, or a pharmaceutically acceptable salt thereof.

89. 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; or a pharmaceutically acceptable salt thereof.

90. 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; or a pharmaceutically acceptable salt thereof.

91. R １ is cyano, halogen, and C ３ ~C ６ -C optionally substituted with one or more substituents selected from -cycloalkyl １ ~C ４ -Alkyl-O-C ２ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

92. R １ is optionally substituted with one or more substituents selected from cyano, halogen, and cyclopropyl; １ ~C ３ -Alkyl-O-C ２ ~C ３ - alkylene, or a pharmaceutically acceptable salt thereof.

93. R １ is optionally substituted with 1, 2, or 3 substituents selected from cyano, halogen, and cyclopropyl; １ ~C ３ -Alkyl-O-C ２ ~C ３ - alkylene, or a pharmaceutically acceptable salt thereof.

94. 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, or a pharmaceutically acceptable salt thereof.

95. 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, or a pharmaceutically acceptable salt thereof.

96. 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, or a pharmaceutically acceptable salt thereof.

97. R １ is C ３ ~C ７ -cycloalkyl-O-C ２ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

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

99. R １ One or more C １ ~C ４ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein - is 3- to 7-membered heterocyclyl optionally substituted with an alkyl substituent.

100. R １ However, one or more C １ ~C ４ - 4-5 membered heterocyclyl optionally substituted with alkyl substituents; or a pharmaceutically acceptable salt thereof.

101. R １ is one C １ ~C ４ - 4-5 membered heterocyclyl optionally substituted with alkyl substituents; or a pharmaceutically acceptable salt thereof.

102. R １ 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein is 4-membered heterocyclyl.

103. R １ 100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein is oxetan-3-yl or pyrrolidin-3-yl, each group optionally substituted with one methyl substituent.

104. R １ 100. The compound of claim 99, wherein is oxetan-3-yl or 1-methylpyrrolidin-3-yl, or a pharmaceutically acceptable salt thereof.

105. R １ However, one or more C １ ~C ４ -3- to 7-membered heterocyclyl-C optionally substituted with alkyl substituents １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

106. R １ is optionally substituted with one or more methyl substituents; ２ -, or a pharmaceutically acceptable salt thereof.

107. R １ is optionally substituted with one or more methyl substituents; ２ -, or a pharmaceutically acceptable salt thereof.

108. R １ is (4- to 5-membered heterocyclyl)CH optionally substituted with one methyl substituent ２ -, or a pharmaceutically acceptable salt thereof.

109. R １ is optionally substituted with one methyl substituent; ２ -, or a pharmaceutically acceptable salt thereof.

110. R １ 106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein is (oxetanyl)methyl or (silolanyl)methyl, each group optionally substituted with one or two methyl substituents.

111. R １ 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, or a pharmaceutically acceptable salt thereof.

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

113. 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, or a pharmaceutically acceptable salt thereof.

114. R １ is selected from (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl, or a pharmaceutically acceptable salt thereof.

115. R １ is selected from oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl, and (1,1-dimethylsiloran-3-yl)methyl, or a pharmaceutically acceptable salt thereof.

116. R １ is selected from oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl, or a pharmaceutically acceptable salt thereof.

117. R １ but halogen and C １ ~C ４ -C optionally substituted with one or more substituents selected from haloalkyl ４ ~C ８ -bicycloalkyl-C １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

118. R １ is optionally substituted with one or more substituents selected from fluoro and trifluoromethyl (C ５ ~C ６ -bicycloalkyl)CH ２ -, or a pharmaceutically acceptable salt thereof.

119. R １ is optionally substituted with one substituent selected from fluoro and trifluoromethyl (C ５ ~C ６ -bicycloalkyl)CH ２ -, or a pharmaceutically acceptable salt thereof.

120. 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, or a pharmaceutically acceptable salt thereof.

121. 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, or a pharmaceutically acceptable salt thereof.

122. 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.

123. R １ is optionally substituted with one or more halogen substituents ４ ~C ８ -bicycloalkyl-C １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

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

125. R １ is optionally substituted with one fluoro substituent (C ５ -bicycloalkyl)CH ２ -, or a pharmaceutically acceptable salt thereof.

126. R １ 124. The compound of claim 123, wherein is (bicyclo[1.1.1]pentanyl)methyl optionally substituted with one fluoro substituent; or a pharmaceutically acceptable salt thereof.

127. R １ is (bicyclo[1.1.1]pentan-1-yl)methyl optionally substituted with one fluoro substituent; or a pharmaceutically acceptable salt thereof.

128. R １ 124. The compound of claim 123, wherein is (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, or a pharmaceutically acceptable salt thereof.

129. R １ C optionally substituted with one or more halogen substituents ４ ~C ７ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: -cycloalkenyl.

130. R １ C optionally substituted with one halogen substituent ４ -cycloalkenyl, or a pharmaceutically acceptable salt thereof.

131. R １ 130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein is cyclobutenyl optionally substituted with one fluoro substituent.

132. R １ 130. The compound of claim 129, wherein is cyclobut-2-en-1-yl optionally substituted with one fluoro substituent, or a pharmaceutically acceptable salt thereof.

133. R １ 130. The compound of claim 129, or a pharmaceutically acceptable salt thereof, wherein is 3-fluorocyclobut-2-en-1-yl.

134. R １ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is 5-11 membered spiro-heterocyclyl.

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

136. R １ 135. The compound of claim 134, or a pharmaceutically acceptable salt thereof, wherein is oxaspiro[3.3]heptanyl.

137. R １ 135. The compound of claim 134, wherein is 2-oxaspiro[3.3]heptan-6-yl, or a pharmaceutically acceptable salt thereof.

138. R １ is C ５ ~C １１ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is -spiro-cycloalkyl.

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

140. R １ 139. The compound of claim 138, or a pharmaceutically acceptable salt thereof, wherein is spiro[3.3]heptanyl.

141. R １ 139. The compound of claim 138, wherein is spiro[3.3]heptan-2-yl, or a pharmaceutically acceptable salt thereof.

142. R １ is cubanyl-C １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

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

144. R １ 4- to 8-membered heterobicyclyl-C １ ~C ４ 7. The compound of claim 1, wherein R is -alkylene, or a pharmaceutically acceptable salt thereof.

145. R １ is a 6-membered heterobicyclyl-CH ２ -, or a pharmaceutically acceptable salt thereof.

146. R １ 145. The compound of claim 144, wherein is (2-oxabicyclo[2.1.1]hexanyl)methyl, or a pharmaceutically acceptable salt thereof.

147. R １ 145. The compound of claim 144, wherein 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.

148. Formula (Ie): 【Chemistry 63】 10. The compound of claim 1, wherein: 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, 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 The group is halogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, cyano, C ３ ~C ６ - optionally substituted with one or more substituents selected from cycloalkyl, and hydroxyl; compound.

149. R １ But 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 The group is halogen, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, cyano, C ３ ~C ６ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from: -cycloalkyl, and hydroxyl.

150. R １ However, (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 １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

151. R １ However, (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 １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

152. R １ (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 １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

153. R １ is selected from (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, and spiro[3.3]heptanyl; and each R １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

154. R １ (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 １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

155. 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; and each R １ 149. The compound of claim 148, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.

156. R １ (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.

157. R １ However, (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, wherein the compound is selected from (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, and 2-fluoropropyl; or a pharmaceutically acceptable salt thereof.

158. R １ (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.

159. 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; or a pharmaceutically acceptable salt thereof.

160. R １ (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.

161. R １ (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 pyryl, (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-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-methyl cyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, and (S)-2-fluoropropyl. The compound of claim 148, or a pharmaceutically acceptable salt thereof.

162. R １ (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.

163. R １ (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.

164. Formula (Ie): 【Hua 64】 10. The compound of claim 1, wherein: 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, 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 The group is halogen, C １ ~C ４ - optionally substituted with one or more substituents selected from haloalkyl, cyano, and hydroxyl; compound.

165. R １ However, (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 - is selected from, Each R １ The group is halogen, C １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from haloalkyl, cyano, and hydroxyl.

166. R １ However, (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 - is selected from, Each R １ The group is halogen, C １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents selected from haloalkyl, cyano, and hydroxyl.

167. R １ However, (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 - is selected from, Each R １ The group is halogen, C １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, and hydroxyl.

168. R １ However, (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 The group is halogen, C １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, cyano, and hydroxyl.

169. R １ But 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 １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

170. R １ is selected from methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, pentyl, and (bicyclo[1.1.1]pentanyl)methyl; and each R １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

171. R １ But 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 １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

172. 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 １ 165. The compound of claim 164, or a pharmaceutically acceptable salt thereof, wherein the group is optionally substituted with 1, 2, 3, or 4 substituents selected from fluoro, hydroxyl, cyano, and difluoromethyl.

173. R １ But 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.

174. R １ 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.

175. R １ But 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.

176. R １ 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.

177. Formula (Ie): 【Chemistry 65】 10. The compound of claim 1, wherein: R １ is 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. R １ But 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; or a pharmaceutically acceptable salt thereof.

179. R １ But C ２ ~C ３ -Alkyl, cyclopropyl, C ３ ~C ４ -cycloalkyl-CD ２ -, and C ３ ~C ４ -cycloalkyl-CH ２ -, wherein each group is optionally substituted with 1, 2, or 3 halogen substituents; or a pharmaceutically acceptable salt thereof.

180. R １ But C ２ ~C ３ -Alkyl, cyclopropyl, and C ３ ~C ４ -cycloalkyl-CH ２ -, wherein each group is optionally substituted with 1, 2, or 3 halogen substituents; or a pharmaceutically acceptable salt thereof.

181. R １ is ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents; or a pharmaceutically acceptable salt thereof.

182. R １ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 halogen substituents; or a pharmaceutically acceptable salt thereof.

183. R １ is ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents; or a pharmaceutically acceptable salt thereof.

184. R １ is selected from ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl, each group optionally substituted with 1, 2, or 3 fluoro substituents; or a pharmaceutically acceptable salt thereof.

185. R １ 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ 178. The compound of claim 177, wherein the compound is selected from (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

186. 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; or a pharmaceutically acceptable salt thereof.

187. R １ 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ 178. The compound of claim 177, wherein the compound is selected from (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

188. 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.

189. R １ C optionally substituted with one or two halogen substituents ３ ~C ７ -cycloalkyl-C １ ~C ４ - alkylene, or a pharmaceutically acceptable salt thereof.

190. R １ (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ and (cyclobutyl)methyl, each group optionally substituted with 1 or 2 halogen substituents; or a pharmaceutically acceptable salt thereof.

191. R １ 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with 1 or 2 halogen substituents.

192. R １ (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ and (cyclobutyl)methyl, each group optionally substituted with 1 or 2 fluoro substituents; or a pharmaceutically acceptable salt thereof.

193. R １ 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein is (cyclopropyl)methyl or (cyclobutyl)methyl, each group optionally substituted with 1 or 2 fluoro substituents.

194. R １ (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ 190. The compound of claim 189, wherein the compound is selected from (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

195. R １ 190. The compound of claim 189, or a pharmaceutically acceptable salt thereof, wherein is selected from (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.

196. R １ (cyclopropyl)methyl, (cyclopropyl)methyl-d ２ 190. The compound of claim 189, wherein the compound is selected from (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof.

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

198. R １ is optionally substituted with 1, 2, or 3 halogen substituents; １ ~C ６ - alkyl, or a pharmaceutically acceptable salt thereof.

199. R １ 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein is ethyl or propyl, each group optionally substituted with 1, 2, or 3 halogen substituents.

200. R １ 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein is ethyl or propyl, each group optionally substituted with 1, 2, or 3 fluoro substituents.

201. R １ 200. The compound of claim 198, or a pharmaceutically acceptable salt thereof, wherein is selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl.

202. R １ is C ３ ~C ７ -cycloalkyl; or a pharmaceutically acceptable salt thereof.

203. R １ 203. The compound of claim 202, or a pharmaceutically acceptable salt thereof, wherein is cyclopropyl.

204. 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.

205. 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.

206. 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.

207. 207. A pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof.

208. A pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

209. 207. A pharmaceutical composition comprising a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

210. 207. A method for preparing a pharmaceutical composition, comprising admixing a compound of any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

211. A method for treating a vesicular monoamine transporter 2 (VMAT2) disease or disorder in a subject in need of 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.

212. 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 diseases; 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.

213. A method for treating a neurological disorder or nerve disorder or mental disorder or psychiatric disorder in a subject requiring treatment thereof, the method comprising administering to the subject 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.

214. A method for treating a neurological disorder or nerve disorder or mental disorder or psychiatric disorder in a subject requiring treatment thereof, the method comprising administering to the subject 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, wherein the neurological disorder or nerve disorder or mental disorder or psychiatric 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-related tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocytic chorea.

215. A method for treating a neurological disorder or nerve disorder or mental disorder or psychiatric disorder in a subject requiring treatment thereof, the method comprising administering to the subject 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, wherein the neurological disorder or nerve disorder or mental disorder or psychiatric disorder is hyperkinetic movement disorder.

216. 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.

217. 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.

218. 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.

219. 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.

220. 215. 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.

221. 215. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizophrenia.

222. 215. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizoaffective disorder.

223. 215. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is obsessive-compulsive disorder.

224. 215. 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.

225. 215. The method of claim 213 or 214, wherein the neurological disease or disorder or the psychiatric disease or disorder is an autism spectrum disorder.

226. 226. The method of any one of claims 211 to 225, comprising using the compound, the salt, the product, or the composition in adjunctive therapy.

227. 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 VMAT2 disorder.

228. 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 VMAT2 disorder selected from ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities, or abnormalities; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; 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 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.

229. 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.

230. 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 neurological or psychiatric disease or disorder selected from the group consisting of hyperactivity and 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.

231. 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 hyperkinetic movement disorder.

232. 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 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.

233. 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.

234. 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 Huntington's disease.

235. 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 chorea associated with Huntington's disease.

236. 230. 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.

237. 230. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizophrenia.

238. 230. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is schizoaffective disorder.

239. 230. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is obsessive-compulsive disorder.

240. 230. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder.

241. 230. The use of claim 228 or 229, wherein the neurological disease or disorder or the psychiatric disease or disorder is an autism spectrum disorder.

242. 242. The use of a compound, salt, product, or composition according to any one of claims 227 to 241, wherein treating comprises using the compound, salt, product, or composition in adjunctive therapy.

243. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method of treatment of the human or animal body by therapy.

244. A compound 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, for use in a method for treating a vesicular monoamine transporter 2 (VMAT2) disease or VMAT2 disorder.

245. 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, 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 malformations, deformities, or abnormalities; dementia; diseases of the oral cavity, salivary glands, or jaw; dyskinesia; dystonia; endocrine, nutritional, or metabolic disease; 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 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.

246. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method for treating a neurological disease or disorder or a psychiatric disease or disorder.

247. 209. 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, for use in a method for treating a neurological or psychiatric disease or disorder selected from the group consisting of hyperactivity and movement disorder, schizophrenia, schizoaffective disorder, a 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.

248. 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 disorders.

249. 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 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.

250. A compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208, or a pharmaceutical composition according to claim 209, for use in a method for treating tardive dyskinesia.

251. 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, for use in a method for treating Huntington's disease.

252. 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, for use in a method for treating chorea associated with Huntington's disease.

253. 247. 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.

254. 247. 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.

255. 247. 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.

256. 247. 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.

257. 247. 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.

258. 247. 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.

259. 259. The compound, salt, product, or composition for use according to any one of claims 244 to 258, wherein the method for treating comprises using the compound, salt, product, or composition in adjunctive therapy.

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