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

Abstract

The present disclosure relates, inter alia, to certain compounds, compositions, and pharmaceutical compositions thereof that modulate the activity of transporter vesicular monoamine transporter 2 (VMAT2), and to methods for treating transporter vesicular monoamine transporter 2 mediated disorders, such as neurological or psychiatric diseases or disorders, including but not limited to hyperdyskinesia (e.g., hyperdyskinesia). Delayed dyskinesia, Tourette's Syndrome, Huntington's Disease, twitch, ataxia, chorea (such as chorea associated with Huntington's Disease), muscular dystonia, lateral spasm, muscular spasm, restless leg Syndrome, and tremor). The present disclosure also relates to synthetic processes and intermediates useful for preparing the compounds.

Description

Technical Field

[0001] The present disclosure relates in particular to certain compounds, compositions and pharmaceutical compositions thereof that modulate the activity of the transporter vesicular monoamine transporter-2 (VMAT2), and to methods for treating transporter vesicular monoamine transporter-2 mediated disorders such as neurological or psychiatric diseases or disorders, including but not limited to hyperkinesia (e.g., tardive dyskinesia, Tourette syndrome, Huntington's disease, tics, ataxia, chorea (such as chorea associated with Huntington's disease), dystonia, hemifacial spasm, myoclonus, restless legs syndrome and tremor. The present disclosure also relates to synthetic methods and intermediates for preparing the compounds.

[0002] Description of Related Technology

[0003] Dysregulation of the dopaminergic system is an integral part of several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinesia, and conditions such as schizophrenia and mood disorders. The transporter vesicular monoamine transporter-2 (VMAT2) plays an important role in presynaptic dopamine release and regulates monoamine uptake from the cytoplasm to synaptic vesicles for storage and release.

[0004] (±)-Tetrabenazine ((±)-TBZ) has been used as a drug for decades. (±)-TBZ is reported to be a potent and reversible inhibitor of catecholamine uptake by VMAT2 (IC 50=3.2 nM) (see, e.g., Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8) and is currently used to treat various hyperactivity disorders. (±)-TBZ inhibition of VMAT2 causes 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 the rat brain (see, e.g., Login et al., (1982) Ann. Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521). After oral administration to humans, (±)-TBZ exhibits extensive first-pass metabolism, with little or no (±)-TBZ observed in the systemic circulation. Therefore, it is believed that the pharmacological activity of (±)-TBZ is mainly mediated by active metabolites. (±)-TBZ has two chiral centers and is a racemic mixture of two stereoisomers. It has been determined that (±)-TBZ is rapidly and extensively metabolized to 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinoline-2-ol (also referred to as dihydrotetrabenazine (DHTBZ)) by carbonyl reductase in vivo. The inhibition constants of these four metabolites to VMAT2 have been reported in, such as WO2008 / 058261, Example 7. As shown, only two ([+]-α-DHTBZ and [+]-β-DHTBZ) in four DHTBZ isomers show significant efficacy as VMAT2 inhibitors.

[0005] (±)-TBZ metabolites <![CDATA[pK i ]]> <![CDATA[K i ]]> [+]-α-DHTBZ(2R,3R,11bR) 8.7±0.2(n＝6) 1.9nM [+]-β-DHTBZ(2S,3R,11bR) 7.9±0.1(n＝5) 13nM [-]-α-DHTBZ(2S,3S,11bS) 6.7±0.1(n＝3) 202nM [-]-β-DHTBZ(2R,3S,11bS) 6.1±0.1(n＝4) 714nM

[0006] In patients administered (±)-TBZ, [-]-α-DHTBZ (2S, 3S, 11bS-DHTBZ) and [+]-β-DHTBZ (2S, 3R, 11bR-DHTBZ) were the most abundant DHTBZ isomers, while [-]-β-DHTBZ (2R, 3S, 11bS-DHTBZ) and [+]-α-DHTBZ (2R, 3R, 11bR-DHTBZ) were present as minor metabolites. It was determined that the [+]-α-DHTBZ (2R, 3R, 11bR-DHTBZ) isomer was present in the smallest amount of all four isomers. Therefore, [+]-β-DHTBZ (2S, 3R, 11bR-DHTBZ) appears to be the main DHTBZ isomer that contributes to the pharmacological activity of (±)-TBZ. Once formed, [+]-β-DHTBZ (2S,3R,11bR-DHTBZ) has a relatively short half-life (approximately 5 hours), which necessitates a suboptimal (TID) dosing regimen for (±)-TBZ.

[0007] (±)-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, drowsiness, fatigue, tension, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia, and Parkinson's disease. In general, the probability of observing side effects is a function of the plasma concentration achieved from a given dosing regimen. Given equal dosing intervals, a drug with a longer half-life (t 1 / 2 Compounds with longer half-lives and lower clearance rates will have lower peak-to-trough fluctuations in plasma exposure. These longer half-life compounds may exhibit improved tolerability by maintaining drug concentrations at levels required for efficacy but below levels that may cause side effects.

[0008] The basic and effective strategy to improve 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 fluid that removes the drug from the body per unit time. Clearance is a basic pharmacokinetic parameter, and is usually measured in drug research and development because this parameter affects drug properties, such as half-life, and ultimately affects the dosing regimen. When optimizing compound and dosage selection, the benefits of small plasma-concentration fluctuations visible in compounds with low clearance include potential reduced steady-state peak concentrations, increased trough concentrations, and the prospect of improving drug compliance due to the risk-benefit characteristics that may be improved.

[0009] Although progress has been made in the art, there is still a need in the art for improved VMAT2 inhibitors, including compounds, compositions and methods related thereto. Identifying long half-life / low clearance VMAT2 small molecule inhibitors is advantageous for drug development, particularly when developed for long-term administration. In certain disease populations where patient compliance and pill burden are ongoing challenges, reducing dosing frequency is highly desirable and provides increased patient benefit.

[0010] The present disclosure satisfies these benefits, such as improved in vitro VMAT2 potency or improved pharmacokinetics, or both, as well as other needs, as will become apparent by reference to the following disclosure. Summary of the invention

[0011] One aspect of the present disclosure specifically encompasses compounds of formula (Ia):

[0012]

[0013] or a pharmaceutically acceptable salt thereof,

[0014] in:

[0015] R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl, C5-C 11 - spirocycloalkyl, cubic alkyl-C1-C4-alkylene and 4-8 membered heterobicyclyl-C1-C4-alkylene;

[0016] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0017] Also provided herein is a pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound as described herein or a pharmaceutically acceptable salt thereof.

[0018] Also provided herein is a pharmaceutical product selected from the group consisting of a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0019] Also provided herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0020] Also provided herein is a method for preparing a pharmaceutical composition, comprising the step of mixing a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0021] Also provided herein are methods of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein.

[0022] Also provided herein is a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the VMAT2 disease or condition is selected from: ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood disorders or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and mood disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

[0023] Also provided herein are methods of treating a neurological or psychiatric disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein.

[0024] Also provided herein is a method of treating a neurological or psychiatric disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the neurological or psychiatric disease or condition is selected from: hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, and chorea-acanthocytosis.

[0025] Also provided herein are methods of treating a neurological or psychiatric disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the neurological or psychiatric disease or condition is hypermovement disorder.

[0026] Also provided herein is a method of treating a hypermovement disorder in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the hypermovement disorder is selected from the group consisting of tardive dyskinesia, Tourette syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor.

[0027] Also provided herein are methods of treating a hypermovement disorder in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the hypermovement disorder is tardive dyskinesia.

[0028] Also provided herein is a method of treating a hypermobility disorder in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the hypermobility disorder is Huntington's disease.

[0029] Also provided herein is a method of treating a hypermovement disorder in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the hypermovement disorder is chorea associated with Huntington's disease.

[0030] Also provided herein is a method for treating a neurological or psychiatric disease or condition in an individual in need thereof, the method comprising administering to the individual a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein; wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is schizophrenia. In some embodiments, the neurological or psychiatric disease or condition is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is autism spectrum disorder. In some embodiments, the method comprises using the compound, salt, product or composition in adjunctive therapy.

[0031] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.

[0032] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or condition selected from the group consisting of ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or abnormalities; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood disorders or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and mood disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

[0033] Also provided herein is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein, in the preparation of a medicament for treating a neurological or psychiatric disease or disorder.

[0034] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating a neurological or psychiatric disease or condition selected from the group consisting of hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, treatment-resistant obsessive-compulsive disorder, neurological 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.

[0035] Also provided herein is a use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating hypermobility disorder.

[0036] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating a hypermovement disorder, wherein the hypermovement disorder is selected from the group consisting of tardive dyskinesia, Tourette syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome and tremor.

[0037] Also provided herein is a use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating tardive dyskinesia.

[0038] Also provided herein is a use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating Huntington's disease.

[0039] Also provided herein is the use of a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein in the preparation of a medicament for treating chorea associated with Huntington's disease.

[0040] Also provided herein is a compound as described herein or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein for use in the preparation of a medicament for treating a neurological or psychiatric disease or condition, wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is schizophrenia. In some embodiments, the neurological or psychiatric disease or condition is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is autism spectrum disorder. In some embodiments, treatment comprises using the compound, salt, product or composition in adjunctive therapy.

[0041] Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating the human or animal body by therapy.

[0042] Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.

[0043] Also provided herein are compounds as described herein or pharmaceutically acceptable salts thereof for use in a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition selected from: ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood disorders or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and mood disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

[0044] Also provided herein are compounds as described herein, or pharmaceutically acceptable salts thereof, for use in a method of treating a neurological or psychiatric disease or disorder.

[0045] Also provided herein are compounds as described herein or pharmaceutically acceptable salts thereof for use in a method of treating a neurological or psychiatric disease or condition selected from: hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, and chorea-acanthocytosis.

[0046] Also provided herein are compounds as described herein or pharmaceutically acceptable salts thereof for use in a method of treating hypermobility disorder.

[0047] Also provided herein is a compound as described herein or a pharmaceutically acceptable salt thereof for use in a method of treating a hypermovement disorder; wherein the hypermovement disorder is selected from the group consisting of tardive dyskinesia, Tourette syndrome, Huntington's disease, tics, chorea associated with Huntington's disease, ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, and tremor.

[0048] Also provided herein are compounds as described herein or pharmaceutically acceptable salts thereof for use in a method of treating tardive dyskinesia.

[0049] Also provided herein are compounds described herein or pharmaceutically acceptable salts thereof for use in a method of treating Huntington's disease.

[0050] Also provided herein are compounds as described herein or pharmaceutically acceptable salts thereof for use in a method of treating chorea associated with Huntington's disease.

[0051] 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 condition, wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is schizophrenia. In some embodiments, the neurological or psychiatric disease or condition is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or condition is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or condition is autism spectrum disorder. In some embodiments, the method for treatment includes using the compound, salt, product or composition in adjunctive therapy.

[0052] These and other aspects of the invention disclosed herein will be set forth in more detail as this patent disclosure proceeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1AA general synthetic scheme is shown for preparing certain compounds of formula (Ia) and intermediates related thereto, wherein R 1 In this representative example, R 1 is a methyl group and is introduced into compound 2-3.

[0054] Figure 1B A general synthetic scheme is shown for preparing certain compounds of formula (Ia) and intermediates related thereto, wherein R 1 In this representative example, the compounds (ie, Compound 15, Compound 76, Compound 77, and Compound 78) were separated by supercritical fluid chromatography (SFC) as described in Example 1.

[0055] Figure 2A A general synthetic scheme for the 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) is shown, which uses the intermediate (±)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one (Compound 2-17) and (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-23). The resolution step of 3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19) with (2S,3S)-2,3-bis(4-methylbenzyloxy)succinic acid (DPTTA) provides (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 then deprotected to provide compound 2-22.

[0056] Figure 2BA general synthetic scheme for the 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) is shown, which uses the intermediates 1-(tert-butoxy)propan-2-one (Compound 2-25) and 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (Compound 2-26) to give (±)-9-( 1-a]isoquinolin-2-ol (compound (±)-2-19). A resolution procedure using compound (±)-2-19 with (2S,3S)-2,3-bis(4-methylbenzyloxy)succinic acid (DPTTA) provides (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 then deprotected to provide compound 2-22.

[0057] Figure 3 A general synthetic scheme is shown for preparing compounds of formula (Ia) using 3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol and different alkylating agents; wherein R 1 has the same meaning as herein, LG 1 is a leaving group, and R 3a It can be H or C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of 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 LG 1 A variety of leaving groups may be used, such as those described herein and those known in the art.

[0058] Figure 4 A general synthetic scheme for preparing compounds of formula (Ie) using (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 is shown; wherein R 1 has the same meaning as herein, LG1 is a leaving group, and R 3a It can be H or C1-C4-alkyl optionally substituted by one or more substituents selected from the group consisting of 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 LG 1 A variety of leaving groups may be used, such as those described herein and those known in the art.

[0059] Figure 5 The in vivo pharmacology of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compound 18 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 Sprague Dawley rats in the open field hypolocomotor model described in Example 15 is shown. DETAILED DESCRIPTION

[0060] definition

[0061] For clarity and consistency, the following definitions will be used throughout this patent document.

[0062] 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.

[0063] The terms "adjuvant therapy," "adjuvant therapy," "co-therapy," "combination therapy," and "combination therapy" as used herein refer to treating a patient in need thereof by administering a compound (as described herein) in combination with one or more drugs, wherein administration is by any suitable means, such as simultaneously, sequentially, separately or in a single pharmaceutical formulation.

[0064] As used herein, the terms "administering" and "administration" refer to providing a compound described herein or other therapy to a subject in a form that can be introduced into the subject's body in a therapeutically useful form and in a therapeutically useful amount, including but not limited to: oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as intravenous (IV), intramuscular (IM), subcutaneous (SC), etc.; transdermal dosage forms, including creams, gels, powders and patches; buccal dosage forms; inhalation powders, sprays, suspensions, etc.; and rectal dosage forms such as suppositories.

[0065] A health care practitioner may provide the compounds described herein in the form of a sample directly to an individual, or may provide the compounds indirectly to an individual by providing an oral or written prescription of the compound. In addition, for example, an individual may obtain the compound by himself without the participation of a health care practitioner. When a compound is administered to an individual, the body is transformed by the compound in some way. When a compound as described herein is provided in combination with one or more other agents, "administering" and "administration" should be understood to include the compound and at least one other agent being administered at the same time or at different times. When the combined agents are administered simultaneously, they may be administered together in a single composition, or they may be administered separately. The preferred method of administration may vary according to various factors, such as the components of the pharmaceutical preparation, the site of the disease, and the severity of the disease.

[0066] The term "composition" refers to a compound or its crystalline form, including but not limited to salts, solvates and hydrates of the compounds described herein, in combination with at least one additional component, such as a composition obtained / prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), etc.

[0067] The term "compound" as used herein refers to all stereoisomers, geometric isomers, tautomers and isotopic variants of the structure described herein. The term also means compounds described herein prepared in any manner, such as synthetically, by biological processes (such as metabolism or enzyme conversion) or a combination thereof. All compounds and pharmaceutically acceptable salts thereof can be found together with other substances (such as water and solvents) (for example, hydrates and solvates) or can be separated. When in a solid state, the compounds described herein and their salts can exist in various forms, and can, for example, be expressed as cocrystals or solvates (including hydrates). The compound can be in any solid form, such as a polymorph or solvate, so unless otherwise explicitly indicated, the compounds and their salts mentioned in this specification should be understood to cover any solid form of the compound. In some embodiments, the compound described herein or its salt is substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition rich in compounds described herein. Substantially isolated 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.

[0068] As used herein, the term "solvate" refers to a compound as described herein or a pharmaceutically acceptable salt thereof that includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0069] The term "hydrate" as used herein refers to a compound as 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.

[0070] The term "in need of treatment" and the term "in need of" are used interchangeably in reference to treatment and refer to a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of humans); a veterinarian in the case of animals (including non-human mammals) that an individual or animal requires treatment or will benefit from treatment. In addition to including the knowledge that the individual or animal is or will become ill due to a disease, condition, or disorder that can be treated by the compounds described herein, this judgment is based on a variety of factors that are within the caregiver's expertise. Thus, the compounds described herein can be used in a protective or preventive manner; or the compounds described herein can be used to alleviate, inhibit, or mitigate a disease, condition, or disorder.

[0071] The term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In the context of a clinical trial or screening or activity trial, an individual may be a healthy volunteer or healthy participant without a potential VMAT2-mediated disorder or condition, or a volunteer or participant who has received a diagnosis of a disorder or condition that requires medical treatment as determined by a health care professional. In the context of a clinical trial outside of a clinical trial, an individual who has received a diagnosis of a disorder or condition under the care of a health care professional is typically described as an individual.

[0072] The term "pediatric subject" refers to an individual under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (2 years to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday)), see, e.g., 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.

[0073] The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0074] The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient; the active ingredient includes, but is not limited to, salts, solvates, and hydrates of the compounds described herein, whereby the composition can be studied for a specific effective result in a mammal (e.g., but not limited to, a human). One of ordinary skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired effective result based on the needs of the skilled artisan.

[0075] The terms "prevention", "preventing" and "prevention" refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular condition. For example, the terms "prevention", "preventing" and "prevention" may refer to the administration of therapy to an individual who may eventually exhibit at least one symptom of a condition but has not yet done so, on the basis of prevention or treatment. Such individuals may be identified based on risk factors (such as the presence of biomarkers) known to be associated with the subsequent occurrence of the disease. Alternatively, prophylactic therapy may be administered as a preventive measure without the need to identify risk factors in advance. Delaying the onset of at least one onset of a condition and / or symptoms may also be considered prevention or treatment. In some embodiments, the individual may be a pediatric individual.

[0076] The terms "treat," "treating," and "treatment" refer to the medical management of a disease, disorder, or condition of an individual (e.g., an individual) (see, e.g., Stedman's Medical Dictionary). Generally, appropriate dosages and treatment regimens provide an amount of VMAT2 inhibitor sufficient to provide a therapeutic benefit. Therapeutic benefits for individuals administered a VMAT2 inhibitor compound described herein include, for example, improved clinical outcomes, where the goal is to prevent or slow or delay (mitigate) undesirable physiological changes associated with a disease, or to prevent or slow or delay (mitigate) the expansion or severity of such a disease. The effectiveness of one or more VMAT2 inhibitors may include beneficial or desired clinical results, including but not limited to eliminating, alleviating or relieving symptoms caused by or associated with the disease being treated; reducing the incidence of symptoms; improving quality of life; extending the disease-free state (i.e., reducing the likelihood or tendency that an individual will present symptoms based on a disease diagnosis made); alleviating the extent of the disease; stabilizing (i.e., not worsening) the disease state; delaying or slowing disease progression; improving or alleviating the disease state; and alleviating (whether partially or completely), whether detectable or undetectable; and / or overall survival. In some embodiments, the individual may be a pediatric individual.

[0077] 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 medicinal response in a tissue, system, animal or human that is being sought by an individual, researcher, veterinarian, physician or other clinician or caregiver, which response may include one or more of the following:

[0078] (1) preventing a disorder, e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or display the associated pathology or symptoms;

[0079] (2) inhibiting a disorder, e.g., inhibiting a disease, condition, or disorder in a subject who is experiencing or exhibiting the associated pathology or symptoms (i.e., preventing further development of the pathology and / or symptoms); and

[0080] (3) Alleviating a condition, e.g., ameliorating a disease, condition, or disorder in a subject who is experiencing or exhibiting the associated pathology or symptoms (ie, reversing the pathology and / or symptoms).

[0081] The term "contacting" refers to the gathering of the indicated moiety in an in vitro system or in an in vivo system. For example, "contacting" a VMAT2 protein with a compound provided herein includes administering a compound provided herein (or a pharmaceutically acceptable salt thereof) to an individual (such as a human) having a VMAT2 protein, and, for example, introducing a compound provided herein into a sample containing a cell preparation or a purified preparation containing a VMAT2 protein.

[0082] Chemical Group

[0083] Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents, applications, published applications and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for a term in this article, those defined in this section shall prevail unless otherwise stated.

[0084] The term "α-member" (where "α" is an integer) before the group name refers to the number of atoms in the group. For example, oxetane contains 4 atoms and is a 4-membered heterocyclyl; 2-oxaspiro [3.3] heptyl is an example of a 7-membered spiro heterocyclyl; and piperidinyl is an example of a 6-membered heterocyclyl ring. Similarly, the term "ab member" (where "a" and "b" are integers) before the group name refers to the inclusion range of atoms in the group. For example, a "3-7-membered heterocyclyl" group refers to all "heterocyclyl" groups with 3 to 7 atoms (i.e., 3, 4, 5, 6, and 7 atoms), where "heterocyclyl" is defined in this article; and a "4-5-membered heterocyclyl" refers to all "heterocyclyl" groups with 4 to 5 atoms (i.e., 4 and 5 atoms). If "a" and "b" are not specified for a group, the widest range described in these definitions is assumed.

[0085] For compounds as described herein or pharmaceutically acceptable salts thereof in which a variable occurs more than once, each variable may be a different portion of a group independently selected from the group defining the variable. For example, when describing a structure having, for example, two R groups present simultaneously on the same compound, the two R groups may represent different portions independently selected from the group defined for R, or the two R groups may be the same.

[0086] Whenever a group is described as "substituted", the group may be substituted with one or more of the specified substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituents may be selected from one or more of the specified substituents. It is understood that substitution at a given atom is limited by valence. In addition, it is understood that "optionally substituted" means that the group is unsubstituted or substituted.

[0087] The term "C" before the group namea -C b " (wherein "a" and "b" are integers) refers to the inclusive range of carbon atoms in the group. For example, "C1-C4-alkyl" refers to the alkyl group having 1 to 4 carbons (i.e., 1, 2, 3 and 4 carbons), such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl (CH3CH2CH(CH3)-) and tert-butyl ((CH3)3C-). If "a" and "b" are not specified for a group, the broadest range described in these definitions is assumed.

[0088] In addition to the foregoing, as used in the specification and claims, the following terms have the indicated meanings unless otherwise indicated.

[0089] The terms "C1-C4-alkylene" and "C2-C4-alkylene" refer to a straight or branched saturated aliphatic divalent group having a defined number of carbons (1 to 4 carbon atoms or 2 to 4 carbon atoms), respectively. Some embodiments contain 1 to 2 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 carbon atom. Some embodiments contain 2 to 3 carbons. Some embodiments contain 2 carbon atoms. Examples include, but are not limited to, methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2- and -CH(CH3)-), n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, and tert-butylene. When one or more substituents are present on an "alkylene" group, the substituents may be bonded to any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, "alkylene" may be substituted or unsubstituted.

[0090] The term "C1-C4-alkyl-O-C2-C4-alkylene" refers to a group consisting of a "C1-C4-alkyl" bonded to an oxygen atom, and the oxygen atom is bonded to a "C2-C4-alkylene", wherein "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, "C1-C4-alkyl-O-C2-C4-alkylene" refers to a group selected from the following: 2-methoxyethyl (i.e., CH3-O-CH2CH2-), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl and 3-isopropoxypropyl. When one or more substituents are present on "C1-C4-alkyl-O-C2-C4-alkylene", the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, the "C1-C4-alkyl-O-C2-C4-alkylene" group may be substituted or unsubstituted.

[0091] The term "alkoxy" refers to a group comprising an "alkyl" directly connected to an oxygen atom, wherein "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 (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0092] The term "alkyl" refers to a fully saturated straight or branched hydrocarbon group. In some embodiments, the alkyl group may have 1 to 6 carbons (i.e., "C1-C6-alkyl"). Some embodiments are 1 to 5 carbons (i.e., "C1-C5-alkyl"), some embodiments are 1 to 4 carbons (i.e., "C1-C4-alkyl"), some embodiments are 1 to 3 carbons (i.e., "C1-C3-alkyl"), and some embodiments are 1 or 2 carbons. As an example only, "C1-C4-alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], and n-hexyl. When one or more substituents are present on an "alkyl", the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, an "alkyl" may be substituted or unsubstituted.

[0093] The term "alkylsulfonyl" refers to a group consisting of an "alkyl" group bonded to a sulfone group of the formula -S(=O)2-, wherein "alkyl" has the same definition as described herein. An "alkylsulfonyl" group may have from 1 to 4 carbon atoms (i.e., "C1-C4-alkylsulfonyl"). Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, and tert-butylsulfonyl.

[0094] The term "amino" refers to the group -NH2.

[0095] The term "bicycloalkyl" refers to a group comprising two fused or bridged cycloalkyl rings. In some embodiments, the "bicycloalkyl" group contains 4 to 8 ring carbon atoms. In some embodiments, the "bicycloalkyl" group contains 5 to 8 ring carbon atoms. In some embodiments, the "bicycloalkyl" group contains 5 to 7 ring carbon atoms. In some embodiments, the "bicycloalkyl" group contains 5 or 6 ring carbon atoms. Examples include but are not limited to bicyclo[1.1.0]butyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl and bicyclo[3.2.1]octyl. When one or more substituents are present on the "bicycloalkyl" group, the substituents can be bonded at any available carbon atom. When there are more than one substituent, the substituents can be the same or different. In some embodiments, the "bicycloalkyl" group can be substituted or unsubstituted.

[0096] The term "C4-C8-bicycloalkyl-C1-C4-alkylene" refers to a group consisting of a "C4-C8-bicycloalkyl" and a "C1-C4-alkylene" bonded together, wherein "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]butyl-1-yl)methyl (i.e., (bicyclo[1.1.0]butyl-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]hexan-1-yl)methyl, (bicyclo[2.2.1]heptan-1-yl)methyl, and (bicyclo[2.2.2]octan-1-yl)methyl. When one or more substituents are present on a "C4-C8 bicycloalkyl-C1-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "C4-C8-bicycloalkyl-C1-C4-alkylene" group may be substituted or unsubstituted.

[0097] The term "4-8 membered heterobicyclyl" refers to a group comprising two fused or bridged rings comprising carbon atoms and at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen, and when there are more than one heteroatom in the ring, the heteroatoms may be the same or different. In some embodiments, a "4-8 membered heterobicyclyl" is a group selected from the following: 2-oxabicyclo [2.1.1] hex-1-yl and 2-oxabicyclo [2.1.1] hex-4-yl. When one or more substituents are present on a "4-8 membered heterobicyclyl" group, the substituents may be bonded at any available ring atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, a "4-8 membered heterobicyclyl" group may be substituted or unsubstituted.

[0098] The term "carbonyl" refers to the group -C(=O)-.

[0099] The term "cubic alkyl" refers to a group having the following structure:

[0100]

[0101] The term "cuban-C1-C4-alkylene" refers to a group consisting of a "cuban-C1-C4-alkylene" bonded to a "cuban-C1-C4-alkylene" group, wherein "cuban-C1-C4-alkylene" and "cuban-C1-C4-alkylene" have the same definitions as described herein. Examples include, but are not limited to, (cuban-C1-C4-alkylene)methyl. When one or more substituents are present on a "cuban-C1-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "cuban-C1-C4-alkylene" group may be substituted or unsubstituted.

[0102] The term "cyano" refers to the group -CN.

[0103] The term "cyano-C1-C4-alkylene" refers to a group consisting of a "cyano" and a "C1-C4-alkylene" bond, wherein "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.

[0104] The term "cycloalkenyl" refers to a non-aromatic monocyclic hydrocarbon ring system containing at least one double bond in the ring. A "cycloalkenyl" group may contain 4 to 7 atoms (i.e., "C4-C7-cycloalkenyl") in the ring. Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. In some embodiments, "cycloalkenyl" is selected from: cyclobut-1-ene-1-yl, cyclobut-2-ene-1-yl, cyclopent-1-ene-1-yl, cyclopent-2-ene-1-yl, and cyclopent-3-ene-1-yl. When one or more substituents are present on a "cycloalkenyl", the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, a "cycloalkenyl" group may be substituted or unsubstituted.

[0105] The term "cycloalkyl" refers to a monocyclic ring system of all carbons that is fully saturated. 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", the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, a "cycloalkyl" group may be substituted or unsubstituted.

[0106] The term "C3-C7-cycloalkyl-C1-C4-alkylene" refers to a group consisting of a "C3-C7-cycloalkyl" and a "C1-C4-alkylene" bonded to each other, wherein "C3-C7-cycloalkyl" and "C1-C4-alkylene" have the same definitions as described herein. Examples include, but are not limited to, cyclopropylmethyl (cyclopropyl-CH2-), cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl (cyclopropyl-CH2CH2-), 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclopropylethyl (cyclopropyl-CH(CH3)-), 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 "C3-C7-cycloalkyl-C1-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "C3-C7-cycloalkyl-C1-C4-alkylene" group may be substituted or unsubstituted.

[0107] The term "C3-C7-cycloalkyl-O-C2-C4-alkylene" refers to a group consisting of a "C3-C7-cycloalkyl" bonded to an oxygen atom, and the oxygen atom is bonded to a "C2-C4-alkylene", wherein "C3-C7-cycloalkyl" and "C2-C4-alkylene" have the same definitions as described herein. Examples include, but are not limited to, 2-cyclopropyloxyethyl (i.e., cyclopropyl-O-CH2CH2-), 2-cyclobutoxyethyl, 2-cyclopentyloxyethyl, 2-cyclohexyloxyethyl, 2-cycloheptyloxyethyl, 1-cyclopropyloxyethyl (i.e., cyclopropyl-O-CH(CH3)-), 1-cyclobutoxyethyl, 1-cyclopentyloxyethyl, 1-cyclohexyloxyethyl, 1-cycloheptyloxyethyl, 3-cyclopropyloxypropyl, 3-cyclobutoxypropyl, 3-cyclopentyloxypropyl, 3-cyclohexyloxypropyl, and 3-cycloheptyloxypropyl. It will be understood that the chemical group "(cyclopropyl)methyl-d2" refers to a group in which a deuterium atom is bonded to a methylene carbon (i.e., cyclopropyl-CD2-), see, for example, compound 99. When one or more substituents are present on a "C3-C7-cycloalkyl-O-C2-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "C3-C7-cycloalkyl-O-C2-C4-alkylene" group may be substituted or unsubstituted.

[0108] The term "dialkylamino" refers to an amino group (-NH2) in which the nitrogen is replaced by two "alkyl" groups. The two alkyl groups may be the same or different. The term "alkyl" has the same definition as described herein. A "dialkylamino" group may 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)).

[0109] The term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more of the hydrogen atoms of the alkyl group has been replaced by a halogen atom. In some embodiments, the haloalkyl group may have from 1 to 6 carbon atoms (i.e., "C1-C6-haloalkyl"). The halo C1-C6 alkyl group may be fully substituted, in which case it may be represented by the formula C n L 2n+1 Represents, wherein L is halogen and "n" is 1, 2, 3, 4, 5 or 6. When there is more than one halogen, they may be the same or different and are selected from: fluorine, chlorine, bromine and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons (i.e., "C1-C5-haloalkyl"). In some embodiments, haloalkyl contains 1 to 4 carbons (i.e., "C1-C4-haloalkyl"). In some embodiments, haloalkyl contains 1 to 3 carbons (i.e., "C1-C3-haloalkyl"). In some embodiments, haloalkyl contains 1 or 2 carbons. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 4,4,4-trifluorobutyl.

[0110] The term "halogen" or "halo" refers to a fluorine, chlorine, bromine or iodine group. In some embodiments, the halogen or halogen is fluorine, chlorine or bromine. In some embodiments, the halogen or halogen is fluorine or chlorine. In some embodiments, the halogen or halogen is fluorine.

[0111] The term "heterocyclyl" refers to a non-aromatic monocyclic ring system containing carbon atoms and at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. When more than one heteroatom is present in the ring, the heteroatoms may be the same or different. In some embodiments, "3-7 membered heterocyclyl" refers to a ring system containing 3 to 7 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4-5 membered heterocyclyl" refers to a ring system containing 4 or 5 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4-7 membered heterocyclyl" refers to a ring system containing 4 to 7 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "3-6 membered heterocyclyl" refers to a ring system containing 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4-6 membered heterocyclyl" refers to a ring system containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, one or two heteroatoms in the ring system are independently selected from: O (oxygen) and N (nitrogen). In some embodiments, the heterocyclic group may include a carbonyl (C=O) group adjacent to a heteroatom, i.e., substituted by oxo on a carbon adjacent to a heteroatom, wherein the substituted ring system is a lactam, a lactone, a cyclic imide, a cyclic thioimide, or a cyclic carbamate. Examples include, but are not limited to, aziridine, azetidinyl, piperidinyl, morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiopyranyl. When one or more substituents are present on a "heterocyclic group", the substituents may be bonded at any available carbon atom and / or heteroatom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, the "heterocyclic group" may be substituted or unsubstituted.

[0112] The term "4-8 membered heterobicyclyl-C1-C4-alkylene" refers to a group consisting of a "4-8 membered heterobicyclyl" and a "C1-C4-alkylene" bond, wherein "4-8 membered heterobicyclyl" and "C1-C4-alkylene" have the same definitions as described herein. In some embodiments, "4-8 membered heterobicyclyl-C1-C4-alkylene" is a group selected from the following: (2-oxabicyclo [2.1.1] hex-1-yl) methyl and (2-oxabicyclo [2.1.1] hex-4-yl) methyl. When one or more substituents are present on the "4-8 membered heterobicyclyl-C1-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, the "4-8 membered heterobicyclyl-C1-C4-alkylene" group may be substituted or unsubstituted.

[0113] The term "3-7 membered heterocyclyl-C1-C4-alkylene" refers to a group consisting of a "3-7 membered heterocyclyl" and a "C1-C4-alkylene" bonded together, wherein "3-7 membered heterocyclyl" and "C1-C4-alkylene" have the same definitions as described herein. Examples include, but are not limited to, aziridine-1-ylmethyl (i.e., (aziridine-1-yl)CH2-), aziridine-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 -ylmethyl (i.e., (oxetan-2-yl))CH2-), 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl)CH2CH2-), 2-oxetan-2-ylethyl (i.e., (oxetan-2-yl)CH2CH2-), imidazolidinylmethyl, piperazin-1-ylmethyl, piperazin-2-ylmethyl, pyrrolidin-3-ylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl and tetrahydrothiopyranylmethyl. In some embodiments, "3-7 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 a "3-7 membered heterocyclyl-C1-C4-alkylene" group, the substituents may be bonded at any available carbon atom. When more than one substituent is present, the substituents may be the same or different. In some embodiments, a "3-7 membered heterocyclyl-C1-C4-alkylene" group may be substituted or unsubstituted.

[0114] The term "spirocycloalkyl" refers to a non-aromatic all carbon bicyclic ring system in which the two rings are linked together by a single common ring carbon. 11-spirocycloalkyl" refers to a spiro ring system containing 5 to 11 ring carbons. In some embodiments, "C5-C8-spirocycloalkyl" refers to a spiro ring system containing 5 to 8 ring carbons. In some embodiments, "C5-C7-spirocycloalkyl" refers to a spiro ring system containing 5 to 7 ring carbons. In some embodiments, "C7-spirocycloalkyl" refers to a spiro ring system containing 7 ring carbons (i.e., spiro[3.3]heptyl and spiro[2.4]heptyl). Examples include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[ 3.3]heptyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[3.4]octyl, spiro[2.6]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.7]decyl, spiro[3.6]decyl, and spiro[4.5]decyl. When one or more substituents are present on a "spirocycloalkyl" group, the substituents may be bonded at any available carbon atom. When there are more than one substituent, the substituents may be the same or different. In some embodiments, a "spirocycloalkyl" group may be substituted or unsubstituted.

[0115] The term "spiroheterocyclyl" refers to a bicyclic ring system containing carbon atoms and at least one heteroatom, wherein the two rings are connected together by a single common ring carbon. In some embodiments, "5-11 yuan spiroheterocyclyl" refers to a spiroheterocyclyl containing 5 to 11 ring atoms. In some embodiments, "5-8 yuan spiroheterocyclyl" refers to a spiroheterocyclyl containing 5 to 8 ring atoms. In some embodiments, "5-7 yuan spiroheterocyclyl" refers to a spiroheterocyclyl containing 5 to 7 ring atoms. Examples include but are not limited to azaspiro [2.2] pentyl, azaspiro [2.3] hexyl, oxaspiro [2.3] hexyl, oxaspiro [3.3] heptyl, azaspiro [3.3] heptyl, azaspiro [3.4] octyl, azaspiro [3.5] nonyl and oxaspiro [3.5] nonyl-9-yl. When one or more substituents are present on a "spiroheterocyclyl" group, the substituents may be bonded at any available carbon atom and / or heteroatom. When more than one substituent is present, the substituents may be the same or different.In some embodiments, a "spiroheterocyclyl" group may be substituted or unsubstituted.

[0116] The term "hydroxy" refers to the group -OH.

[0117] As used herein, "excipient" refers to a substance added to a composition to provide (but not limited to) volume, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. "Diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the volume of an effective drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Those skilled in the art may further formulate the compounds disclosed and described herein in an appropriate manner and according to generally recognized practices (e.g., those disclosed in Remington above).

[0118] As used herein, "dose" or "dosage" refers to the measured amount of a drug substance taken by an individual at one time. In certain embodiments where the drug substance is not a free base or free acid, the amount is equivalent to the molar amount of the corresponding amount of the free base or free acid.

[0119] As used herein, "pharmaceutically acceptable salts" refer to salts of compounds having acidic or basic moieties that are biologically or otherwise suitable for use in pharmaceutical products. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by the presence of acidic or basic moieties (e.g., amino and / or carboxyl groups or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining compounds having basic moieties with inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed by combining compounds having acidic moieties with inorganic and organic bases.

[0120] Compounds described herein may have one or more stereocenters. Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers are contemplated. It should be understood that in any compound described herein with one or more chiral centers, if absolute stereochemistry is not clearly indicated, each center may be independently (R)-configuration or (S)-configuration or a mixture thereof. Therefore, compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomerically mixed. The preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by splitting a racemic mixture or by using enantiomerically pure or enriched raw materials or by stereoselective or stereospecific synthesis. Stereochemical definitions can be found in EL E Liel, SH Wilen & L. N. Mander, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference in its entirety. In some embodiments, when the compounds described herein are chiral or otherwise include one or more stereocenters, the compounds can be prepared with an enantiomeric excess or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%.

[0121] The resolution of the racemic mixture of the compound can be carried out by any of a variety of methods known in the art. Exemplary methods include the use of chiral resolution organic acids and the fractional recrystallization of racemic compounds containing basic groups. Other chiral resolution agents suitable for fractional crystallization methods include methylbenzylamine (e.g., S and R forms, or diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, the stereoisomerically pure forms of 2-diaminocyclohexane, etc. Similarly, the fractional recrystallization using chiral resolution bases can be used together with racemic compounds containing basic groups.

[0122] Resolution of the racemic mixture can also be performed by elution on a chiral column. Suitable elution solvent compositions can be determined by those skilled in the art.

[0123] In some embodiments, the compounds described herein can be prepared with an enantiomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or at least about 99.9%, or an enantiomeric excess within the range defined by any of the preceding figures. In some embodiments, the compounds described herein can be prepared with an enantiomeric excess of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or at least 99.9%, or an enantiomeric excess within the range defined by any of the preceding figures.

[0124] In some embodiments, the compounds described herein can be prepared with a diastereomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, at least about 99.5%, or at least about 99.9%, or a diastereomeric excess within the range defined by any of the preceding figures. In some embodiments, the compounds described herein can be prepared with a diastereomeric excess of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or at least 99.9%, or a diastereomeric excess within the range defined by any of the preceding figures.

[0125] Additionally, it is understood that when the compounds described herein contain one or more double bonds (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.

[0126] Compounds described herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are in isomeric protonation states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0127] The compounds described herein and their pharmaceutically acceptable salts may exist together with other substances (such as water and solvents) in the form of, for example, hydrates or solvates. When in the solid state, the compounds described herein and their salts may exist in various forms, and may, for example, be in the form of solvates (including hydrates). The compound may be in any solid form, such as a crystalline form, an amorphous form, a solvated form, etc., and unless otherwise expressly stated, reference to the compound and its salt in the specification should be understood to cover any solid form of the compound.

[0128] The compounds described herein can be used in a neutral form, such as a free acid or free base. Alternatively, the compounds can be used in the form of a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt or base addition salt.

[0129] In some embodiments, the compounds described herein or their salts are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially isolated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched with the compounds described herein. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the compounds described herein or their salts by weight.

[0130] isotope

[0131] The compounds disclosed and described herein allow and encompass that the atoms at each position of the compound independently have: 1) an isotopic distribution of the proportion of the chemical element that is usually present in nature, or 2) an isotopic distribution different from the proportion of the chemical element that is usually present in nature, unless the context clearly dictates otherwise. A specific chemical element has an atomic number defined by the number of protons in the nucleus. Each atomic number determines a specific chemical element, not an isotope; atoms of a given element can have a wide range in the number of neutrons. The number of both protons and neutrons in the nucleus is the mass number of the atom, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of a chemical element that is different from the proportion of isotopes that is usually present in nature are generally referred to as isotopically labeled. Each chemical element as represented in the compound structure may include any isotopic distribution of the element. For example, in the compound structure, hydrogen atoms may be explicitly disclosed or understood to be present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be an isotopic distribution of hydrogen, including but not limited to protium ( 1 H) and deuterium ( 2 H). Therefore, unless the context clearly dictates otherwise, reference to compounds herein encompasses all potential isotopic distributions of each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those skilled in the art, any of the compounds as disclosed and described herein may include radioactive isotopes. Therefore, also contemplated are the uses of compounds as disclosed and described herein in which one or more atoms have an isotopic distribution different from that normally found in nature, such as having a greater proportion than that found in nature. 2 H or 3 H, or a greater proportion 11 C. 13 C or 14 C. As a general example, but not limited to, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Carbon isotopes include carbon-11 (11C), carbon-12 (12C), 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 ( 34 P), 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). Isotopes of bromine include bromine-75 ( 75 Br), bromine-76( 76 Br), bromine-77( 77 Br), bromine-79( 79 Br), bromine-81( 81 Br) and bromine-82( 82 Br). 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, the atoms at each position of the compound have an isotopic distribution of the proportion of each chemical element that is usually present in nature. In some embodiments, the atoms at one position of the compound have an isotopic distribution of chemical elements that is different from the proportion of the chemical element that is usually present in nature (the remaining atoms have the isotopic distribution of the proportion of the chemical element that is usually present in nature). In some embodiments, the atoms at at least two positions of the compound independently have an isotopic distribution of chemical elements that is different from the proportion of the chemical element that is usually present in nature (the remaining atoms have the isotopic distribution of the proportion of the chemical element that is usually present in nature). In some embodiments, the atoms at at least three positions of the compound independently have an isotopic distribution of chemical elements that is different from the proportion of the chemical element that is usually present in nature (the remaining atoms have the isotopic distribution of the proportion of the chemical element that is usually present in nature). In some embodiments, the atoms at at least four positions of the compound independently have an isotopic distribution of chemical elements that is different from the proportion of the chemical element that is usually present in nature (the remaining atoms have the isotopic distribution of the proportion of the chemical element that is usually present in nature). In some embodiments, the atoms at at least five positions of the compound independently have an isotopic distribution of the chemical element in a proportion different from that which is usually found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportion that is usually found in nature). In some embodiments, the atoms at at least six positions of the compound independently have an isotopic distribution of the chemical element in a proportion different from that which is usually found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportion that is usually found in nature).

[0132] Certain compounds, such as those incorporated with 3 H and 14 Compounds containing radioactive isotopes of C can also be used to determine the tissue distribution of drugs or substrates. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. Isotopes (e.g., deuterium ( 2 H)) compounds may gain certain therapeutic advantages due to greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements). Isotopically labeled compounds can generally be prepared by following procedures routinely practiced in the chemical arts. Methods for measuring such isotopic perturbations or enrichments are readily available, such as mass spectrometry, and for isotopes that are radioactive isotopes, additional methods are available, such as radioactive detectors used in conjunction with HPLC or GC.

[0133] As used herein, "isotopic variant" means a compound that contains an unnatural ratio of isotopes at one or more of the atoms that make up such compound. In certain embodiments, an "isotopic variant" of a compound contains an unnatural ratio 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 I). In certain embodiments, an "isotopic variant" of a compound is a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to protium ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14N), 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 in an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound described herein contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O) and oxygen-15( 15 O). It is to be understood that in the compounds provided herein, as an example, any hydrogen may include 2 H as the major isotopic form, or as an example, any carbon including 13 C as the major isotopic form, or as an example, any nitrogen may include 15 N as the major isotopic form, and as an example, any oxygen may include 18 O as the major isotopic form. In certain embodiments, an "isotopic variant" of a compound contains an unnatural proportion of deuterium ( 2 H).

[0134] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d," it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is about 0.015%. In certain embodiments, positions designated as having deuterium generally have a minimum isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. Similarly, with respect to compounds provided herein, when any atomic position is designated as a particular isotope, it is understood that the abundance of the particular isotope at that position is significantly greater than the natural abundance of that isotope. In certain embodiments, 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% isotopic incorporation at each designated position.

[0135] 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, incorporate active levels of tritium into target molecules as follows:

[0136] A. Catalytic reduction with tritium gas: This method generally produces high specific activity products and requires halogenated or unsaturated precursors.

[0137] B. Use sodium borohydride [ 3 H] Reduction: This method is relatively cheap and requires precursors containing reducible functional groups (such as aldehydes, ketones, lactones, esters, etc.).

[0138] C. Using lithium aluminum hydride [ 3 H] Reduction: This method provides products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

[0139] D. Tritium Gas Exposure Labeling: This method involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0140] E. Use methyl iodide [ 3 H]: This method is usually used to treat N-methylation of 3 H) Treat appropriate precursors to prepare O-methyl or N-methyl ( 3 H) Product. This method generally allows higher specific activities, for example about 70-90 Ci / mmol.

[0141] To increase the activity level 125 The synthetic method of incorporating I into the target molecule includes:

[0142] A. Sandmeyer reaction: This method converts an arylamine or heteroarylamine into a diazonium salt, such as diazonium tetrafluoroborate, and then uses Na 125 I is converted to 125 I-labeled compounds. A representative method was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948.

[0143] B. The ortho position of phenol 125 Iodination: This method allows incorporation at the ortho position of phenol 125 I, as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.

[0144] C. Aryl and Heteroaryl Bromides 125I exchange: This method is generally a two-step process. The first step is to convert the aryl or heteroaryl bromide into the corresponding trialkyltin intermediate using, for example, a Pd catalyzed reactant [Pd(Ph3P)4] or by an aryl or heteroaryl lithium in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3]. A representative method is reported by Le Bas, M.-D. and co-workers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

[0145] Radiolabeled forms of the compounds described herein can be used in screening assays to identify / evaluate compounds. In general, the ability of a newly synthesized or identified compound (i.e., a test compound) to reduce the binding of a radiolabeled form of a compound disclosed herein to VMAT2 can be assessed. The ability of a test compound to compete with a radiolabeled form of a compound described herein for binding to VMAT2 is related to its binding affinity.

[0146] Compound

[0147] One aspect of the present disclosure specifically encompasses compounds of formula (Ia):

[0148]

[0149] or a pharmaceutically acceptable salt thereof,

[0150] in:

[0151] R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl, C5-C 11 - spirocycloalkyl, cubic alkyl-C1-C4-alkylene and 4-8 membered heterobicyclyl-C1-C4-alkylene;

[0152] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0153] Another aspect of the present disclosure encompasses, inter alia, compounds of formula (Ia):

[0154]

[0155] or a pharmaceutically acceptable salt thereof,

[0156] in:

[0157] R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl and C5-C 11 - spirocycloalkyl;

[0158] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0159] In some embodiments, R 1 The group is optionally substituted with one, two, three, four, five, six, seven, or eight substituents. 1 The group is optionally substituted with one, two, three, four, five, six, or seven substituents. 1 The group is optionally substituted with one, two, three, four, five, or six substituents. 1 The group is optionally substituted with one, two, three, four or five substituents. 1 The group is optionally substituted with one, two, three or four substituents. 1 The group is optionally substituted with one, two or three substituents. 1 The group is optionally substituted with one or two substituents. 1 The group is optionally substituted with a substituent. 1 The group is unsubstituted.

[0160] In some embodiments, R 1 The group is substituted with one, two, three, four, five, six, seven or eight substituents. 1The group is substituted with one, two, three, four, five, six or seven substituents. 1 The group is substituted with one, two, three, four, five or six substituents. 1 The group is substituted with one, two, three, four or five substituents. 1 The group is substituted with one, two, three or four substituents. 1 The group is substituted with one, two or three substituents. 1 The group is substituted with one or two substituents. 1 The group is substituted with a substituent.

[0161] Some embodiments provide compounds of formula (Ic):

[0162]

[0163] or a pharmaceutically acceptable salt thereof, wherein: R 1 Having the same definitions as described herein above and below. It is to be understood that the stereochemistry of the compound of formula (Ic) includes both the 2S,3R,11bR isomer and the 2R,3R,11bR isomer.

[0164] Some embodiments provide compounds of formula (Ie):

[0165]

[0166] or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definitions as described herein above and below. The stereochemistry of the compound of formula (Ie) is 2R, 3R, 11bR isomers.

[0167] Some embodiments provide compounds of formula (Ig):

[0168]

[0169] or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definitions as described herein above and below. The stereochemistry of the compound of formula (Ig) is 2S, 3R, 11bR isomers.

[0170] Some embodiments provide compounds of formula (Ii):

[0171]

[0172] or a pharmaceutically acceptable salt thereof, wherein: R 1has the same definitions as described herein above and below. The stereochemistry of the compound of formula (Ii) is 2R,3S,11bS isomers.

[0173] Some embodiments provide compounds of formula (Ik):

[0174]

[0175] or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definitions as described herein above and below. The stereochemistry of the compound of formula (Ik) is 2S, 3S, 11bS isomers.

[0176] Some embodiments provide a compound as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an elimination t of ≥ 420 minutes 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 elimination t of ≥ 400 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 375 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 350 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 325 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 300 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 275 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 250 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 225 minutes. 1 / 2 In some embodiments, the compound has an elimination t of ≥ 200 minutes. 1 / 2 .

[0177] Some embodiments provide a compound as described herein or a pharmaceutically acceptable salt thereof, wherein the compound has an IC 50 IC > 6,000 nM determined by a method such as that described in Example 18 50 In some embodiments, the compound has an IC of >5,000 nM for CYP2D6 50 In some embodiments, the compound has an IC of >4,000 nM for CYP2D6 50 In some embodiments, the compound has an IC of >3,000 nM for CYP2D6 50 In some embodiments, the compound has an IC of >2,000 nM for CYP2D650 In some embodiments, the compound has an IC of >5,000 nM against CYP3A4 50 In some embodiments, the compound has an IC of >4,000 nM for CYP3A4 50 In some embodiments, the compound has an IC of >3,000 nM for CYP3A4 50 In some embodiments, the compound has an IC of >2,000 nM for CYP3A4 50 In some embodiments, the compound is substantially inactive against CYP2D6. In some embodiments, the compound is substantially inactive against CYP3A4.

[0178] Some embodiments provide a compound as described herein or a pharmaceutically acceptable salt thereof, wherein the compound has an IC 50 IC > 12,000 nM determined by a method such as that described in Example 19 50 In some embodiments, the compound has an IC of >11,000 nM for hERG 50 In some embodiments, the compound has an IC > 10,000 nM for hERG 50 In some embodiments, the compound has an IC of >9,000 nM for hERG 50 In some embodiments, the compound has an IC of >8,000 nM for hERG 50 In some embodiments, the compound has an IC of >7,000 nM for hERG 50 In some embodiments, the compound is substantially inactive towards hERG.

[0179] The phrase "compound as described herein" or "compounds as described herein" refers to any one or more compounds of the present disclosure above and below. In some embodiments, the compound is of formula (la). In some embodiments, the compound is of formula (lc). In some embodiments, the compound is of formula (le). In some embodiments, the compound is of formula (Ig). In some embodiments, the compound is of formula (Ii). In some embodiments, the compound is of formula (Ik).

[0180] In some embodiments, R 1Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl, C5-C 11 - spirocycloalkyl, cubic alkyl-C1-C4-alkylene and 4-8 membered heterobicyclyl-C1-C4-alkylene;

[0181] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

[0182] In some embodiments, R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl and C5-C 11 - spirocycloalkyl;

[0183] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

[0184] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-;

[0185] Each R 1The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

[0186] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl;

[0187] Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

[0188] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-;

[0189] Each R 1 The group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0190] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl;

[0191] Each R 1 The group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0192] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-;

[0193] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0194] In some embodiments, R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl;

[0195] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0196] In some embodiments, R 1 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 spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-;

[0197] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0198] In some embodiments, R 1Selected 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 spiroheterocyclyl and C7-spirocycloalkyl;

[0199] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

[0200] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl, and (2-oxabicyclo[2.1.1]hexyl)methyl;

[0201] Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0202] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl;

[0203] Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0204] In some embodiments, R 1Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl;

[0205] wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0206] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl;

[0207] wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0208] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl;

[0209] wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0210] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl and (cyclobutyl)ethyl;

[0211] wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0212] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl;

[0213] wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0214] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl and (cyclobutyl)ethyl;

[0215] wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0216] In some embodiments, R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1 .1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[2.1.1]hex-1-yl)methyl and (2-oxabicyclo[2.1.1]hex-4-yl)methyl;

[0217] Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0218] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;

[0219] Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0220] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1 .1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[2.1.1]hex-1-yl)methyl and (2-oxabicyclo[2.1.1]hex-4-yl)methyl;

[0221] wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0222] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl;

[0223] wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

[0224] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, 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-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[2.1.1]hex-1-yl)methyl and (2-oxabicyclo[2.1.1]hex-4-yl)methyl;

[0225] wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0226] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, and 1-(cyclobutyl)ethyl;

[0227] wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0228] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, 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-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[2.1.1]hex-1-yl)methyl and (2-oxabicyclo[2.1.1]hex-4-yl)methyl;

[0229] wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0230] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, and 1-(cyclobutyl)ethyl;

[0231] wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

[0232] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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 1-(difluoromethyl)cyclopropyl)methyl, 1,1,1-trifluoropropyl-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 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, 1-(1-methyl)pyrrolidin-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 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-dimethylsiloxane-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.

[0233] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl) methyl , 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]pent-1-yl)methyl, fluoromethyl, (2,2 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2, 2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl and (2,2-difluorocyclobutyl)methyl.

[0234] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl 1-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.

[0235] In some embodiments, R 1 is (cyclopentyl)methyl. In some embodiments, R 1 In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 is (1-(cyanomethyl)cyclopropyl)methyl. In some embodiments, R 1 In some embodiments, R 1 is (1-fluorocyclobutyl)methyl. In some embodiments, R 1 In some embodiments, R 1 is 2-(cyano(cyclopropyl)methoxy)ethyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is (1-hydroxycyclobutyl)methyl. In some embodiments, R 1 is 2-cyclopropyloxyethyl. In some embodiments, R 1 is 2-fluoro-2-methylpropyl. In some embodiments, R 1 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 In some embodiments, R 1 is (1-fluorocyclopropyl)methyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is ethyl-d5. In some embodiments, R 1 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 In some embodiments, R 1 In some embodiments, R 1 is 2-((2-cyanoprop-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 1In some embodiments, R 1 is oxetan-3-ylmethyl. In some embodiments, R 1 is (oxetan-2-yl)methyl. In some embodiments, R 1 is 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R 1 is 4,4,4-trifluorobutyl. 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 In some embodiments, R 1 is (2,2-difluorocyclopropyl)methyl. In some embodiments, R 1 is 2-(trifluoromethoxy)ethyl. In some embodiments, R 1 In some embodiments, R 1 is (1-methylcyclobutyl)methyl. In some embodiments, R 1 is (2-methylcyclopropyl)methyl. In some embodiments, R 1 is (2,2-difluorocyclopentyl)methyl. In some embodiments, R 1 is 3-fluorocyclobut-2-en-1-yl. In some embodiments, R 1 is 2-oxaspiro[3.3]hept-6-yl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 3,3-dimethylcyclobutyl. In some embodiments, R 1 is spiro[3.3]hept-2-yl. In some embodiments, R 1 is 1-methylpyrrolidin-3-yl. In some embodiments, R 1 is (3-methyloxetan-3-yl)methyl. In some embodiments, R 1 is (1-methylcyclopropyl)methyl. In some embodiments, R 1 In some embodiments, R 1 is (2-fluorocyclopropyl)methyl. In some embodiments, R 1is (2,2-difluoro-3-methylcyclopropyl)methyl. In some embodiments, R 1 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. 1 In some embodiments, R 1 In some embodiments, R 1 is 3-(dimethylamino)cyclobutyl. In some embodiments, R 1 In some embodiments, R 1 is (1-cyanocyclobutyl)methyl. In some embodiments, R 1 is (1-cyanocyclopropyl)methyl. In some embodiments, R 1 In some embodiments, R 1 is (1-(methylsulfonyl)cyclopropyl)methyl. In some embodiments, R 1 is 3-(methylsulfonyl)propyl. In some embodiments, R 1 is 2-(methylsulfonyl)ethyl. In some embodiments, R 1 is 3,3-difluorocyclobutyl. In some embodiments, R 1 is (2,2-difluorocyclobutyl)methyl. In some embodiments, R 1 is (cuban-1-yl)methyl. In some embodiments, R 1 is (bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is (bicyclo[2.1.1]hex-1-yl)methyl. In some embodiments, R 1 is (1,1-dimethylsiloxane-3-yl)methyl. In some embodiments, R 1 is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is (2-oxabicyclo[2.1.1]hex-1-yl)methyl. In some embodiments, R 1 It is (2-oxabicyclo[2.1.1]hex-4-yl)methyl.

[0236] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl 1-(2-((2-cyanopropyl)oxy)ethyl)-1,1,1-trifluoropropyl-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 pentyl, (3-fluorobicyclo[1.1.1]pent-1-yl)methyl, fluoromethyl, (2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl )methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, 3,3-difluorocyclobutyl and (2,2-difluorocyclobutyl)methyl.

[0237] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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-cyanoprop-2-yl)oxy)ethyl, 1,1,1-trifluoroprop-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclo propyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-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 methyl, ((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-cyano 1-(methylsulfonyl)cyclopropyl)methyl, (R)-3,3,3-trifluoro-2-hydroxypropyl, (S)-2-hydroxypropyl, (R)-2-methoxypropyl, (S)-2-methoxypropyl, (1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, (2,2-difluorocyclobutyl)methyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, (1r,3R)- 3-methoxycyclobutyl, (1r,3R)-3-(dimethylamino)cyclobutyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsiloxane-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. .

[0238] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanoprop-2-yl)oxy)ethyl, 1,1,1-trifluoroprop-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1S,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-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 1-(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 methyl, (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.

[0239] It should be understood that the R 1 The stereochemistry of the group is based on the R bonded to the oxygen as shown in the formulae provided herein (e.g., Formula (Ia), Formula (Ic), Formula (Ie), Formula (Ig), Formula (Ii), and Formula (Ik)). 1 Group specified.

[0240] 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, R1 is (1s,3S)-3-fluorocyclobutyl. In some embodiments, R 1 is ((1R,2S)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((1S,2R)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl. In some embodiments, R 1 is ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl. In some embodiments, R 1 is (S)-1-cyclobutylethyl. In some embodiments, R 1 is (R)-1-cyclobutylethyl. In some embodiments, R 1 is ((1S,2S)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((1R,2R)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((S)-2,2-dimethylcyclopropyl)methyl. In some embodiments, R 1 is (1s,3S)-3-(trifluoromethyl)cyclobutyl. In some embodiments, R 1 is (R)-2-fluoropropyl. 1 is (S)-2-fluoropropyl. 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. 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. 1 is (1r,3R)-3-methoxycyclobutyl. In some embodiments, R 1 It is (1r,3R)-3-(dimethylamino)cyclobutyl.

[0241] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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-cyanoprop-2-yl)oxy)ethyl, 1,1,1-trifluoroprop-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclo propyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl , (R)-1-cyclobutylethyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((1R,2R)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (1s,3S)-3-methoxycyclobutyl, cyanomethyl, (1 -cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (R)-3,3,3-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-methyl Oxycyclobutyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsiloxane-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.

[0242] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl) methoxy) ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3, 3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanoprop-2-yl)oxy)ethyl, 1,1,1-trifluoroprop-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptyl, (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-difluoro cyclopentyl)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. .

[0243] In some embodiments, R 1 It is C3-C7-cycloalkyl-C1-C4-alkylene.

[0244] In some embodiments, R 1 It is a C3-C7-cycloalkyl-C1-C4-alkylene group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0245] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl, cyano and C1-C4-alkylsulfonyl.

[0246] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl and cyano.

[0247] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one, two or three substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl and cyano.

[0248] In some embodiments, R 1 is C3-C5-cycloalkyl-C1-C2-alkylene which is optionally substituted by one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C1-haloalkyl, methyl, cyano and methylsulfonyl.

[0249] In some embodiments, R 1 is C3-C5-cycloalkyl-C1-C2-alkylene which is optionally substituted by one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C1-haloalkyl, methyl and cyano.

[0250] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)ethyl; wherein each group is optionally substituted by one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl, methyl and methylsulfonyl.

[0251] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl, methyl and methylsulfonyl.

[0252] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)ethyl; wherein each group is optionally substituted by one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl and methyl.

[0253] In some embodiments, R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl and methyl.

[0254] In some embodiments, R 1Selected 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, (1-(methylsulfonyl)cyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl.

[0255] In some embodiments, R 1 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.

[0256] In some embodiments, R 1 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.

[0257] In some embodiments, R 1 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.

[0258] In some embodiments, R 1 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, ((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.

[0259] In some embodiments, R 1Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S, 1-(methylsulfonyl)cyclopropyl)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.

[0260] In some embodiments, R 1 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, ((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 1-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 and (2,2-difluorocyclobutyl)methyl.

[0261] In some embodiments, R 1Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl) methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl, (R)-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.

[0262] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl and ((R)-2,2-difluorocyclopropyl)methyl.

[0263] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl and ((R)-2,2-difluorocyclopropyl)methyl.

[0264] In some embodiments, R 1 It is C1-C6-alkyl.

[0265] In some embodiments, R 1 is C1-C6-alkyl which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0266] In some embodiments, R 1 is C1-C6-alkyl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C4-alkoxy and C1-C4-alkylsulfonyl.

[0267] In some embodiments, R 1 is C1-C6-alkyl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano and C1-C4-alkoxy.

[0268] In some embodiments, R 1 is C1-C6-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano and C1-C4-alkoxy.

[0269] In some embodiments, R 1 is C1-C5-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano, methoxy and methylsulfonyl.

[0270] In some embodiments, R 1 is C1-C5-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano and methoxy.

[0271] In some embodiments, R 1 Selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from: fluoro, hydroxy, cyano, methoxy and methylsulfonyl.

[0272] In some embodiments, R 1 is selected from the group consisting of isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of fluoro, hydroxy, cyano, methoxy and methylsulfonyl.

[0273] In some embodiments, R 1 Selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from: fluoro, hydroxy, cyano and methoxy.

[0274] In some embodiments, R 1 is selected from the group consisting of isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of fluoro, hydroxy, cyano and methoxy.

[0275] In some embodiments, R 1Selected 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.

[0276] In some embodiments, R 1 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.

[0277] In some embodiments, R 1 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.

[0278] In some embodiments, R 1 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.

[0279] In some embodiments, R 1Selected 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-trifluoroprop-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.

[0280] In some embodiments, R 1 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-trifluoroprop-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.

[0281] In some embodiments, R 1 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.

[0282] In some embodiments, R 1Selected 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.

[0283] In some embodiments, R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl and ethyl-d5.

[0284] In some embodiments, R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and ethyl.

[0285] In some embodiments, R 1 It is C3-C7-cycloalkyl.

[0286] In some embodiments, R 1 is a C3-C7-cycloalkyl group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0287] In some embodiments, R 1 is C3-C7-cycloalkyl which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C2-C4-dialkylamino.

[0288] In some embodiments, R 1 is C3-C7-cycloalkyl which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy.

[0289] In some embodiments, R 1 is C3-C7-cycloalkyl which is optionally substituted by one or two substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy.

[0290] In some embodiments, R 1 is C3-C5-cycloalkyl which is optionally substituted by one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl, methoxy and dimethylamino.

[0291] In some embodiments, R 1 is C3-C7-cycloalkyl which is optionally substituted by one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl and methoxy.

[0292] In some embodiments, R 1 Selected from: cyclopentyl, cyclobutyl and cyclopropyl; wherein each group is optionally substituted by one or two substituents selected from: cyano, fluoro, methyl, trifluoromethyl, methoxy and dimethylamino.

[0293] In some embodiments, R 1 Selected from: cyclopentyl, cyclobutyl and cyclopropyl; wherein each group is optionally substituted with one or two substituents selected from: cyano, fluoro, methyl, trifluoromethyl and methoxy.

[0294] In some embodiments, R 1 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.

[0295] In some embodiments, R 1 Selected from cyclopentyl, cyclobutyl, cyclopropyl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, 3-(trifluoromethyl)cyclobutyl, 3-methoxycyclobutyl and 3,3-difluorocyclobutyl.

[0296] In some embodiments, R 1 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.

[0297] In some embodiments, R 1Selected 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.

[0298] In some embodiments, R 1 It is C1-C4-alkyl-O-C2-C4-alkylene.

[0299] In some embodiments, R 1 is C1-C4-alkyl-O-C2-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0300] In some embodiments, R 1 is C1-C4-alkyl-O-C2-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen and C3-C6-cycloalkyl.

[0301] In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen and cyclopropyl.

[0302] In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene which is optionally substituted by one, two or three substituents selected from the group consisting of cyano, halogen and cyclopropyl.

[0303] In some embodiments, R 1 Selected from: methoxyethyl, ((propyl)oxy)ethyl and methoxypropyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, fluoro and cyclopropyl.

[0304] In some embodiments, R 1 Selected from: 2-(methoxy)ethyl, 2-methoxyethyl, 2-((prop-2-yl)oxy)ethyl and 3-methoxypropyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, fluoro and cyclopropyl.

[0305] In some embodiments, R 1 Selected from: 2-(cyano(cyclopropyl)methoxy)ethyl, 2-methoxyethyl, 2-((2-cyanoprop-2-yl)oxy)ethyl, 3-methoxypropyl and 2-(trifluoromethoxy)ethyl.

[0306] In some embodiments, R 1 It is C3-C7-cycloalkyl-O-C2-C4-alkylene.

[0307] In some embodiments, R 1 It is C3-C7-cycloalkyl-O-C2-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0308] In some embodiments, R 1 It is cyclopropyloxyethyl.

[0309] In some embodiments, R 1 It is a 3-7 membered heterocyclic group.

[0310] In some embodiments, R 1 It is a 3-7 membered heterocyclic group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0311] In some embodiments, R 1 is a 3- to 7-membered heterocyclyl group which is optionally substituted by one or more C1-C4-alkyl substituents.

[0312] In some embodiments, R 1 is a 4-5 membered heterocyclyl group which is optionally substituted by one or more C1-C4-alkyl substituents.

[0313] In some embodiments, R 1 is a 4-5 membered heterocyclyl group which is optionally substituted by one C1-C4-alkyl substituent.

[0314] In some embodiments, R 1 It is a 4-membered heterocyclic group.

[0315] In some embodiments, R 1is oxetan-3-yl or pyrrolidin-3-yl; wherein each group is optionally substituted with one methyl substituent.

[0316] In some embodiments, R 1 It is oxetan-3-yl or 1-methylpyrrolidin-3-yl.

[0317] In some embodiments, R 1 It is a 3-7 membered heterocyclyl-C1-C4-alkylene group.

[0318] In some embodiments, R 1 It is a 3-7 membered heterocyclyl-C1-C4-alkylene group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0319] In some embodiments, R 1 is 3-7 membered heterocyclyl-C1-C4-alkylene optionally substituted by one or more C1-C4 alkyl substituents.

[0320] In some embodiments, R 1 is (4-5 membered heterocyclyl)CH2- optionally substituted by one or more methyl substituents.

[0321] In some embodiments, R 1 is (4-membered heterocyclyl)CH2- optionally substituted by one or more methyl substituents.

[0322] In some embodiments, R 1 is (4-5 membered heterocyclyl)CH2- optionally substituted by one methyl substituent.

[0323] In some embodiments, R 1 is (4-membered heterocyclyl)CH2- optionally substituted by one methyl substituent.

[0324] In some embodiments, R 1 is (oxetanyl)methyl or (siloxanyl)methyl; wherein each group is optionally substituted with one or two methyl substituents.

[0325] In some embodiments, R 1 Selected from (oxetan-3-yl)methyl, (oxetan-2-yl)methyl and (siloxane-3-yl)methyl; wherein each group is optionally substituted with one or two methyl substituents.

[0326] In some embodiments, R 1is (oxetan-3-yl)methyl or (oxetan-2-yl)methyl; wherein each group is optionally substituted with one methyl substituent.

[0327] In some embodiments, R 1 Selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl and (1,1-dimethylsiloxane-3-yl)methyl.

[0328] In some embodiments, R 1 Selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl and (3-methyloxetan-3-yl)methyl.

[0329] In some embodiments, R 1 Selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl and (1,1-dimethylsiloxane-3-yl)methyl.

[0330] In some embodiments, R 1 Selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl and (3-methyloxetan-3-yl)methyl.

[0331] In some embodiments, R 1 It is a C4-C8-bicycloalkyl-C1-C4-alkylene group.

[0332] In some embodiments, R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from halogen and C1-C4-haloalkyl.

[0333] In some embodiments, R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted by one or more substituents selected from fluorine and trifluoromethyl.

[0334] In some embodiments, R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted by one substituent selected from fluoro and trifluoromethyl.

[0335] In some embodiments, R 1 is (bicyclo[1.1.1]pentyl)methyl or (bicyclo[2.1.1]hexyl)methyl; wherein each group is optionally substituted with one substituent selected from the group consisting of fluoro and trifluoromethyl.

[0336] In some embodiments, R 1is (bicyclo[1.1.1]pentan-1-yl)methyl or (bicyclo[2.1.1]hexan-1-yl)methyl; wherein each group is optionally substituted with one substituent selected from the group consisting of fluoro and trifluoromethyl.

[0337] In some embodiments, R 1 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.

[0338] In some embodiments, R 1 It is a C4-C8-bicycloalkyl-C1-C4-alkylene group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0339] In some embodiments, R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene which is optionally substituted by one or more halogen substituents.

[0340] In some embodiments, R 1 is (C5-bicycloalkyl)CH2- optionally substituted by one or more fluorine substituents.

[0341] In some embodiments, R 1 is (C5-bicycloalkyl)CH2- optionally substituted by one fluorine substituent.

[0342] In some embodiments, R 1 is (bicyclo[1.1.1]pentyl)methyl optionally substituted by one fluoro substituent.

[0343] In some embodiments, R 1 is (bicyclo[1.1.1]pent-1-yl)methyl optionally substituted by one fluoro substituent.

[0344] In some embodiments, R 1 It is a C4-C7-cycloalkenyl group.

[0345] In some embodiments, R 1is a C4-C7-cycloalkenyl group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0346] In some embodiments, R 1 is C4-C7-cycloalkenyl which is optionally substituted by one or more halogen substituents.

[0347] In some embodiments, R 1 is C4-cycloalkenyl optionally substituted by one halogen substituent.

[0348] In some embodiments, R 1 is cyclobutenyl optionally substituted by one fluoro substituent.

[0349] In some embodiments, R 1 is cyclobut-2-en-1-yl optionally substituted by one fluoro substituent.

[0350] In some embodiments, R 1 It is a 5-11 membered spiroheterocyclic group.

[0351] In some embodiments, R 1 It is a 5-11 membered spiroheterocyclyl group which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0352] In some embodiments, R 1 It is a 5-11 membered spiroheterocyclic group.

[0353] In some embodiments, R 1 It is a 7-membered spiroheterocyclic group.

[0354] In some embodiments, R 1 It is oxaspiro[3.3]heptyl.

[0355] In some embodiments, R 1 It is C5-C 11 -spirocycloalkyl.

[0356] In some embodiments, R 1 is C5-C 11- Spirocycloalkyl: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

[0357] In some embodiments, R 1 It is C5-C 11 -spirocycloalkyl.

[0358] In some embodiments, R 1 It is a C7-spirocycloalkyl group.

[0359] In some embodiments, R 1 It is spiro[3.3]heptyl.

[0360] In some embodiments, R 1 It is cubane-C1-C4-alkylene.

[0361] In some embodiments, R 1 It is (cuban-1-yl)methyl.

[0362] In some embodiments, R 1 It is a 4-8 membered heterobicyclyl-C1-C4-alkylene group.

[0363] In some embodiments, R 1 It is a 6-membered heterobicyclic group -CH2-.

[0364] In some embodiments, R 1 It is (2-oxabicyclo[2.1.1]hexyl)methyl.

[0365] In some embodiments, R 1 It is (2-oxabicyclo[2.1.1]hex-1-yl)methyl or (2-oxabicyclo[2.1.1]hex-4-yl)methyl.

[0366] One aspect of the present disclosure specifically encompasses compounds of formula (Ie):

[0367]

[0368] or a pharmaceutically acceptable salt thereof,

[0369] in:

[0370] R 1Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7 membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C5-C 11 - spirocycloalkyl and cubic alkyl-C1-C4-alkylene;

[0371] Each R 1 The radical is optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl and hydroxy.

[0372] One embodiment relates to compounds of formula (Ie):

[0373]

[0374] or a pharmaceutically acceptable salt thereof,

[0375] in:

[0376] R 1 Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7 membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene and C5-C 11 - spirocycloalkyl;

[0377] Each R 1 The radical is optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl and hydroxy.

[0378] In some embodiments, R 1 Selected from: R 1 Selected from: (C3-C5-cycloalkyl)CH2-, (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-spirocycloalkyl and (cubic alkyl)CH2-;

[0379] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0380] In some embodiments, R 1Selected from: R 1 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-spirocycloalkyl;

[0381] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0382] In some embodiments, R 1 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]pentyl)methyl, spiro[3.3]heptyl, (cubanyl)methyl and (bicyclo[2.1.1]hexyl)methyl;

[0383] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0384] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl and spiro[3.3]heptyl;

[0385] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0386] In some embodiments, R 1Selected 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-((prop-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]hept-2-yl, (cuban-1-yl)methyl and (bicyclo[2.1.1]hex-1-yl)methyl;

[0387] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0388] In some embodiments, R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, and spiro[3.3]hept-2-yl;

[0389] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

[0390] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-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-cyanoprop-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) 1-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl ... 1-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, and (bicyclo[2.1.1]hex-1-yl)methyl.

[0391] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanoprop-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2-yl) methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3 1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pent-1-yl)methyl, (2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, and 2-fluoropropyl.

[0392] In some embodiments, R 1 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, ethyl-d5, isopropyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl) methyl, (2,2-difluoro 1-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, (cuban-1-yl)methyl, and (bicyclo[1.1.1]pentan-1-yl)methyl.

[0393] In some embodiments, R 1Selected 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]hept-2-yl, (1-methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-dimethylcyclopropyl)methyl, 3-(trifluoromethyl)cyclobutyl and 2-fluoropropyl.

[0394] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-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- 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]pent-1-yl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclo 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]hept-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluorocyclopentyl)methyl 1-yl)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]hex-1-yl)methyl.

[0395] In some embodiments, R 1Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2- 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]pent-1-yl)methyl, ((S)-2,2-difluorocyclopropyl 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]hept-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl and (S)-2-fluoropropyl.

[0396] In some embodiments, R 1Selected from: (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-dimethyl cyclobutyl, spiro[3.3]hept-2-yl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl and (R)-2-fluoropropyl, (cuban-1-yl)methyl and (bicyclo[1.1.1]pent-1-yl)methyl.

[0397] In some embodiments, R 1 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, ((S)-2,2-difluorocyclopropyl) methyl, ((R)-2,2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl and (R)-2-fluoropropyl.

[0398] One embodiment relates to compounds of formula (Ie):

[0399]

[0400] or a pharmaceutically acceptable salt thereof,

[0401] in:

[0402] R 1 Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene and C4-C8-bicycloalkyl-C1-C4-alkylene;

[0403] Each R 1 The group is optionally substituted by one or more substituents selected from halogen, C1-C4-haloalkyl, cyano and hydroxy.

[0404] In some embodiments, R 1 Selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-;

[0405] Each R 1 The group is optionally substituted with one or more substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

[0406] In some embodiments, R 1 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-;

[0407] Each R 1 The group is optionally substituted with one or more substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

[0408] In some embodiments, R 1 Selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-CCH2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered heterocyclyl and (4-membered heterocyclyl)CH2-;

[0409] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

[0410] In some embodiments, R 1Selected 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-;

[0411] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

[0412] In some embodiments, R 1 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;

[0413] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

[0414] In some embodiments, R 1 is selected from the group consisting of: methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, pentyl and (bicyclo[1.1.1]pentyl)methyl;

[0415] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

[0416] In some embodiments, R 1 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;

[0417] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

[0418] In some embodiments, R 1is selected from the group consisting of: methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, 2-methoxyethyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, butyl, 3-methoxypropyl, (cyclobutyl)methyl, pentyl and (bicyclo[1.1.1]pent-1-yl)methyl;

[0419] Each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

[0420] In some embodiments, R 1 Selected from: 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-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.

[0421] In some embodiments, R 1 Selected from: 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, 3-oxacyclopropyl 1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl.

[0422] In some embodiments, R 1Selected from: 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, oxacyclopentane-3-yl 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.

[0423] In some embodiments, R 1 Selected from: methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl , ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.

[0424] One embodiment relates to compounds of formula (Ie):

[0425]

[0426] or a pharmaceutically acceptable salt thereof,

[0427] in:

[0428] R 1 Selected from: C1-C6-alkyl, C3-C7-cycloalkyl and C3-C7-cycloalkyl-C1-C4-alkylene; each of which is optionally substituted by one or more halogen substituents.

[0429] In some embodiments, R1 Selected from: C1-C6-alkyl, C3-C7-cycloalkyl and C3-C7-cycloalkyl-C1-C4-alkylene; wherein each group is optionally substituted by one, two or three halogen substituents.

[0430] In some embodiments, R 1 Selected from: C2-C3-alkyl, cyclopropyl, C3-C4-cycloalkyl-CD2- and C3-C4-cycloalkyl-CH2-; wherein each group is optionally substituted by one, two or three halogen substituents.

[0431] In some embodiments, R 1 Selected from: C2-C3-alkyl, cyclopropyl and C3-C4-cycloalkyl-CH2-; wherein each group is optionally substituted by one, two or three halogen substituents.

[0432] In some embodiments, R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three halogen substituents.

[0433] In some embodiments, R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three halogen substituents.

[0434] In some embodiments, R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three fluorine substituents.

[0435] In some embodiments, R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three fluorine substituents.

[0436] In some embodiments, R 1 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.

[0437] In some embodiments, R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

[0438] In some embodiments, R 1 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.

[0439] In some embodiments, R 1 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.

[0440] In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or two halogen substituents.

[0441] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.

[0442] In some embodiments, R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.

[0443] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two fluorine substituents.

[0444] In some embodiments, R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl; wherein each group is optionally substituted with one or two fluoro substituents.

[0445] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

[0446] In some embodiments, R 1 Selected from: (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

[0447] In some embodiments, R 1Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.

[0448] In some embodiments, R 1 is C1-C6-alkyl optionally substituted with one, two or three halogen substituents. 1 is ethyl or propyl; wherein each group is optionally substituted with one, two or three halogen substituents. 1 is ethyl or propyl; wherein each group is optionally substituted with one, two or three fluorine substituents. 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and ethyl.

[0449] In some embodiments, R 1 It is C3-C7-cycloalkyl.

[0450] In some embodiments, R 1 It is cyclopropyl.

[0451] Some embodiments include each combination of one or more compounds selected from the group of compounds shown in Table A below and pharmaceutically acceptable salts thereof. Some embodiments include each combination of one or more compounds selected from the group shown in Table A below.

[0452] Table A

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471] 1 A mixture of trans isomers (cyclopropyl).

[0472] 2 A mixture of cis isomers (cyclopropyl).

[0473] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups: (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-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2); 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-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 4); 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-butyloxy)-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-butyloxy)-9-cyclobutyloxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 8); 2-(2-(((2R,3R,11b (R)-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-cyclopropyloxyethoxy)-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-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 19); -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 Quinolin-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 Hydrogen-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-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)-1,3,4,6,7,11b-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- (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); (2 R,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]pent-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]hept-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-fluorocyclobutyloxy)-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-fluorocyclobutyloxy)-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-dimethylcyclobutyloxy)-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]hept-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-methylpyrrolidin-3-yl)oxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 59); 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-methylcyclobutyloxy)-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-1,3,4,6,7,11 b-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)cyclobutyloxy)-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-methoxycyclobutyloxy)-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)cyclobutyloxy)-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-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)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,11b R)-3-(tert-butoxy)-9-(3,3-difluorocyclobutyloxy)-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- (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutyloxy)-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-methoxycyclobutyloxy)-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)cyclobutyloxy)-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); cis-(2R,3R,11bR)-3-(tert-butoxy)-9-((2-fluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 97). ,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. ;

[0474] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups: (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-(cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2); 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-(cyclobutylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 4); 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-butyloxy)-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-butyloxy)-9-cyclobutyloxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 8); 2-(2-(((2R,3R,11b (R)-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-cyclopropyloxyethoxy)-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-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 19); -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 Quinolin-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 Hydrogen-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-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)-1,3,4,6,7,11b-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- (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); (2 R,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]pent-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]hept-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-fluorocyclobutyloxy)-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-fluorocyclobutyloxy)-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-dimethylcyclobutyloxy)-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]hept-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-Butyloxy)-10-methoxy-9-(1-methylcyclobutyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 60); (2R,3R,11bR)-3-(tert-Butyloxy)-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-Butyloxy)-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); 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)cyclobutyloxy)-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)-1 0-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-methoxycyclobutyloxy)-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-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Idio[2,1-a]isoquinolin-2-ol (Compound 80); 1-((((2R,3R,11bR)-3-(tert-butyloxy)-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-butyloxy)-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,3 R,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 (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-difluorocyclobutyloxy)-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-2-ol -9-yl)oxy)cyclobutane-1-carbonitrile (Compound 92); (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-((1r,3R)-3-(trifluoromethyl)cyclobutyloxy)-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-methoxycyclobutyloxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol. 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-butyloxy)-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. ;

[0475] Some embodiments of the present invention include every combination of one or more compounds selected from the following groups: (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]isoquinolin-2-ol (Compound 10 0); (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,11b R)-3-(tert-butoxy)-9-((1,1-dimethylsiloxane-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)-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 105); )-9-((2-oxabicyclo[2.1.1]hex-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]hex-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.

[0476] Applicable intermediates

[0477] Certain intermediates as described herein above and below are novel and useful for preparing compounds such as compounds of Formula (Ia), Formula (Ic), Formula (Ie), Formula (Ig), Formula (Ii) and Formula (Ik). Figure 2A and Figure 2B Some intermediates are shown in .

[0478] In some embodiments, the compound is selected from: 3-(tert-butoxy)-4-(dimethylamino)butan-2-one; 1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one; 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-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 their salts.

[0479] In some embodiments, the compound is: 3-(tert-butoxy)-4-(dimethylamino)butan-2-one or a salt thereof:

[0480]

[0481] 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.

[0482] In some embodiments, the compound is selected from: 1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one; 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-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.

[0483] 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:

[0484]

[0485] 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.

[0486] 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:

[0487]

[0488] 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.

[0489] 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:

[0490]

[0491] In some embodiments, the salt is (2S,3S)-2,3-bis(4-methylbenzyloxy)succinic acid (DPTTA) salt. In some embodiments, the compound is:

[0492]

[0493] 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.

[0494] 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:

[0495]

[0496] 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.

[0497] It should also be understood that, for clarity, certain features described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0498] Pharmaceutical compositions, preparations and dosage forms

[0499] The present disclosure also provides pharmaceutical products, such as pharmaceutical compositions, formulations, unit dosage forms, and kits; each comprising a compound as described herein or a pharmaceutically acceptable salt thereof.

[0500] The present disclosure also provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the methods described herein, such as for treating hyperkinesia. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance; an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)).

[0501] The composition can also be formulated into pills, capsules, granules or tablets, which, in addition to the VMAT2 inhibitor, also contain diluents, dispersants and surfactants, binders and lubricants. Those skilled in the art can also further formulate the VMAT2 inhibitor in an appropriate manner and according to generally recognized practices, such as those disclosed in Remington above.

[0502] Methods of administration include systemic administration of VMAT2 inhibitors as described herein, preferably in the form of pharmaceutical compositions as discussed above. Systemic administration used herein includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions.

[0503] Pharmaceutical preparations for oral administration can be obtained by any suitable method, generally by uniformly mixing the compound with a liquid or finely divided solid carrier or both in the desired proportion, and processing the mixture after adding suitable auxiliaries, if desired, and, if desired, forming the resulting mixture into the desired shape to obtain tablets or dragee cores.

[0504] Conventional excipients, such as adhesives, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations can be in the form of dry powders, which can be reconstituted with water or another suitable liquid vehicle before use. Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filtering the solution before lyophilization, or simply filling and sealing a suitable vial or ampoule.

[0505] Some embodiments provide a method for preparing a pharmaceutical composition, comprising the step of admixing a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0506] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the drug substance such carriers as are known in the art to be appropriate.

[0507] In preparing a pharmaceutical composition, the drug substance is typically mixed (i.e., blended) with an excipient, diluted with an excipient or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid or liquid material that serves as a vehicle, carrier or medium for the drug substance. Thus, the composition can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in a solid state or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0508] For preparing pharmaceutical compositions in solid form, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, the excipient may be one or more substances which may also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. Also included are solid form preparations for conversion into liquid form preparations for oral administration immediately prior to use. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these preparations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0509] To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed uniformly therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0510] Liquid form preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents.

[0511] The pharmaceutical composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain a formulation agent such as a suspending agent, a stabilizing agent and / or a dispersing agent. Alternatively, the pharmaceutical composition may be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization from a solution, for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use.

[0512] The pharmaceutical composition can be formulated as an aqueous solution, a water-alcohol solution, a solid suspension, an emulsion, a liposomal suspension, or a lyophilized powder for reconstitution. Such a pharmaceutical composition can be administered directly or as a further diluted / reconstituted mixture. The routes of administration include intravenous push, intravenous infusion, perfusion, and drip.

[0513] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as desired.

[0514] Aqueous suspensions suitable for oral use may be prepared by dispersing the finely powdered drug substance with a viscous material in water.

[0515] For topical administration to the epidermis, the compounds described herein, or pharmaceutically acceptable salts thereof, may be formulated into gels, ointments, creams or lotions, or into transdermal patches. Additionally, formulations suitable for topical administration in the oral cavity include lozenges comprising the drug substance in a flavored matrix.

[0516] The solution or suspension can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or sprayer. The preparation can be provided in a single dose or multiple dose form. In the latter case of a dropper or pipette, this can be achieved by administering a solution or suspension of an appropriate predetermined volume to the patient. In the case of a sprayer, this can be achieved, for example, by a metered atomizing spray pump.

[0517] Administration to the respiratory tract can also be achieved by providing an aerosol formulation with a suitable propellant in a pressurized pack. If the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them, is administered as an aerosol, for example, as a nasal aerosol or by inhalation, this can be performed, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation device, a metered dose inhaler, or a dry powder inhaler.

[0518] Alternatively, the pharmaceutical composition can be provided in dry powder form, for example, a powder mixture of the compound in a suitable powder matrix (such as lactose, starch, starch derivatives). Suitably, the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example in gelatin capsules or cartridges, or blister packs, from which the powder can be administered by an inhaler.

[0519] The compounds as described herein, or pharmaceutically acceptable salts thereof, may also be administered via fast dissolving or sustained release compositions, wherein the compositions comprise a biodegradable fast dissolving or sustained release carrier.

[0520] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the drug substance. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or can be an appropriate number of any of these dosage forms in packaged form. In some embodiments, the pharmaceutical preparation is a tablet or capsule for oral administration. In some embodiments, the pharmaceutical preparation is a liquid formulated for intravenous administration.

[0521] The composition can be formulated in unit dosage form, each dose containing the drug substance or an equivalent mass of the drug substance. The term "unit dosage form" refers to physically discrete units of preparations suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, and a suitable excipient as described herein.

[0522] Liquid forms containing the drug substance may be incorporated for oral administration or administration by injection, including aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils.

[0523] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques, or can be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0524] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the composition is administered by oral or nasal respiratory route for local or systemic effect. The composition may be atomized by the use of an inert gas. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be connected to a mask support or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0525] If desired, the composition may be present in a package or dispenser device, which may contain one or more unit dosage forms containing a drug substance. The package may, for example, include a metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by notes associated with the container, which are in the form prescribed by a government agency that manages the manufacture, use or sale of the drug, and the notes reflect that the agency approves the drug form for human or veterinary administration. Such notes, for example, may be a label for a prescription drug approved by the U.S. Food and Drug Administration, or an approved product instruction sheet. Compositions of compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0526] For preparing solid compositions, such as tablets, the drug substance can be mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of the components. When referring to these preformulation compositions as homogeneous, the drug substance is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets and capsules.

[0527] Kits are provided having unit doses, typically oral or injectable doses, of one or more compounds described herein or pharmaceutically acceptable salts thereof. Such kits may include a container containing the unit dose, an informational package insert describing the use of the drug in treating the relevant pathological condition and the attendant benefits, and optionally an implement or device for delivering the composition.

[0528] The compounds described herein, or pharmaceutically acceptable salts thereof, can be effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual, the severity of the individual's symptoms, etc.

[0529] The amount of the compound or composition administered to an individual will also vary depending on the drug being administered, the purpose of the administration (such as prevention or treatment), the state of the individual, the mode of administration, etc. In therapeutic applications, the composition can be administered to an individual already suffering from a disease in an amount sufficient to cure or at least partially prevent the symptoms and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease condition being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and overall condition of the individual.

[0530] The desired dose can be conveniently presented in a single dose or in a divided dose administered at appropriate intervals (e.g., twice, three times, four times or more sub-doses per day). The sub-dose itself can be further divided into, for example, multiple discrete loose intervals for administration. The daily dose can be divided into several, for example, two, three or four parts for administration, particularly when it is considered that a relatively large amount of administration is suitable. If appropriate, it may be necessary to deviate upward or downward from the indicated daily dose, depending on individual behavior.

[0531] It will be apparent to those skilled in the art that the dosage forms described herein may include a compound described herein or a pharmaceutically acceptable salt thereof.

[0532] preparation

[0533] As used herein, a "preparation" is the product of a process for preparing or isolating a compound as disclosed and described herein, wherein the preparation comprises at least one other component in addition to the compound. In some embodiments, a preparation comprises a chemical entity.

[0534] As used herein, a "chemical entity" defined in the context of a "formulation" refers to a compound as disclosed and described herein and at least one other component in addition to the compound. For example, a chemical entity can be a co-crystal or salt of a compound as disclosed and described herein.

[0535] Some embodiments provide formulations comprising compounds as disclosed and described herein. In some embodiments, the compound is a component of a chemical entity. In some embodiments, the chemical entity is a salt of a compound as disclosed and described herein. In some embodiments, the chemical entity is a (2S, 3S)-2,3-bis(4-methylbenzyloxy)succinic acid (DPTTA) salt of a compound as disclosed and described herein.

[0536] In some embodiments, the compound of the formulation is in an enantiomeric excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, 99.9%, or 100%, or an enantiomeric excess within the range defined by any of the preceding numbers. In some embodiments, the compound of the formulation is in 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 the range defined by any of the preceding numbers.

[0537] In some embodiments, the compound of the formulation is in 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 the range defined by any of the preceding numbers. In some embodiments, the compound of the formulation is in 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 the range defined by any of the preceding numbers.

[0538] In some embodiments, the preparation comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 93% of the compound by weight, or the percentage compound within the range defined by any of the aforementioned numbers. In some embodiments, the preparation comprises at least 50%, 60%, 70%, 80%, 90% or 93% of the compound by weight, or the percentage compound within the range defined by any of the aforementioned numbers. In some embodiments, the preparation comprises up to 50%, 60%, 70%, 80%, 90%, 93% or 95% of the compound by weight, or the percentage compound within the range defined by any of the aforementioned numbers.

[0539] In some embodiments, the formulation comprises at least 50% of the compound by weight. In some embodiments, the formulation is in solid form, i.e., a solid formulation. In some embodiments, the formulation is used to prepare a pharmaceutical composition.

[0540] How to use

[0541] Compounds described herein are inhibitors of VMAT2. Therefore, the present disclosure includes methods of inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing the expression of VMAT2) by contacting VMAT2 with compounds disclosed and described herein or pharmaceutically acceptable salts thereof. In some embodiments, contact can be performed in vitro, such as VMAT2 being located in a purified preparation or in a cell outside the organism (e.g., in a tissue sample or cell preparation). In some embodiments, contact can be performed in vivo, such as VMAT2 being located in an organism.

[0542] The VMAT2 inhibitors described herein can reduce the level of monoamines in the central nervous system. Therefore, the present disclosure includes a method of reducing the level of monoamines in the central nervous system of an individual, comprising administering to the individual an amount of a compound as described herein or a pharmaceutically acceptable salt thereof sufficient to reduce the level of monoamines relative to the level before administration.

[0543] VMAT2 inhibitors as disclosed and described herein are believed to have utility in a wide range of therapeutic applications and can be used to treat or prevent various conditions caused by or associated with inhibition of human vesicular monoamine transporter isoform 2. These conditions include neurological and psychiatric conditions, such as hyperkinesia, schizophrenia, and mood disorders. The compounds as described herein, or pharmaceutically acceptable salts thereof, can be used in any of the methods of treatment disclosed and described herein.

[0544] Therefore, in various embodiments as disclosed herein, a method of treating or preventing a neurological and / or psychiatric disease or condition in an individual in need thereof is provided by administering to the individual a pharmaceutically effective amount of a VMAT2 inhibitor as described herein or a pharmaceutically acceptable salt thereof. The neurological and / or psychiatric disease or condition may be, for example, hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder (e.g., restricted and repetitive behaviors associated with autism spectrum disorder (ASD)), Rett syndrome or chorea-acanthocytosis.

[0545] In various other embodiments as disclosed herein, a method of treating or preventing a vesicular monoamine transporter-2 (VMAT2) disease or disorder in an individual in need thereof is provided by administering to the individual a pharmaceutically effective amount of a VMAT2 inhibitor as described herein or a pharmaceutically acceptable salt thereof. The VMAT2 disease or disorder can be, for example, ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood disorders or psychotic disorders; neurological disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

[0546] Thus, in various embodiments as disclosed herein, a method of treating or preventing hyperkinesia in an individual in need thereof is provided by administering to an individual in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the hyperkinesia is tardive dyskinesia, Tourette syndrome, Huntington's disease, chorea associated with Huntington's disease, or tics. In other embodiments, the hyperkinesia is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, or tremor.

[0547] In some embodiments, a method of treating or preventing a mood disorder in an individual in need thereof is provided by administering a pharmaceutically effective amount of a VMAT2 inhibitor as described herein or a pharmaceutically acceptable salt thereof to an individual in need thereof. In some embodiments, the mood disorder is bipolar disorder, major depressive disorder, mania in a mood disorder, or depression in a mood disorder.

[0548] In some embodiments as disclosed herein, methods are provided for treating or preventing schizophrenia or schizoaffective disorder in an individual in need thereof by administering to the individual in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof.

[0549] In some embodiments, the neurological or psychiatric disease or disorder is hypermovement disorder.

[0550] In some embodiments, the hypermovement disorder is tardive dyskinesia.

[0551] In some embodiments, the hypermovement disorder is Tourette's syndrome.

[0552] In some embodiments, the hypermovement disorder is Huntington's disease.

[0553] In some embodiments, the hypermovement disorder is convulsions.

[0554] In some embodiments, the hypermovement disorder is chorea associated with Huntington's disease.

[0555] In some embodiments, the hypermovement disorder is ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

[0556] In some embodiments, the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder.

[0557] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.

[0558] In some embodiments, the neurological or psychiatric disease or condition is schizoaffective disorder.

[0559] In some embodiments, the neurological or psychiatric disease or disorder is obsessive compulsive disorder.

[0560] In some embodiments, the neurological or psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder.

[0561] In some embodiments, the neurological or psychiatric disease or condition is an autism spectrum disorder.

[0562] In some embodiments, the neurological or psychiatric disease or condition is restricted and repetitive behaviors associated with autism spectrum disorder (ASD).

[0563] In some embodiments, the neurological or psychiatric disease or condition is obsessions and compulsions in some and non-responders (or completely refractory) with obsessive-compulsive disorder (OCD). In some embodiments, the neurological or psychiatric disease or condition is obsessions and compulsions in some 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 can be used as adjunctive therapy or adjunctive treatment for schizophrenia. In some embodiments, the compounds described herein are administered as adjunctive therapy, wherein the primary therapy is treatment with an antidepressant.

[0564] In some embodiments, the neurological or psychiatric disease or condition is bipolar I disorder. In some embodiments, the compounds described herein are administered as monotherapy for the treatment of bipolar I disorder. In some embodiments, the compounds described herein are administered as maintenance therapy for the treatment of bipolar I disorder. In some embodiments, the compounds described herein are administered as monotherapy or maintenance therapy for the treatment of bipolar I disorder.

[0565] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat or prevent a disease or condition selected from:

[0566] ataxia or spinal muscular atrophy, such as spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital bulbar muscular atrophy, dentate-pallidum atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia;

[0567] Chorea, such as benign hereditary chorea, chorea, chorea associated with mitochondrial disease / etiology, chorea associated with Wilson's disease, chorea of ​​pregnancy, chorea-acanthocytosis, drug-induced chorea, hemiballismus, rheumatic / petit chorea, and thyrotoxic / hyperthyroid chorea;

[0568] Congenital malformations, deformations or anomalies, such as Angelman syndrome, congenital neurological disorders, Ehrlich syndrome, neurofibromatosis, congenital facial nerve dysplasia, Moebius syndrome type II, Cockayne syndrome, Sjögren-Larson syndrome, Laumontg syndrome, fragile X syndrome and Prader-Willi syndrome;

[0569] Dementia, such as AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, dementia with Lewy bodies, microinfarct dementia, presenile dementia, senile dementia, and vascular dementia;

[0570] Oral, salivary gland, and jaw disorders, such as burning tongue / mouth syndrome and temporomandibular joint disorder;

[0571] Movement disorders, such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal dyskinesia, paroxysmal non-dyskinesia, and respiratory dyskinesia;

[0572] Dystonias such as blepharospasm, bucco-lingual syndrome, acute drug-induced dystonia, dystonia, early-onset primary dystonia, hereditary torsion dystonia, hand dystonia / writer's cramp, idiopathic non-familial dystonia, idiopathic orofacial dystonia / Meige's disease, laryngeal dystonia, oromandibular dystonia, and spasmodic torticollis / cervical dystonia;

[0573] Endocrine, nutritional and metabolic diseases, such as Wilson's disease, diabetes, obesity, X-linked syndromes and Lesch-Nyhan syndrome;

[0574] Epilepsy, such as Baltic myoclonic epilepsy, benign familial neonatal seizures, epilepsy, congenital epilepsy, myoclonic epilepsy of Laforna, severe myoclonic epilepsy of infancy, and convulsions;

[0575] Habit and impulse disorders, such as bulimia, kleptomania, impulse control disorders, trichotillomania, intermittent explosive disorder, pathological gambling, and pyromania;

[0576] Huntington's disease or a related disorder, such as Huntington's disease, Huntington's disease-like syndrome 1-3, Huntington's disease and X-linked MacLeod neuroacanthocytosis syndrome;

[0577] Mood or psychotic disorders, such as schizophrenia, psychosis, mania, bipolar disorder, depression, and mood disorders;

[0578] Other diseases or conditions, such as groping disorder, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit syndrome, spasticity, high and low phenomena, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders, and rheumatoid arthritis;

[0579] Neurotic, stress-related and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder and psychomovement disorders;

[0580] Other degenerative diseases of the basal ganglia, such as pantothenate kinase-related neurodegenerative diseases, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglia degenerative diseases, and neuroferritinopathy;

[0581] Other extrapyramidal and movement disorders, such as hemiballismus, extrapyramidal disorders, essential tremor, chin tremor, startle hyperactivity, akathisia, ballismus / hemiballismus, myoclonus, and restless legs syndrome / Wells-Ekbom syndrome;

[0582] Other neurological or motor functions, such as sleep-related bruxism, abnormal involuntary movement disorders, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, clonic hemifacial spasm, olfactory nerve hypoplasia, congenital cranial nerve palsy, motor ataxia syndrome, familial periodic paralysis, congenital hemiplegia, fine motor delay, fine motor skill dysfunction, gross motor delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, alternating hemiplegia of childhood, motor delay, cerebral palsy, pediatric cerebral palsy, postural disorders, pseudoplegia, psychomotor hyperactivity, bradykinesia, synkinesia, akinesia, Riley-Day syndrome and cheilemyopathies;

[0583] Parkinsonism / parkinsonism, such as parkinsonism, drug-induced parkinsonism, micrographia, and parkinsonism;

[0584] Childhood-onset behavioral and mood disorders such as attention deficit hyperactivity disorder, attention deficit disorder, hyperkinesia, hyperkinesia (neonatal), oppositional defiant disorder, transient tic disorder, persistent (long-lasting) motor or vocal tic disorder, stereotypic movement disorder, and stereotypic and Tourette syndrome;

[0585] Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger syndrome, pervasive developmental disorder NOS, and dyslexia; and

[0586] Substance abuse or dependence, such as addictive disorders, alcoholism, cocaine dependence, illicit drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine analog abuse, nicotine dependence, polydrug abuse, and prescription drug abuse.

[0587] In some embodiments, a compound as described herein or a pharmaceutically acceptable salt thereof is administered to a patient to treat or prevent paralysis. In some embodiments, the paralysis is selected from: spastic cerebral palsy (including but not limited to spastic hemiplegic cerebral palsy, spastic diplegic cerebral palsy, and spastic quadriplegic cerebral palsy), dyskinetic cerebral palsy, ataxic cerebral palsy, and "mixed" cerebral palsy.

[0588] In some embodiments, the palsy is spastic cerebral palsy.

[0589] In some embodiments, the paralysis is dyskinetic cerebral palsy.

[0590] In some embodiments, the palsy is ataxic cerebral palsy.

[0591] In some embodiments, the palsy is "mixed" cerebral palsy.

[0592] The phrase "mixed" cerebral palsy includes a mixture of symptoms associated with other types of cerebral palsy.

[0593] In some embodiments, it has been determined that the patient being treated has 22q11.2 deletion syndrome. In some embodiments, because the patient suffers from 22q11.2 deletion syndrome, the patient is prone to developing a psychotic disorder. In some embodiments, it has been determined that the patient has COMT haploinsufficiency. In some embodiments, because the patient suffers from COMT haploinsufficiency, the patient is prone to developing a psychotic disorder.

[0594] In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in vivo in a mammal to compounds that can inhibit human vesicular monoamine transporter isoform 2. Thus, these VMAT2 inhibitors can have additional utility in altering the in vivo properties of metabolites in mammals, such as maximum concentration or duration of action.

[0595] Characterization of any VMAT2 inhibitor described herein can be determined using the methods described herein and those skilled in the art. For example, dopamine consumption can be determined using a motor activity (LMA) assay. Another in vivo animal model includes a conditioned avoidance response (CAR) test, which has been shown to be an effective and reliable preclinical model for evaluating the antipsychotic activity of a compound.

[0596] Combination therapy

[0597] Compounds disclosed herein and pharmaceutically acceptable salts thereof can be used as monotherapy, or used in combination with one or more other agents. In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are administered together (simultaneously or sequentially) with one or more selected from the following drugs: antidepressants, antipsychotics (typical or atypical), antiepileptics, antibacterials, antiarrhythmics, mood stabilizers and gastrointestinal drugs. In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are used for adjunctive therapy, which refers to the treatment used in conjunction with the primary treatment, and its purpose is to assist the primary treatment. Adjunctive therapy is generally a therapy administered in conjunction with the primary treatment. As an example of adjunctive therapy, if obsessive-compulsive disorder is being treated, the primary therapy may be, for example, an antidepressant, and the co-administration of compounds as described herein will be considered as adjunctive therapy.

[0598] Compound synthesis

[0599] Detailed methods of synthesizing the compounds are described herein in the Examples. Typically, the starting components are commercially available chemicals and can be obtained from commercial sources or can be prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature.

[0600] In general, the compounds used in the reactions described herein can be prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. Methods known to those of ordinary skill in the art can be identified through various reference books and databases. Suitable reference books and papers detailing the synthesis of reactants that can be used to prepare compounds of the present disclosure or providing references to articles describing the preparations include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; T L Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992.

[0601] Specific and similar reactants can also be identified by indexes of known chemical substances prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries and by online databases (the American Chemical Society, Washington, DC, can be contacted for more details). Known but unlisted chemicals can be prepared by custom chemical synthesis agencies according to known methods, and many standard chemical supply agencies (such as those listed above) provide custom synthesis services.

[0602] Example

[0603] The following examples are included to illustrate embodiments of the present disclosure. However, based on the present disclosure, it will be appreciated by those skilled in the art that many changes may be made to the disclosed specific embodiments without departing from the spirit and scope of the present disclosure, and still obtaining the same or similar results. Other exemplary syntheses of the compounds of the present invention are illustrated in the accompanying drawings, wherein the symbols have the same definitions as used in the present disclosure.

[0604] In a UV detector (Dionex TM UVD 170u UV / VIS detector), corona array detector (Thermo TM Veo TM RS) and mass spectrometer (Dionex MSQ Plus TM Analytical HPLC analysis was performed on a Phenomenex LC-MS system using an ACN / water gradient containing 0.05% TFA. 18 Reverse phase preparative HPLC purification was performed on a Kinetix 5μ100A 150 x 21.2 mm column. The column was equipped with a UV detector (Waters TM 2998PhotodiodeArray Detector TM ) and mass spectrometer (Waters TM Acquity QDa Detector TM Waters TM Prep 100q TM Supercritical fluid chromatography (SFC) was performed using a Waters TM Viridis TM BEH 2-Ethylpyridine 5 μm, 30 mm x 100 mm column with CO2 and 0.3% NH4OH / MeOH gradient, run at 100 mL / min, 40°C and 105 bar back pressure regulator. All final compounds were analyzed by analytical HPLC and peaks for purity were monitored at 210, 254 and 280 nm. The Z gradient was recorded in an appropriate NMR solvent such as 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. 1 H. 1H chemical signals are given in parts per million (ppm), with the residual solvent signal used as reference. Chemical shifts are expressed in ppm (δ), and coupling constants (J) are reported in Hertz (Hz). Unless otherwise stated, reactions were performed under a dry nitrogen atmosphere.

[0605] 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,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).

[0606]

[0607]

[0608] Step 1: Preparation of N,N,N-trimethyl-3-oxobutane-1-ammonium iodide (Compound 2-2).

[0609]

[0610] 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 iodomethane (55.4 g, 390 mmol, 3.0 equiv) and the mixture was stirred overnight at room temperature (RT). The mixture was concentrated in vacuo to give crude N,N,N-trimethyl-3-oxobutan-1-ammonium iodide (compound 2-2, 31.51 g, 123 mmol, 94%) as a light red solid which was used without further purification. 1 H NMR (400MHz, 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).

[0611] 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).

[0612]

[0613] To a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline (compound 2-3, 6.60 g, 34.5 mmol, 1.0 equiv) in MeOH (66 mL) was added N,N,N-trimethyl-3-oxobutane-1-ammonium iodide (compound 2-2, 13.3 g, 51.8 mmol, 1.5 equiv), and the mixture was stirred at reflux for 1 hour. The mixture was cooled to RT and stirred for 1 hour. The mixture was concentrated in vacuo, suspended in water, and extracted three times with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was subjected to two chromatography separations: a silica gel column (220 g) loaded with DCM was run with an increasing gradient of MeOH (0-5%, over 20 minutes) / DCM, and a silica gel column (40 g) loaded with DCM was run with an increasing gradient of EtOAc (0-100%, over 20 minutes) / hexanes to further purify the mixed fractions to give (±)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-4, 6.89 g, 26.4 mmol, 77%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 6.71 (s, 1H), 6.70 (s, 1H), 3.72 (s, 6H), 3.46 (brd, J = 11.1Hz, 1H), 3.25-3.16 (m, 1H), 3.14-3.05(m,1H),2.98-2.83(m,2H),2.71-2.56(m,3H),2.49-2.42(m,1H),2.34(dd,J=12.0,14.2Hz,1H),2.23(br d,J=11.2Hz,1H).

[0614] 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).

[0615]

[0616] 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 and 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 used without further purification.

[0617] Step 4: Preparation of sodium (±)-(9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3(4H)-ylidene)methoxide (Compound 2-6).

[0618]

[0619] To a solution of (±)-3-((dimethylamino)methylene)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-5, 4.19 g, 13.2 mmol, 1.0 equiv) in water (80 mL) was added aqueous HCl (12.1 M, 2.7 mL, 33.0 mmol, 2.5 equiv) at 0 °C and stirred for 30 minutes. The mixture was allowed to warm 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 diatomaceous earth vacuum filtration. The filtrate was concentrated to give crude (±)-(9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3(4H)-ylidene)methoxide sodium as a solid (compound 2-6, 5.61 g), of which 2.10 g was directly used in the next step (ie, the 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)).

[0620] 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).

[0621]

[0622] To a solution of crude (±)-(9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3(4H)-ylidene)sodium methoxide (compound 2-6, 2.10 g) in DCM (6.5 mL) was added triethylamine (1.97 mL, 14.1 mmol). The mixture was cooled to 0°C and then tosyl azide (1.27 g, 6.42 mmol) was added. The reaction was stirred at 0°C for 1 h and then allowed to warm 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 minutes. The mixture was extracted three times with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. A silica gel column (24 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-100% over 12 minutes) / hexanes 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, 2-step yield 24%) as a brown solid. 1 H NMR (500MHz, DMSO-d6): δ (ppm) 6.75 (s, 1H), 6.68 (s, 1H), 4.01 (d, J = 12.6Hz, 1H), 3.76-3.69 (m, 2H), 3.71 (s, 6H), 3.05 (td, J = 4.6, 11 .1Hz,1H),2.97(dd,J=4.1,17.5Hz,1H),2.88-2.81(m,1H),2.68(td,J=4.0,15.9Hz,1H),2.53(m,1H),2.14(dd,J=11.2,17.5Hz,1H).

[0623] 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).

[0624]

[0625] 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 h. The mixture was cooled to RT, filtered through celite, and concentrated in vacuo. A silica gel column (4 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-50% over 20 minutes) / hexanes 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 (400MHz, DMSO-d6): δ (ppm) 6.72 (s, 1H), 6.69 (s, 1H), 4.37 (dd, J = 6.8, 11.0Hz, 1H), 3.72 (s, 6H), 3.46 (br d,J=11.0Hz,1H),3.21-3.10(m,2H),2.96-2.84(m,2H),2.72-2.64(m,1H),2.58-2.42(m,3H),1.15(s,9H).

[0626] 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 separation of Compound 15, Compound 76, Compound 77 and Compound 78.

[0627]

[0628] To a solution of (±)-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound (±)-2-8, 27 mg, 0.0810 mmol, 1.0 equiv) in MeOH (2.0 mL) at 0°C was added NaBH4 (4.6 mg, 0.121 mmol, 1.5 equiv). The mixture was warmed to RT and stirred overnight. The reaction mixture was quenched with water and extracted three times with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. A silica gel column (4 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-100% over 20 minutes) / hexanes to afford (±)-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 resulting four isomers was achieved by preparing a solution in a minimal volume of MeOH and performing preparative chiral SFC. The product was prepared using a HPLC-MS / MS equipped with a UV detector and an Advion TM Pic Solution for Mass Spectrometer TM SFC-PICLAB-Prep 200 TM Chiral compounds were separated using a supercritical fluid chromatography (SFC) system. TM ChiralPak TM IG / SFC 5 μm, 20 mm×250 mm column, run under an isocratic gradient of 85% CO 2 and 15% 0.5% DMEA / MeOH at 150 mL / min, 55° C. and 110 bar back pressure regulator.

[0629] The following amounts of Compound 15, Compound 76, Compound 77 and Compound 78 were obtained:

[0630] (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%, the latest retention time of the four isomers);

[0631] (2S,3R,11bR)-3-(tert-Butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 76, 3 mg, 0.00894 mmol, 11%, earliest retention time of four isomers);

[0632] (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%, the second earliest retention time of the four isomers);

[0633] (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%, the second latest retention time of four isomers).

[0634] 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).

[0635]

[0636] Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15).

[0637]

[0638] 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) was added aqueous NaOH (6N, 68.3 mL, 410 mmol, 2.1 equiv) and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0 ° C and then acidified to pH 1-2 with concentrated H2SO4. The aqueous layer was extracted 5 times with MTBE. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give crude 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15, 33.1 g, 190 mmol, 97%) as a clear brown oil which was carried out without any further purification. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

[0639] 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).

[0640]

[0641] 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 hours. The mixture was cooled to RT and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with MTBE. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give crude (±)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one (Compound 2-17) as a brown oil. To a solution of the crude material in MeOH (378 mL) were 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 loaded with DCM and run with an increasing gradient of EtOAc (0-50% over 20 minutes) / hexanes 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% yield over two steps) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.46-7.31 (m, 5H), 6.81 (s, 1H), 6.75 (s, 1H), 5.03 (s, 2H), 4.37 (dd, J = 7.0, 10.9Hz, 1H), 3.74 (s, 3H), 3.46 (br d,J=11.9Hz,1H),3.23-3.09(m,2H),2.95-2.84(m,2H),2.70-2.62(m,1H),2.59-2.42(m,3H),1.15(s,9H).

[0642] (Reduction, Method A)

[0643] 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).

[0644]

[0645] 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) was added NaBH4 (2.01 g, 53.2 mmol, 2.0 equiv) in portions at 0°C. The mixture was stirred for 30 minutes, then warmed to RT and stirred for 1 h. The reaction mixture was diluted with water (100 mL) and NaOH (1 M, 100 mL) and filtered. It was then extracted three times with DCM. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. A silica gel column (220 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-80% over 20 minutes) / hexanes 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) (8.64 g, 21.0 mmol, 79%) as a 1.4:1 mixture of diastereomers.

[0646] (Reduction, Method B)

[0647] 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).

[0648] 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 DIBAL-H (1.0 M in hexanes, 42.8 mL, 42.8 mmol, 1.5 equiv) dropwise at 0°C. The mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with acetone. The mixture was diluted with an aqueous solution of Rochelle 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 MgSO4, filtered and concentrated in vacuo 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) (11.70 g, 28.4 mmol, 99%) as a 6.5:1 mixture of diastereomers, which was used directly in the next step (i.e., the 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).

[0649] 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).

[0650]

[0651] Diastereomerically pure compound (±)-2-20 can be obtained by chromatography of compound (±)-2-19 (0.432 g, 1.05 mmol, 1.4:1 dr). A silica gel column (4 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-100% over 20 minutes) / hexanes 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%). 1H NMR (400MHz, DMSO-d6): δ (ppm) 7.45-7.41 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 1H), 6.77 (s ,1H),6.74(s,1H),5.01(s,2H),4.61(d,J=4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J=11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J=10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

[0652] 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).

[0653]

[0654] To a solution of crude (±)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound (±)-2-19, 6.5:1dr, 11.70 g, 28.5 mmol, 1 eq) in EtOH (250 mL) was added (2S,3S)-2,3-bis(4-methylbenzyloxy)succinic acid (DPTTA, 11.00 g, 28.5 mmol, 1.0 eq). The solution was heated to reflux with stirring, which became a suspension upon heating. After addition of MeOH (60 mL), the mixture was kept 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 kept at a constant temperature for 1 hour and 30 minutes. The mixture was cooled to room temperature at a rate of 8°C per hour and then stirred for two days. The resulting precipitate was collected by vacuum filtration and dried to provide compound 2-21·DPTTA (7.357 g, 6.26 mmol, 32% over two steps of compound (±)-2-18 prepared in step 2 of Example 2 above) as a white solid. The optical purity of 100%ee and the diastereomeric purity of ≥99% were determined by chiral supercritical fluid chromatography (SFC) analysis. The chiral salt pair was suspended in DCM and water was added. The mixture was alkalized with a saturated aqueous solution of NH4OH until pH~10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO4, filtered and concentrated in vacuo to give 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% yield over two steps from compound (±)-2-18 prepared in step 2 of Example 2 above) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.45-7.41 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 1H), 6.77 (s ,1H),6.74(s,1H),5.01(s,2H),4.61(d,J=4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J=11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J=10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

[0655] Example 3: Preparation of salts 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)succinic acid (Compound 2-2·DPTTA).

[0656]

[0657] 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-methylbenzyloxy)succinic acid (DPTTA, 0.156 g, 0.403 mmol, 1.0 equiv). The mixture was heated to 50° C. with stirring and maintained 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 the mixture became a clear solution. The sample was cooled to RT under stirring within 30 minutes and then stirred at RT overnight. The resulting precipitate was collected by vacuum filtration and rinsed with EtOH (0.5 mL) and dried to provide compound 2-21·DPTTA (0.116 g, 0.145 mmol, 36%) as a white solid. The precipitate was purified by chromatography using a UV detector (WatersTM Acquity UPC2 PDA Detector TM ) and mass spectrometer (Waters TM Acquity QDaDetector TM Waters TM Ultra-Performance Convergence Chromatography(UPC2) TM Chiral purity analysis was performed using a supercritical fluid chromatography (SFC) system. TM ChiralPak TMIBU / SFC 1.6 μm, 2.1 mm x 50 mm column, and an isocratic gradient of 95% CO2 and 5% 0.5% DMEA / MeOH at 1.5 mL / min, 40°C and 1500 psi back pressure regulator. An extraction wavelength of 281 nm was used for %ee quantification and analysis. The optical purity of the single diastereomer was determined to be 100%ee by chiral SFC analysis. The assigned structure was confirmed by a single crystal x-ray structure.

[0658] 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).

[0659] (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 about 50°C in a capped vial to obtain a clear solution, which was then allowed to cool to RT. After 2 days, the solution was kept clear and slowly evaporated at RT. On the 3rd day, the solution was found to contain blocks of single crystal quality.

[0660] The crystal structure of compound 2-21·DPTTA was determined to have the formula C 25 H 34 NO4·C 20 H 17 A mixed ethanol and methanol solvate of O8·0.851(C2H6O)·0.149(CH4O). The solvate was refined to a disordered state between a large amount of ethanol and a small amount of methanol. The chiral centers at N1 (protonated), C2, C3, and C5 were determined to have an R configuration. The chiral centers at both C27 and C28 (O,O'-di-p-toluoyl-tartaric acid) had an S configuration. The unit system and space group of compound 2-21·DPTTA are shown in Table 1. The data collection and improvement parameters for compound 2-21·DPTTA are shown in Table 2.

[0661]

[0662]

[0663] Example 4A: Preparation of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (Compound 2-16).

[0664]

[0665] To a solution of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (23.2 g, 86.6 mmol, 1.0 equiv) in 1:1 MTBE / THF (230 mL) was added HCl (4M in dioxane, 22.7 mL, 91.0 mmol, 1.05 equiv) dropwise at RT over 20 min. 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 (400MHz, DMSO-d6): δ (ppm) 12.94 (br s,1H),8.94(s,1H),7.54(s,1H),7.49-7.46(m,2H),7.45-7.40(m,2H),7.40-7.35(m, 1H), 7.29 (s, 1H), 5.27 (s, 2H), 3.88-3.84 (m, 2H), 3.81 (s, 3H), 3.06 (t, J = 8.4Hz, 2H).

[0666] 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).

[0667]

[0668] 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:H2O (20 mL) was added aqueous HCl (12.1 M, 0.47 mL, 5.69 mmol, 1.2 equiv) dropwise with stirring at 0°C. The mixture was stirred for 10 minutes. Palladium on carbon (10% w / w, 0.252 g, 0.237 mmol, 0.05 equiv) and ammonium formate (2.988 g, 47.4 mmol, 10 equiv) were added and the mixture was stirred at 50°C for 30 minutes. The mixture was cooled to 0 ° C and acidified to pH = 1 with aqueous HCl (12.1 M). The suspension was filtered and the solid was rinsed with MeOH (4 mL). The filtrate was transferred to a round-bottom flask equipped with a stirring bar and basified to pH = 7 with aqueous NaOH (6 M). The volume was reduced to 20 mL by concentrating in vacuo, at which time a white solid precipitated. The solid was collected by vacuum filtration to provide (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 (500MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 4.58 (d, J = 4.9Hz, 1H), 3.72 (s, 3H), 3.32-3.25 (m, 2H), 2.98 (br d,J=11.0Hz,1H),2.90-2.77(m,3H),2.47-2.42(m,2H),2.32-2.26(m,1H),2.02(t,J=10.4Hz,1H),1.23(q,J=11.6Hz,1H),1.17(s,9H).

[0669] 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).

[0670]

[0671] Step 1: Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15).

[0672]

[0673] To a suspension of ethyl 4-(tert-butoxy)-3-oxobutanoate (Compound 2-14, 100 g, 494 mmol, 1.0 equiv) in water (1 L) at 0°C was added 6N aqueous NaOH (173 mL, 1040 mmol, 2.1 equiv) over 5 minutes, and the mixture was stirred at RT for 16 hours. The reaction mixture was acidified to pH 1-2 with aqueous H2SO4 (18.1 M) and extracted 5 times with MTBE. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15, 83.8 g, 481 mmol, 97%) as a clear light brown oil, which was used without further purification. 1 H NMR (500MHz, DMSO-d6): δ (ppm) 12.53 (bs, 1H), 4.05 (s, 2H), 3.43 (s, 2H), 1.14 (s, 9H).

[0674] Step 2: Preparation of 1-(tert-butoxy)propan-2-one (Compound 2-25).

[0675]

[0676] 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 h. 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 (400MHz, CDCl3): δ (ppm) 3.96 (s, 2H), 2.20 (s, 3H), 1.25 (s, 9H).

[0677] Step 3: Preparation of 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (Compound 2-26).

[0678]

[0679] To a solution of 1-(tert-butoxy)propan-2-one (compound 2-25, 55.1 g, 423.3 mmol, 1.0 eq.) in EtOH (275 mL) was added dimethylamine hydrochloride (51.8 g, 635 mmol, 1.5 eq.), paraformaldehyde (25.4 g, 847 mmol, 2.0 eq.) and aqueous HCl (12.1 N, 1.75 mL, 21.2 mmol, 0.05 eq.) and the mixture was stirred at 75 °C for 22 h. The mixture was cooled to RT, diluted with water, basified to pH = 12 with aqueous NaOH (1 M), and extracted 5 times with MTBE. The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo. The crude material was separated and subjected to two separate separations: a silica gel column (330 g) loaded with DCM and run with an increasing gradient of MeOH (0-10% over 20 min) / DCM; and a silica gel column (220 g) loaded with DCM and run with an increasing gradient of MeOH (0-10% over 20 min) / DCM to afford 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (compound 2-26, 25.1 g, 83% purity (w / w), 111 mmol, 26%) as an oil. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 3.94 (t, J = 6.6Hz, 1H), 2.45–2.35 (m, 2H), 2.13 (s, 6H), 2.08 (s, 3H), 1.10 (s, 9H).

[0680] 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).

[0681]

[0682] 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 time a precipitate formed. The mixture was cooled to room temperature and the precipitate was filtered. The solid was rinsed with 50% (v / v) MeOH / water (200 mL) and dried under vacuum 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%). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.46-7.31 (m, 5H), 6.81 (s, 1H), 6.75 (s, 1H), 5.03 (s, 2H), 4.37 (dd, J = 7.0, 10.9Hz, 1H), 3.74 (s, 3H), 3.46 (br d,J=11.9Hz,1H),3.23-3.09(m,2H),2.95-2.84(m,2H),2.70-2.62(m,1H),2.59-2.42(m,3H),1.15(s,9H).

[0683] 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).

[0684]

[0685] 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) was added DIBAL-H (1.0 M in hexanes, 75.4 mL, 75.4 mmol, 1.5 equiv) dropwise at 0°C. 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 room temperature, diluted with DCM (200 mL) and Rochelle salt aqueous solution (10% w / w), and stirred vigorously until the emulsion disappeared. The mixture was extracted three times with MTBE. The combined organic extracts were dried over MgSO4, 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, 20.5 g, 49.8 mmol, 99%) as a mixture of diastereomers, which was used directly in the next step (synthesis of compound 2-21).

[0686] 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).

[0687]

[0688] 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-methylbenzyloxy)succinic acid (DPTTA, 19.2 g, 49.8 mmol, 1.0 equiv). The solution was heated to reflux with stirring, which became a suspension upon further heating. After addition of MeOH (150 mL), the mixture was kept at reflux until a clear solution was obtained. The solution was cooled to 75°C and then seeded with compound 2-21·DPTTA (0.070 g, see Example 1) and kept at a constant temperature for 30 minutes. The mixture was cooled to room temperature at a rate of 8 ° C per hour and then 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 provide compound 2-21·DPTTA (16.1 g, 20.1 mmol, 40% yield from compound (±)-2-18) as a white solid. The optical purity of 100% ee and diastereomeric purity ≥ 99% were determined by chiral supercritical fluid chromatography (SFC) analysis. The chiral salt pair was suspended in DCM and water was added. The mixture was alkalized with a saturated aqueous solution of NH4OH until pH ~ 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO4, filtered and concentrated in vacuo to give (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (compound 2-21, 8.13 g, 19.8 mmol, 39% yield from compound (±)-2-18) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.45-7.41 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 1H), 6.77 (s ,1H),6.74(s,1H),5.01(s,2H),4.61(d,J=4.7Hz,1H),3.73(s,3H),3.32-3.27(m,2H),3.02(br d,J=11.0Hz,1H),2.92-2.82(m,3H),2.54-2.45(m,2H),2.35-2.29(m,1H),2.04(br t,J=10.3Hz,1H),1.27-1.21(m,1H),1.17(s,9H).

[0689] 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).

[0690]

[0691] 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:H2O (42 mL) was added aqueous HCl (12.1 M, 1.97 mL, 23.8 mmol, 1.2 equiv) dropwise with stirring at 0°C. The mixture was stirred for 10 minutes. Palladium on carbon (10% w / w, 1.06 g, 0.994 mmol, 0.05 equiv) and ammonium formate (12.5 g, 198 mmol, 10 equiv) were added and the mixture was stirred at 50°C for 30 minutes. The mixture was cooled to 0 ° C and acidified to pH = 1 with aqueous HCl (12.1 M). The suspension was filtered and the solid was rinsed with MeOH. The filtrate was transferred to a round-bottom flask equipped with a stirring bar and basified to pH = 8 with aqueous NaOH (6 M), at which time a white solid precipitated. The solid was collected by vacuum filtration and dried in vacuo to provide (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 HNMR (500MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 4.58 (d, J = 4.9Hz, 1H), 3.72 (s, 3H), 3.32-3.25 (m, 2H), 2.98 (br d,J=11.0Hz,1H),2.90-2.77(m,3H),2.47-2.42(m,2H),2.32-2.26(m,1H),2.02(t,J=10.4Hz,1H),1.23(q,J=11.6Hz,1H),1.17(s,9H).

[0692] 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).

[0693]

[0694] To a solution of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22, 0.060 g, 0.187 mmol, 1.0 equiv) in DMF (1.8 mL) was added cesium carbonate (0.183 g, 0.561 mmol, 3.0 equiv) and the resulting mixture was stirred at RT for 10 min. Then, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.056 g, 0.243 mmol, 1.3 equiv) was added and the mixture was stirred for 3 h. 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 chromatographed three times: a silica gel column (4 g) loaded with DCM and run with an increasing gradient of EtOAc (0-60% over 20 minutes) / hexanes; a silica gel column (4 g) loaded with DCM and run with an increasing gradient of EtOAc (0-70% over 25 minutes); and a reverse phase C column loaded with DMSO. 18 Column (6 g) was run with an increasing gradient in ACN (10-50% over 20 min) / water to afford (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. Observed ion (m / z) = 404.3 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δ (ppm) 6.83 (s, 1H), 6.78 (s, 1H), 4.66-4.58 (m, 3H), 3.76 (s, 3H), 3.38-3.26 (m, 2H), 3.04 (br d,J=11.0Hz,1H),2.93-2.81(m,3H),2.57-2.46(m,2H),2.35-2.29(m,1H),2.08-2.02(m,1H),1.29-1.20(m,1H),1.17(s,9H).

[0695] Example 6: Prepara...

Claims

1. Compound of formula (Ia): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl, C5-C 11 - spirocycloalkyl, cubic alkyl-C1-C4-alkylene and 4-8 membered heterobicyclyl-C1-C4-alkylene; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ic): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is a compound of formula (Ie): or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is a compound of formula (Ig): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is a compound of formula (Ii): or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is a compound of formula (Ik): or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl and C5-C 11 - spirocycloalkyl; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxy, C1-C4-alkoxy and C2-C4-dialkylamino.

8. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl, C5-C 11 - spirocycloalkyl, cubic alkyl-C1-C4-alkylene and 4-8 membered heterobicyclyl-C1-C4-alkylene; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

9. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7-cycloalkenyl, 5-11-membered spiroheterocyclyl and C5-C 11 - spirocycloalkyl; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

10. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

11. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl; Each R 1 The group is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, hydroxyl and C1-C4-alkoxy.

12. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)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, hydroxy and methoxy.

13. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl; Each R 1 The group is optionally substituted with one or more substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

14. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

15. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered heterocyclyl, (4-membered heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered spiroheterocyclyl and C7-spirocycloalkyl; Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

16. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 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 spiroheterocyclyl, C7-spirocycloalkyl, (cubic alkyl)CH2- and 6-membered heterobicyclyl-C1-C4-alkylene-CH2-; Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

17. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 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 spiroheterocyclyl and C7-spirocycloalkyl; Each R 1 The group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxy and methoxy.

18. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl, and (2-oxabicyclo[2.1.1]hexyl)methyl; Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

19. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl; Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

20. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

21. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, pyrrolidinyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

22. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl; wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

23. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

24. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl, (cyclobutyl)ethyl, (cubanyl)methyl, (bicyclo[2.1.1]hexyl)methyl, (siloxanyl)methyl and (2-oxabicyclo[2.1.1]hexyl)methyl; wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

25. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptyl, spiro[3.3]heptyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

26. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, 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]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl; Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

27. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl; Each of these groups is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

28. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, 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]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hex-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

29. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, pyrrolidin-3-yl, and 1-(cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three or four substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy, dimethylamino, methylsulfonyl and cyclopropyl.

30. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)oxy 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl; wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

31. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, and 1-(cyclobutyl)ethyl; wherein each group is optionally substituted with one or more substituents selected from the group consisting of cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

32. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)oxy 1-(cyclobutyl)ethyl, (cuban-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (siloxane-3-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl; wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

33. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2-cyclopropyloxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((prop-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pent-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, spiro[3.3]hept-2-yl, and 1-(cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three or four substituents selected from cyanomethyl, fluoro, cyano, hydroxy, difluoromethyl, methyl, trifluoromethyl, methoxy and cyclopropyl.

34. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methyl Oxyethyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2- 2-(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-dimethylsiloxane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[ 1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl.

35. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methyl Oxyethyl, (cyclopropyl) methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2 1-(methylsulfonyl)cyclopropyl)methyl, 3-(methylsulfonyl)propyl, 2-(methylsulfonyl)ethyl, 3,3-difluorocyclobutyl, and (2,2-difluorocyclobutyl)methyl.

36. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methyl Oxyethyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methyl 1-(4-(6-fluoro-1-yl)-2-nitro-1-yl)methyl, (1-(4-(6-fluoro-1-yl)-2-nitro-1-yl)methyl, (1-(4-(6-fluoro-1-yl)-2-nitro-1-yl)methyl, (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-dimethylsiloxane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[ 1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl.

37. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, 2-hydroxypropyl, ethyl, isopropyl, 2-methyl Oxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]hept-6-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, ( 1-methylcyclopropyl)methyl, 1-methylcyclobutyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, 3-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, 3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, 2-methoxypropyl, 3,3-difluorocyclobutyl and (2,2-difluorocyclobutyl)methyl.

38. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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-methoxy ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl 1-methylpyrrolidin-3-yl, (3-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, (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-dimethylsiloxane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[ 1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl.

39. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxy ethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1S,3S)-3-fluorocyclobutyl, 3 ,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, 1-methylpyrrolidin-3-yl, (3-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.

40. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 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-methoxy ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclo butyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl, (R)-1-cyclobutylethyl, ((1S ,2S)-2-fluorocyclopropyl)methyl, ((1R,2R)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (1s,3S)-3-methoxycyclobutyl, cyanomethyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (R)-3,3,3-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]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, (1,1-dimethylsiloxane-3-yl)methyl, (3-(trifluoromethyl)bicyclo[ 1.1.1]pentan-1-yl)methyl, (2-oxabicyclo[ 2.1.1]hex-1-yl)methyl and (2-oxabicyclo[ 2.1.1]hex-4-yl)methyl.

41. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, (1-(cyanomethyl) cyclopropyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-cyclopropyloxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxy ethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropyl-2-yl)oxy)ethyl, 1,1,1-trifluoropropyl-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]pent-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, 2-(trifluoromethoxy)ethyl, neopentyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobut-2-en-1-yl, 2-oxaspiro[3.3]hept-6-yl, (1R,3r)-3-cyanocyclobutyl, (1r,3R) -3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (3-methyloxetan-3-yl)methyl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro -3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl, (R)-1-cyclobutylethyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((1R,2R)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, (1s,3S)-3-methoxycyclobutyl 1-(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.

42. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl, cyano and C1-C4-alkylsulfonyl.

43. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl and cyano.

44. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one, two or three substituents selected from the group consisting of cyano-C1-C4-alkylene, halogen, hydroxy, C1-C4-haloalkyl, C1-C4-alkyl and cyano.

45. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C5-cycloalkyl-C1-C2-alkylene which is optionally substituted by one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C1-haloalkyl, methyl, cyano and methylsulfonyl.

46. ​​The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C5-cycloalkyl-C1-C2-alkylene which is optionally substituted by one, two or three substituents selected from cyanomethyl, halogen, hydroxy, C1-haloalkyl, methyl and cyano.

47. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)ethyl; wherein each group is optionally substituted by one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl, methyl and methylsulfonyl.

48. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl, methyl and methylsulfonyl.

49. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)ethyl; wherein each group is optionally substituted by one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl and methyl.

50. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluorine, hydroxyl and methyl.

51. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 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, (1-(methylsulfonyl)cyclopropyl)methyl, and (2,2-difluorocyclobutyl)methyl.

52. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

53. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

54. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl and (2,2-difluorocyclobutyl)methyl.

55. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 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, ((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.

56. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S, 1-(methylsulfonyl)cyclopropyl)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.

57. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 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, ((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 1-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 and (2,2-difluorocyclobutyl)methyl.

58. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl) methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, (S)-1-cyclobutylethyl, (R)-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.

59. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl and ((R)-2,2-difluorocyclopropyl)methyl.

60. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl and ((R)-2,2-difluorocyclopropyl)methyl.

61. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6-alkyl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C4-alkoxy and C1-C4-alkylsulfonyl.

62. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6-alkyl which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano and C1-C4-alkoxy.

63. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano and C1-C4-alkoxy.

64. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C5-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano, methoxy and methylsulfonyl.

65. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C5-alkyl which is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, hydroxy, cyano and methoxy.

66. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from: fluoro, hydroxy, cyano, methoxy and methylsulfonyl.

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

68. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl-d3, ethyl, ethyl-d5, isopropyl, pentyl and neopentyl; wherein each group is optionally substituted with one, two, three or four substituents selected from: fluoro, hydroxy, cyano and methoxy.

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

70. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

71. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

72. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

73. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

74. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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-trifluoroprop-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.

75. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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-trifluoroprop-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.

76. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

77. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 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. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl and ethyl-d5.

79. The compound according to claim 61 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and ethyl.

80. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C2-C4-dialkylamino.

81. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy.

82. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl which is optionally substituted by one or two substituents selected from the group consisting of cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxy.

83. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C5-cycloalkyl which is optionally substituted by one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl, methoxy and dimethylamino.

84. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl which is optionally substituted by one or two substituents selected from cyano, halogen, methyl, C1-haloalkyl and methoxy.

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

86. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: cyclopentyl, cyclobutyl and cyclopropyl; wherein each group is optionally substituted with one or two substituents selected from: cyano, fluoro, methyl, trifluoromethyl and methoxy.

87. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

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

89. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

90. The compound according to claim 80 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

91. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C4-alkyl-O-C2-C4-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen and C3-C6-cycloalkyl.

92. The compound according to claim 91 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C3-alkyl-O-C2-C3-alkylene which is optionally substituted by one or more substituents selected from the group consisting of cyano, halogen and cyclopropyl.

93. The compound according to claim 91 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C3-alkyl-O-C2-C3-alkylene which is optionally substituted by one, two or three substituents selected from the group consisting of cyano, halogen and cyclopropyl.

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

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

96. The compound according to claim 91 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 2-(cyano(cyclopropyl)methoxy)ethyl, 2-methoxyethyl, 2-((2-cyanoprop-2-yl)oxy)ethyl, 3-methoxypropyl and 2-(trifluoromethoxy)ethyl.

97. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 It is C3-C7-cycloalkyl-O-C2-C4-alkylene.

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

99. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 3- to 7-membered heterocyclyl group which is optionally substituted by one or more C1-C4-alkyl substituents.

100. The compound according to claim 99 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4-5 membered heterocyclyl group which is optionally substituted by one or more C1-C4-alkyl substituents.

101. The compound according to claim 99 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4-5 membered heterocyclyl group which is optionally substituted by one C1-C4-alkyl substituent.

102. The compound according to claim 99 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a 4-membered heterocyclic group.

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

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

105. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is 3-7 membered heterocyclyl-C1-C4-alkylene optionally substituted by one or more C1-C4 alkyl substituents.

106. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is (4-5 membered heterocyclyl)CH2- optionally substituted by one or more methyl substituents.

107. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is (4-membered heterocyclyl)CH2- optionally substituted by one or more methyl substituents.

108. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is (4-5 membered heterocyclyl)CH2- optionally substituted by one methyl substituent.

109. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is (4-membered heterocyclyl)CH2- optionally substituted by one methyl substituent.

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

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

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

113. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl and (1,1-dimethylsiloxane-3-yl)methyl.

114. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl and (3-methyloxetan-3-yl)methyl.

115. The compound according to claim 98 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (3-methyloxetan-3-yl)methyl and (1,1-dimethylsiloxane-3-yl)methyl.

116. The compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl and (3-methyloxetan-3-yl)methyl.

117. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene which is optionally substituted by one or more substituents selected from halogen and C1-C4-haloalkyl.

118. The compound according to claim 117 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted by one or more substituents selected from fluoro and trifluoromethyl.

119. The compound according to claim 117 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C5-C6-bicycloalkyl)CH2- optionally substituted by one substituent selected from fluoro and trifluoromethyl.

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

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

122. The compound according to claim 117 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

123. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene which is optionally substituted by one or more halogen substituents.

124. The compound according to claim 123 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C5-bicycloalkyl)CH2- optionally substituted by one or more fluorine substituents.

125. The compound according to claim 123 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C5-bicycloalkyl)CH2- optionally substituted by one fluorine substituent.

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

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

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

129. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is C4-C7-cycloalkenyl which is optionally substituted by one or more halogen substituents.

130. The compound according to claim 129 or a pharmaceutically acceptable salt thereof, wherein R 1 is C4-cycloalkenyl optionally substituted by one halogen substituent.

131. The compound according to claim 129 or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclobutenyl optionally substituted by one fluorine substituent.

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

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

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

135. The compound according to claim 134 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a 7-membered spiroheterocyclic group.

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

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

138. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 It is C5-C 11 -spirocycloalkyl.

139. The compound according to claim 138 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C7-spirocycloalkyl group.

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

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

142. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 It is cubic alkyl-C1-C4-alkylene.

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

144. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a 4-8 membered heterobicyclyl-C1-C4-alkylene group.

145. The compound according to claim 144 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a 6-membered heterobicyclic group -CH2-.

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

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

148. The compound according to claim 1, wherein the compound is a compound of formula (Ie): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7 membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C5-C 11 - spirocycloalkyl and cubic alkyl-C1-C4-alkylene; Each R 1 The radical is optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl and hydroxy.

149. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7 membered heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene and C5-C 11 - spirocycloalkyl; Each R 1 The radical is optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl and hydroxy.

150. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: R 1 is selected from: (C3-C5-cycloalkyl)CH2-, (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-spirocycloalkyl and (cubic alkyl)CH2-; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

151. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: R 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-spirocycloalkyl; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

152. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: ((cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentyl)methyl, spiro[3.3]heptyl, (cubanyl)methyl, and (bicyclo[2.1.1]hexyl)methyl; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

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

154. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, 2-((prop-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]hept-2-yl, (cuban-1-yl)methyl, and (bicyclo[2.1.1]hex-1-yl)methyl; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl and hydroxy.

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

156. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-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-cyanoprop-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) 1-(trifluoromethoxy)ethyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl ... 1-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, (cuban-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, and (bicyclo[2.1.1]hex-1-yl)methyl.

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

158. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 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, ethyl-d5, isopropyl, (cyclopropyl) methyl, (cyclopropyl) methyl-d2, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl) methyl, (2,2-difluoro 1-(trifluoromethyl)cyclobutyl, 2-fluoropropyl, (cuban-1-yl)methyl, and (bicyclo[1.1.1]pentan-1-yl)methyl.

159. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 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]hept-2-yl, (1-methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, (2,2-dimethylcyclopropyl)methyl, 3-(trifluoromethyl)cyclobutyl and 2-fluoropropyl.

160. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-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- 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]pent-1-yl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclo 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]hept-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluorocyclopentyl)methyl 1-yl)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]hex-1-yl)methyl.

161. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopentyl) methyl, isobutyl, cyclopentyl, (cyclobutyl) methyl, isopentyl, (1-fluorocyclobutyl) methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl) methyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl) methyl, ethyl, isopropyl, (cyclopropyl) methyl, 3-fluoropropyl, 2- 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]pent-1-yl)methyl, ((S)-2,2-difluorocyclopropyl 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]hept-2-yl, (1-methylcyclopropyl)methyl, 1-methylcyclobutyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (3,3-difluorocyclopentyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (R)-2-fluoropropyl and (S)-2-fluoropropyl.

162. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 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, 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-dimethyl cyclobutyl, spiro[3.3]hept-2-yl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl and (R)-2-fluoropropyl, (cuban-1-yl)methyl and (bicyclo[1.1.1]pent-1-yl)methyl.

163. The compound according to claim 148 or a pharmaceutically acceptable salt thereof, wherein R 1 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, ((S)-2,2-difluorocyclopropyl) methyl, ((R)-2,2-difluorocyclopropyl) methyl, (2-methylcyclopropyl) methyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]hept-2-yl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,3R)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1R,3S)-2,2-difluoro-3-methylcyclopropyl)methyl, ((1S,2S)-2-fluorocyclopropyl)methyl, ((S)-2,2-dimethylcyclopropyl)methyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl and (R)-2-fluoropropyl.

164. The compound according to claim 1, wherein the compound is a compound of formula (Ie): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C1-C4-alkylene and C4-C8-bicycloalkyl-C1-C4-alkylene; Each R 1 The group is optionally substituted by one or more substituents selected from halogen, C1-C4-haloalkyl, cyano and hydroxy.

165. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-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 one or more substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

166. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 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 one or more substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

167. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-CCH2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered heterocyclyl and (4-membered heterocyclyl)CH2-; Each R 1 The group is optionally substituted with one, two, three or four substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

168. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein 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-; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from halogen, C1-haloalkyl, cyano and hydroxy.

169. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of 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; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

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

171. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of 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; wherein each R 1 The group is optionally substituted with one, two, three or four substituents selected from fluoro, hydroxy, cyano and difluoromethyl.

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

173. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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-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.

174. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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, 3-oxacyclopropyl 1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, and (2,2-difluorocyclopropyl)methyl.

175. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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, oxacyclopentane-3-yl 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.

176. The compound according to claim 164 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl , ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3-difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, 5,5,5-trifluoropentyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, fluoromethyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.

177. The compound according to claim 1, wherein the compound is a compound of formula (Ie): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: C1-C6-alkyl, C3-C7-cycloalkyl and C3-C7-cycloalkyl-C1-C4-alkylene; wherein each group is optionally substituted by one or more halogen substituents.

178. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C1-C6-alkyl, C3-C7-cycloalkyl and C3-C7-cycloalkyl-C1-C4-alkylene; wherein each group is optionally substituted by one, two or three halogen substituents.

179. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C2-C3-alkyl, cyclopropyl, C3-C4-cycloalkyl-CD2- and C3-C4-cycloalkyl-CH2-; wherein each group is optionally substituted by one, two or three halogen substituents.

180. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: C2-C3-alkyl, cyclopropyl and C3-C4-cycloalkyl-CH2-; wherein each group is optionally substituted by one, two or three halogen substituents.

181. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three halogen substituents.

182. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three halogen substituents.

183. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three fluorine substituents.

184. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two or three fluorine substituents.

185. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

186. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

187. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

188. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 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.

189. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 is C3-C7-cycloalkyl-C1-C4-alkylene which is optionally substituted by one or two halogen substituents.

190. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.

191. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.

192. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2 and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two fluorine substituents.

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

194. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

195. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl and (2,2-difluorocyclopropyl)methyl.

196. The compound according to claim 189 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl and ((R)-2,2-difluorocyclopropyl)methyl.

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

198. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 is C1-C6-alkyl which is optionally substituted by one, two or three halogen substituents.

199. The compound according to claim 198 or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl or propyl; wherein each group is optionally substituted with one, two or three halogen substituents.

200. The compound according to claim 198 or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl or propyl; wherein each group is optionally substituted with one, two or three fluorine substituents.

201. The compound according to claim 198 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and ethyl.

202. The compound according to claim 177 or a pharmaceutically acceptable salt thereof, wherein R 1 It is C3-C7-cycloalkyl.

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

204. The compound according to claim 1, selected from 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-Butyloxy)-9-cyclobutyloxy-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-cyclopropyloxyethoxy)-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-Butyloxy)-9-cyclopropyloxy-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-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)-1,3,4,6,7,11b-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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]hept-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-fluorocyclobutyloxy)-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-fluorocyclobutyloxy)-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-dimethylcyclobutyloxy)-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]hept-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-Butyloxy)-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-Butyloxy)-10-methoxy-9-(1-methylcyclobutyloxy)-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-Butyloxy)-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)cyclobutyloxy)-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-Butyloxy)-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-methoxycyclobutyloxy)-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)cyclobutyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-difluorocyclobutyloxy)-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-Butyloxy)-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)cyclobutyloxy)-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-methoxycyclobutyloxy)-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)cyclobutyloxy)-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 compound according to claim 1, selected from 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-Butyloxy)-9-cyclobutyloxy-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-cyclopropyloxyethoxy)-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-Butyloxy)-9-cyclopropyloxy-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-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)-1,3,4,6,7,11b-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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]hept-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-fluorocyclobutyloxy)-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-fluorocyclobutyloxy)-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-dimethylcyclobutyloxy)-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]hept-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-Butyloxy)-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-Butyloxy)-10-methoxy-9-(1-methylcyclobutyloxy)-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-Butyloxy)-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)cyclobutyloxy)-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-Butyloxy)-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-methoxycyclobutyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-Butyloxy)-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-difluorocyclobutyloxy)-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-Butyloxy)-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)cyclobutyloxy)-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-methoxycyclobutyloxy)-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 compound according to claim 1, selected from the following compounds: (2R,3R,11bR)-3-(tert-Butyloxy)-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-Butyloxy)-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-butyloxy)-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] hex-1-ylmethoxy)-3-(tert-butyloxy)-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-dimethylsiloxane-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] hex-1-yl)methoxy)-3-(tert-butyloxy)-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]hex-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. A pharmaceutical product selected from the group consisting of: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound according to any one of claims 1 to 206, or a pharmaceutically acceptable salt thereof.

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

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

210. A method for preparing a pharmaceutical composition, comprising the step of mixing a compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

211. A method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition in a subject in need thereof, 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.

212. A method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition in an individual in need thereof, comprising administering to the individual 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 VMAT2 disease or condition is selected from: ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood disorders or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and mood disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

213. A method of treating a neurological or psychiatric disease or condition in a subject in need 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 of treating a neurological or psychiatric disease or condition in a subject in need 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 or psychiatric disease or condition is selected from: hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, and chorea-acanthocytosis.

215. A method of treating a neurological or psychiatric disease or condition in an individual in need thereof, the method comprising administering to the individual 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 or psychiatric disease or condition is hyperkinesia.

216. A method of treating a hypermovement disorder in an individual in need thereof, the method comprising administering to the individual 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 hypermovement disorder is selected from the group consisting of tardive dyskinesia, Tourette 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 of treating a hypermovement disorder in an individual in need thereof, comprising administering to the individual 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 hypermovement disorder is tardive dyskinesia.

218. A method of treating a hypermobility disorder in an individual in need thereof, comprising administering to the individual 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 hypermobility disorder is Huntington's disease.

219. A method of treating a hypermovement disorder in an individual in need thereof, comprising administering to the individual 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 hypermovement disorder is chorea associated with Huntington's disease.

220. The method of claim 213 or 214; wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder.

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

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

223. The method of claim 213 or 214; wherein the neurological or psychiatric disease or condition is obsessive compulsive disorder.

224. The method of claim 213 or 214; wherein the neurological or psychiatric disease or condition is treatment-resistant obsessive-compulsive disorder.

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

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

227. 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 preparation of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.

228. 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 preparation of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or condition selected from: ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related conditions; mood or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / Parkinson's syndrome; childhood-onset behavioral and mood 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 preparation of a medicament for the treatment of a neurological or psychiatric disease or condition.

230. 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 preparation of a medicament for treating a neurological or psychiatric disease or condition selected from the group consisting of hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome and chorea-acanthocytosis.

231. 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 preparation of a medicament for treating hypermobility.

232. 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 preparation of a medicament for treating hypermovement disorder; wherein the hypermovement disorder is selected from: tardive dyskinesia, Tourette 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 preparation of a medicament for the treatment of tardive dyskinesia.

234. 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 preparation of a medicament for treating Huntington's disease.

235. 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 preparation of a medicament for treating chorea associated with Huntington's disease.

236. The use according to claim 228 or 229, wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder.

237. The use according to claim 228 or 229; wherein the neurological or psychiatric disease or disorder is schizophrenia.

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

239. The use according to claim 228 or 229; wherein the neurological or psychiatric disease or disorder is obsessive compulsive disorder.

240. The use according to claim 228 or 229; wherein the neurological or psychiatric disease or disorder is refractory obsessive-compulsive disorder.

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

242. Use of a compound, salt, product or composition according to any one of claims 227 to 241, wherein treatment comprises use of 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 according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof; a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition.

245. A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof; a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or condition selected from: ataxia or spinal muscular atrophy; chorea; congenital malformations, deformations or anomalies; dementia; oral, salivary gland or jaw diseases; movement disorders; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic disorders, stress-related disorders and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or conditions; nervous system or motor dysfunction; Parkinson's disease / parkinsonism; childhood-onset behavioral and mood 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 of treating a neurological or psychiatric disease or condition.

247. A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating a neurological or psychiatric disease or condition selected from the group consisting of: hyperkinesia, schizophrenia, schizoaffective disorder, mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome and chorea-acanthocytosis.

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 of treating hypermobility.

249. A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof, a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating a hypermovement disorder; wherein the hypermovement disorder is selected from the group consisting of tardive dyskinesia, Tourette 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 of treating tardive dyskinesia.

251. A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof; a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating Huntington's disease.

252. A compound according to any one of claims 1 to 206 or a pharmaceutically acceptable salt thereof; a pharmaceutical product according to claim 207 or 208; or a pharmaceutical composition according to claim 209 for use in a method of treating chorea associated with Huntington's disease.

253. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or condition is selected from schizophrenia and schizoaffective disorder.

254. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is schizophrenia.

255. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or condition is schizoaffective disorder.

256. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is obsessive compulsive disorder.

257. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or disorder is refractory obsessive compulsive disorder.

258. A compound, salt, product or composition for use according to claim 245 or 246, wherein the neurological or psychiatric disease or condition is an autism spectrum disorder.

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

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