VMAT2 inhibitors and methods of use

Abstract

The present disclosure generally relates to VMAT2 inhibitor compounds of formula (I), compositions and methods related thereto.Also provided herein is a method for treating vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutical product comprising a compound of formula (I), or a pharmaceutical salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutical salt thereof. TIFF2024511053000105.tif2944

Description

[Technical field]

[0001] background Technical Field The present disclosure relates generally to VMAT2 inhibitor compounds, compositions and methods related thereto. [Background technology]

[0002] 2. Description of Related Art Dysregulation of the dopaminergic system is essential in several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include conditions such as hyperkinetic movement disorders, as well as schizophrenia and mood disorders. The transporter protein, vesicular monoamine transporter-2 (VMAT2), plays a key role in presynaptic dopamine release, regulating monoamine uptake from the cytoplasm into synaptic vesicles for storage and release.

[0003] (±)-Tetrabenazine ((±)-TBZ) has been used as a drug for several decades. (±)-TBZ has been reported as a potent, reversible inhibitor of catecholamine uptake by VMAT2 (IC 50=3.2 nM) (see, e.g., Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8) and is currently used in the treatment of various hyperactivity disorders. Inhibition of VMAT2 with (±)-TBZ results in depletion of brain monoamines in vivo (see, e.g., Pettibone et al., Eur. J. Pharmacol. (1984) 102:431-6). (±)-TBZ also inhibits pre- and postsynaptic dopamine receptors in rat brain (see, e.g., Login et al., (1982) Ann. Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521). (±)-TBZ exhibits extensive first-pass metabolism after oral administration to humans, with little or no (±)-TBZ observed in the systemic circulation. Thus, the pharmacological activity of (±)-TBZ is believed to be primarily mediated by active metabolites. (±)-TBZ has two chiral centers and is therefore a racemic mixture of two stereoisomers. It has been determined that (±)-TBZ is rapidly and extensively metabolized in vivo by carbonyl reductase to four metabolic stereoisomers of 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ). The inhibition constants of these four metabolites of VMAT2 have been reported in WO2008 / 058261, Example 7, etc. As shown, only two of the four DHTBZ isomers ([+]-alpha-DHTBZ and [+]-beta-DHTBZ) show significant potency as inhibitors of VMAT2. [Table 17]

[0004] In patients receiving (±)-TBZ, [-]-alpha-DHTBZ (2S,3S,11bS-DHTBZ) and [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) were the most abundant DHTBZ isomers, while [-]-beta-DHTBZ (2R,3S,11bS-DHTBZ) and [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) were present as minor metabolites. The [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) isomer was determined to be present in the least amount of all four isomers. Thus, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) appears to be the major DHTBZ isomer contributing to the pharmacological activity of (±)-TBZ. Once formed, the half-life of [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) is relatively short (approximately 5 hours), necessitating that (±)-TBZ have a suboptimal (TID) dosing regimen.

[0005] (±)-TBZ has a narrow therapeutic window and its clinical use requires careful dose titration. Side effects associated with (±)-TBZ and / or its metabolites include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia and parkinsonism. Generally speaking, the probability of observing a side effect is a function of the plasma concentration achieved by a given dosing regimen. The longer the half-life (t 1 / 2 ) and compounds with lower clearance will have lower peak-to-trough fluctuations in plasma exposure given comparable dosing intervals. These longer half-life compounds may offer improved tolerability by maintaining drug concentrations at levels required for efficacy but below levels that may cause side effects.

[0006] A fundamental 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, defined as the volume of drug fluid removed from the body per unit time. Clearance is a fundamental pharmacokinetic parameter that is commonly measured in drug research and development, as this parameter influences drug attributes such as half-life and ultimately dosing regimens. When compound and dose selection is optimized, the benefits of the smaller plasma concentration fluctuations seen in compounds with low clearance include potentially reduced steady-state peak concentrations, increased trough concentrations, and the prospect of improved drug compliance due to a possibly improved risk-benefit profile.

[0007] Despite the progress made in this field, there remains a need in the art for improved VMAT2 inhibitors, including compounds, compositions and related methods.Identification of VMAT2 small molecules with long half-life / low clearance is advantageous for drug development, especially when developed for chronic administration.In certain disease populations, where patient compliance and pill burden are ongoing issues, reducing dosing frequency is highly desirable and provides increased patient benefits. The present disclosure meets these and other needs, such as improved in vitro VMAT2 potency or improved pharmacokinetics, or both, as will be apparent from reference to the disclosure below. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8 [Non-Patent Document 2] Pettibone et al., Eur. J. Pharmacol. (1984) 102:431-6 [Non-Patent Document 3] Login et al., (1982) Ann. Neurology 12:257-62 [Non-Patent Document 4] Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521 Summary of the Invention [Means for solving the problem]

[0009] overview Some embodiments include a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is R 2A , -(CH2) m -R 2B or -(CH2) n -OR 2C and R 2A are each unsubstituted or one or more R A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted with Each R A is independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, haloC1-C4 alkoxy, haloC1-C4 alkyl, haloC2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH and oxo; R 2B are each unsubstituted or one or more R B aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl substituted by Each R Bis independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, haloC1-C4 alkyl, haloC1-C4 alkylsulfonyl, oxo, and -OH; R 2C are each unsubstituted or one or more R C C1-C4 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted with Each R C are independently -CN or C3-C6 cycloalkyl; m is 0, 1, 2, 3 or 4; n is 1, 2 or 3. to provide.

[0010] Also provided herein is a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0011] Also provided herein is a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form and a kit, each of which comprises a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0012] Also provided herein is a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0013] Also provided herein are pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms and kits, each of which comprises a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0014] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0015] Also provided herein is a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, for use in treating a neurological or psychiatric disease or disorder in a subject in need thereof.

[0016] Also provided herein is a method of inhibiting VMAT2, comprising contacting said VMAT2 with a compound of formula (I).

[0017] Also provided herein is a method of reducing the level of a monoamine in the central nervous system of a subject, comprising administering to the subject an amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in an amount sufficient to reduce the level of a monoamine in the central nervous system compared to pre-administration levels.

[0018] Also provided herein is a method of treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof; a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0019] Also provided herein is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof; a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0020] Also provided herein is a method of treating a neurological or psychiatric disease or disorder in a subject, the method comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0021] Also provided herein is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with an additional pharmaceutical agent selected from an antidepressant, an antipsychotic (typical or atypical), an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, and a gastrointestinal agent.

[0022] Also provided herein is a method of ameliorating one or more symptoms of a neurological or psychiatric disease or disorder, comprising the step of administering to a subject in need thereof an effective amount of at least one compound of Formula (I), or a pharma- ceutically acceptable salt thereof, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, 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 acanthocyocytosis.

[0023] Also provided herein is the use of a compound of formula (I), or a pharma- ceutical product comprising a compound of formula (I), or a pharma- ceutical salt thereof; a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutical salt thereof, in the manufacture of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.

[0024] Also provided herein is the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof; a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder.

[0025] Also provided herein is the use of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder.

[0026] Also provided herein is the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for treating a neurological or psychiatric disease or disorder, wherein the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, 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 acanthocyocytosis.

[0027] Also provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof; a pharmaceutical product comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof; a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0028] Also provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0029] Also provided herein is a compound of formula (I), or a pharma- ceutical product comprising a compound of formula (I), or a pharma- ceutical salt thereof; a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutical salt thereof, for use in a method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.

[0030] Also provided herein is a compound of formula (I), or a pharma- ceutical product comprising a compound of formula (I), or a pharma- ceutical salt thereof; a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutical salt thereof, for use in a method for treating a neurological or psychiatric disease or disorder.

[0031] Also provided herein is a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, for the treatment of a neurological or psychiatric disease or disorder.

[0032] In some embodiments, the neurological or psychiatric disease or disorder is selected from the group consisting of hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, treatment-resistant obsessive-compulsive disorder, 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 acanthocyocytosis.

[0033] In some embodiments, the vesicular monoamine transporter-2 (VMAT2) disease or disorder is selected from ataxias or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jaw diseases; dyskinesia; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson's disease / parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders. [Brief description of the drawings]

[0034] [Figure 1A] FIG. 1A shows a representation of the single crystal structure of (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)).

[0035] [Figure 1B]FIG. 1B shows a representation of the single crystal structure of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)).

[0036] [Diagram 2] FIG. 2 shows the powder X-ray diffraction (PXRD) diffractogram of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1) free base crystalline form I.

[0037] [Diagram 3] FIG. 3 shows the DSC and TGA thermograms of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1) free base crystalline Form I.

[0038] [Figure 4] FIG. 4 shows the powder X-ray diffraction (PXRD) diffractogram of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-15) free base crystalline Form I.

[0039] [Diagram 5] FIG. 5 shows the DSC and TGA thermograms of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-15) free base crystalline Form I.

[0040] [Figure 6] 6 shows a general synthetic scheme for the preparation of compounds of formula (I) and intermediates related thereto, in which R1 has the same meaning as described herein and X is a leaving group such as halo (e.g., I, Cl and Br) or OS(O)2Rz (e.g., mesylate (-OMs), triflate (-OTf) and tosylate (-OTs), where Rz has the same meaning as described herein). As shown in FIG. 6, intermediates Compound 1-B, Compound 1-C, and Compound 1-D (including their corresponding stereoisomers) are novel and useful in the preparation of compounds of formula (I) and pharmaceutical salts thereof as described herein.

[0041] [Figure 7] FIG. 7 shows the synthesis of (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C) using a (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) resolution step. FIG. 1 shows a general synthetic scheme for the preparation of compound 1-D(2R,3R,11bR), which gives (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)).

[0042] [Figure 8]Figure 8 shows a representative reaction for the preparation of (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C(2R,3R,11bR)) and the salt of (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA). See Example 1B.

[0043] [Figure 9] 9 shows a general synthetic scheme for the preparation of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)) and (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)) using chiral supercritical fluid chromatography (SFC). See Example 2.

[0044] [Figure 10]FIG. 10 is a representative as described in Example 3 for the preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)) from (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)). and representative reduction steps for the preparation of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)) from (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)).

[0045] [Figure 11]FIG. 11 is a representative as described in Example 4 for the preparation of (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3R,11bR)) from (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 2-B(3R,11bR)). and representative reduction steps for the preparation of (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3S,11bS)) from (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 2-B(3S,11bS)).

[0046] [Figure 12]Figure 12 shows a representative reaction used in the preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CF3CH2OTf) in the presence of cesium carbonate and acetone to (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1). See Example 5A. In Figure 12, a representative reaction is also shown for use in the preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)) and (R)-2-methyloxirane in the presence of cesium carbonate and DMF to (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55).See Example 5F.

[0047] [Figure 13] FIG. 13 shows a representative reaction scheme used in the preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-1), see Example 7; and (2S,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-3), see Example 8, both of which utilize dimethyl sulfate as the methylating agent and sodium borohydride as the reducing agent.

[0048] [Figure 14] FIG. 14 shows a representative reduction reaction used in the preparation of (2S,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-2), see Example 9; and a representative reduction reaction used in the preparation of (2R,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-4), see Example 10, both reactions utilizing lithium tri-sec-butylborohydride as the reducing agent in THF.

[0049] [Figure 15] FIG. 15 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., Compound 4-1, Compound 4-13, and Compound 4-14) and the comparative compounds (i.e., Compound 4-1C, Compound 4-13C, and Compound 4-14C).

[0050] [Figure 16] FIG. 16 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., Compound 4-15, Compound 4-17, and Compound 4-18) and comparative compounds (i.e., Compound 4-15C, Compound 4-17C, and Compound 4-18C).

[0051] [Figure 17] FIG. 17 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., Compound 4-22, Compound 4-26, and Compound 4-28) and comparative compounds (i.e., Compound 4-22C, Compound 4-26C, and Compound 4-28C).

[0052] [Figure 18]FIG. 18 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., Compound 4-30, Compound 4-32, and Compound 4-38) and the comparative compounds (i.e., Compound 4-30C, Compound 4-32C, and Compound 4-38C).

[0053] [Figure 19] FIG. 19 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (ie, Compound 4-39 and Compound 5-1) and the comparative compounds (ie, Compound 4-39C and Compound 5-1C).

[0054] [Figure 20] FIG. 20 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., Compound 4-27, Compound 4-88, and Compound 4-119) and comparative compounds (i.e., Compound 4-27C, Compound 4-88C, and Compound 4-119C).

[0055] [Figure 21] FIG. 21 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (ie, Compound 4-120 and Compound 4-121) and the comparative compounds (ie, Compound 4-120C and Compound 4-121C).

[0056] [Figure 22] FIG. 22 shows the in vivo pharmacology in Sprague-Dawley rats for Compound 4-1 and Compound 4-15 in the open field hypolocomotion model as described in Example 12.

[0057] [Figure 23] FIG. 23 shows the in vivo pharmacology in Sprague-Dawley rats for Compound 4-27, Compound 4-50 and Compound 4-55 in the open field hypolocomotion model as described in Example 12.

[0058] [Figure 24] FIG. 24 shows the in vivo pharmacology in Sprague-Dawley rats for compounds 4-31 in the open field hypolocomotion model as described in Example 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] Detailed Description definition For clarity and consistency, the following definitions will be used throughout this patent document.

[0060] 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.

[0061] As used herein, "administering" refers to providing a compound or other therapy described herein 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, and the like; injectable dosage forms, such as IV, IM, IP, and the like; transdermal dosage forms, including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.

[0062] A health care professional can directly provide the compounds described herein to a subject in the form of a sample, or can indirectly provide the compounds to a subject by providing an oral or written prescription for the compounds. Also, for example, a subject can obtain the compounds themselves without the involvement of a health care professional. When the compounds are administered to a subject, the body is transformed in some way by the compounds. When the compounds described herein are provided in combination with one or more other agents, it is understood that "administration" includes the compounds and the other agents being administered at the same time or at different times. When the agents of a combination are administered at the same time, they may be administered together in a single composition or may be administered separately. The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical preparation, the site of the disease, and the severity of the disease.

[0063] The term "composition" refers to a compound or crystalline form thereof, including but not limited to salts, solvates and hydrates of the compound described herein, in combination with at least one additional component, such as compositions obtained / prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), etc.

[0064] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopic variants of the depicted structure. This term is also intended to refer to the compounds described herein, regardless of how they are prepared, for example, synthetically, via biological processes (e.g., metabolic or enzymatic conversion), or combinations thereof. All compounds and pharma- ceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds described herein and their salts may appear in various forms, for example, in the form of cocrystals or solvates, including hydrates. The compounds may be in any solid state form, such as polymorphs or solvates, so unless expressly indicated otherwise, references to the compounds and their salts in the specification should be understood to encompass all solid state forms of the compounds. In some embodiments, the compounds described herein or their salts are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in the compounds described herein. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or salts thereof.

[0065] The term "solvate" as used herein refers to a solid state form of a compound described herein, or a pharma- ceutically acceptable salt thereof, that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0066] The term "hydrate," as used herein, refers to a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0067] The term "in need of treatment" and the term "in need of" when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., in the case of humans, a doctor, a nurse, a caregiver, etc.; in the case of animals, including non-human mammals, a veterinarian) that a subject or animal needs or will benefit from treatment. This judgment is made based on a variety of factors that are within the area of ​​expertise of the caregiver, but includes knowledge that the subject or animal is sick or will become sick as a result of a disease, condition, or disorder treatable by the compounds described herein. Thus, the compounds described herein can be used in a protective or preventative manner, or the compounds described herein can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0068] The term "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates and humans.In the context of clinical trials or screening or activity experiments, a subject can be a healthy volunteer or participant without an underlying VMAT2-mediated disorder or condition, or a volunteer or participant who has been diagnosed with a disorder or condition that requires medical treatment as determined by a health care professional.In the context outside of clinical trials, a subject who is under the care of a health care professional who has been diagnosed with a disorder or condition is typically described as a subject.

[0069] The term "pediatric subject" refers to a subject who is under 21 years old at the time of diagnosis or treatment. The term "pediatric subject" can be further divided into various subpopulations, including neonates (birth to 1 month old); infants (1 month to 2 years old); children (2 to 12 years old); and adolescents (12 to 21 years old (up to but not including their 22nd birthday)), see, for example, Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0070] The phrase "pharmacologically acceptable" refers to compounds (and their salts), compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0071] The term "pharmaceutical composition" refers to a specific composition that contains at least one active ingredient, including but not limited to salts, solvates and hydrates of the compounds described herein, whereby the composition is suitable for investigation of a specified effective outcome in a mammal (for example, but not limited to, a human).Those skilled in the art will understand and appreciate the appropriate techniques to determine whether an active ingredient has a desired effective outcome based on the needs of the artisan.

[0072] The terms "prevent", "preventing" and "prevention" refer to the disappearance or reduction of the appearance or onset of one or more symptoms associated with a particular disorder. For example, the terms "prevent", "preventing" and "prevention" can refer to the administration of therapy on a protective or preventative basis to a subject who may eventually manifest at least one symptom of a disorder, but has not yet done so. Such subjects can be identified based on risk factors known to correlate with the subsequent appearance of disease, such as the presence of biomarkers. Alternatively, preventive therapy can be administered as a protective measure without prior identification of risk factors. Delaying the onset of at least one episode and / or symptom of a disorder can also be considered as prevention or protection. In some embodiments, the subject can be a pediatric subject.

[0073] The terms "treat", "treating" and "treatment" refer to the medical management of a disease, disorder or condition of a subject (e.g., a subject) (see, e.g., Stedman's Medical Dictionary). In general, appropriate dosage and treatment regimen provides a sufficient amount of VMAT2 inhibitor to provide therapeutic benefit. The therapeutic benefit for the subject to which the VMAT2 inhibitor compound(s) described herein is administered includes, for example, improved clinical outcome, the purpose of which is to prevent or slow down or retard (reduce) the undesirable physiological changes associated with disease, or to prevent or slow down or retard (reduce) the spread or severity of such disease. The effectiveness of one or more VMAT2 inhibitors can include beneficial or desired clinical results, including but not limited to, amelioration, reduction or alleviation of symptoms caused by or associated with the disease being treated, whether detectable or not; reduction in the occurrence of symptoms; improvement in quality of life; longer disease-free period (i.e., reducing the likelihood or tendency of the subject to present symptoms on which the diagnosis of the disease is based); reduction in the extent of disease; stable (i.e., not worsening) disease state; delay or slowing of disease progression; remission or mitigation of disease state; and remission (whether partial or total); and / or overall survival. In some embodiments, the subject can be a pediatric subject.

[0074] The term "therapeutically effective amount" refers to an amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, that elicits a biological or medicinal response in a tissue, system, animal, or human desired by a subject, researcher, veterinarian, physician, or other clinician or caregiver, which may include one or more of the following: (1) Preventing a disorder, e.g., preventing a disease, condition, or disorder in a subject who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the associated pathology or symptoms; (2) inhibiting a disorder, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and / or symptoms) in a subject experiencing or exhibiting the associated pathology or symptoms; and (3) Ameliorating the disorder, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in a subject experiencing or exhibiting the associated pathology or symptoms.

[0075] As used herein, the term "contact" refers to bringing together the indicated parts in an in vitro system or an in vivo system.For example, "contacting" VMAT2 protein with the compound provided herein includes administering the compound provided herein (or its pharma-ceutically acceptable salt) to a subject, such as a human, that has VMAT2 protein, and introducing the compound provided herein into the sample that contains, for example, cells or purified preparations that contain VMAT2 protein.

[0076] chemical group Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications are incorporated by reference in their entirety.In the event that there are multiple definitions for terms herein, those in this section shall prevail unless otherwise stated.

[0077] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0078] In compounds of formula (I) and pharma- ceutically acceptable salts thereof, in which a variable occurs more than once, each variable can be a different moiety independently selected from the group defining that variable. For example, when a structure is described having, for example, two R groups present simultaneously in the same compound, those two R groups can represent different moieties independently selected from the group defined for R, or those two R groups can be the same.

[0079] Whenever a group is described as "substituted," the group may be substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted," the substituent(s), if substituted, may be selected from one or more of the indicated substituents. It is understood that substitution at a given atom is limited by valence.

[0080] As used herein, "C" is a formula in which "a" and "b" are integers. a ~C b " refers to, for example, the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, these groups can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e., methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), iso-propyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), iso-butyl ((CH3)2CHCH2-), sec-butyl (CH3CH2CH(CH3)-), and tert-butyl ((CH3)3C-). If "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl group, the broadest range described in these definitions should be presumed.

[0081] In addition to the foregoing, as used in the specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated.

[0082] The term "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include allenyl, vinylmethyl, and ethenyl. Examples of alkenyl groups include vinyl (CH2=CH-), prop-1-en-2-yl (CH2=C(Me)-), prop-1-en-1-yl (MeCH=CH-), allyl (CH2=CHCH2-), but-2-en-2-yl (CH3CH=C(Me)-), but-1-en-1-yl (MeCH2CH=CH-), but-1-en-2-yl (CH2=C(Et)-), 2-phenyl-2-phenyl-1 ... -methylprop-1-en-1-yl (Me2C=CH-), but-3-en-2-yl (CH2=CHCH(Me)-), 2-methylallyl (CH2=C(Me)CH2-), but-2-en-1-yl (MeCH=CHCH2-), but-3-en-1-yl (CH2=CHCH2CH2-) and buta-1,3-dien-1-yl (CH2=CHCH=CH-). In some embodiments, an alkenyl group can be unsubstituted or substituted. In some embodiments, an alkenyl group can have 2 to 6 carbon atoms. In some embodiments, an alkenyl group can have 2 to 4 carbon atoms. The alkenyl groups of the compounds may be designated "C2-C6 alkenyl", "C2-C4 alkenyl" or similar designations.

[0083] The term "alkoxy" refers to the formula -OR, where R is alkyl as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy group can be "C1-C6 alkoxy", "C1-C4 alkoxy", or similar designations. In some embodiments, an alkoxy can be substituted or unsubstituted.

[0084] The term "alkyl" refers to a fully saturated straight or branched chain hydrocarbon radical. An alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 20" refer to each integer within the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms. In some embodiments, an alkyl group can have 1 to 6 carbons (i.e., "C1-C6 alkyl"). Some embodiments are 1 to 5 carbons (i.e., C1-C5 alkyl), some 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. By way of example only, a "C1-C4 alkyl" refers to an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms. indicates that there are 4 carbon atoms from 1 to 4, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and the like. When one or more substituents are present on an alkyl group, the substituent(s) may be attached at any available carbon atom. In some embodiments, the alkyl group may be substituted or unsubstituted.

[0085] The term "alkylamino" refers to an amino group (-NH2) in which the nitrogen atom is substituted with an alkyl group. The term "alkyl" has the same definition as described herein. An "alkylamino" group can have 1 to 4 carbon atoms (i.e., C1-C4 alkylamino). Examples of alkylamino groups include -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), and the like.

[0086] The term "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups can have from 2 to 6 carbon atoms. The alkenyl group of a compound may be designated "C2-C6 alkynyl" or similar designations.

[0087] The term "alkylsulfonyl" refers to a radical consisting of an alkyl radical attached to the sulfur of a sulfone radical of the formula: -S(=O)2-, where alkyl has the same definition as described herein. An "alkylsulfonyl" group can have 1 to 4 carbon atoms (i.e., C1-C4 alkylsulfonyl). Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butylsulfonyl, and the like.

[0088] The term "alkylsulfonyloxy" refers to a radical consisting of an alkyl radical attached to the sulfur of a sulfonyloxy radical of the formula: -S(=O)2O-, where alkyl has the same definition as described herein. The "alkylsulfonyloxy" group can have 1 to 4 carbon atoms (i.e., C1-C4 alkylsulfonyloxy). Examples include methylsulfonyloxy (CH3S(=O)2O-), ethylsulfonyloxy, n-propylsulfonyloxy, iso-propylsulfonyloxy, n-butylsulfonyloxy, sec-butylsulfonyloxy, iso-butylsulfonyloxy, t-butylsulfonyloxy, and the like.

[0089] The term "amino" refers to the group -NH2.

[0090] The term "aryl" refers to an aromatic ring system containing 6, 10, or 14 carbon atoms, which may contain a single ring, two fused rings, or three fused rings, such as phenyl, naphthalenyl, and phenanthrenyl. In some embodiments, an aryl group may have 6 or 10 carbon atoms (i.e., C6 or C7). 10 aryl). In some embodiments, the aryl group is phenyl. When one or more substituents are present on the "aryl" ring, the substituent(s) may be attached at any available ring carbon. In some embodiments, the aryl group may be substituted or unsubstituted.

[0091] A "C-amide" group is a "-C(=O)N(R A R B ) group, where R A and R B are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C 10 It can be aryl, heteroaryl or heterocyclyl.

[0092] The term "carbonyl" refers to the group -C(=O)-.

[0093] The term "cycloalkenyl" refers to a mono- or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if there is more than one, the double bonds cannot form a completely delocalized pi-electron system (i.e., aromatic system) through all rings, otherwise the group would be "aryl" as defined herein. When composed of two or more rings, the rings can be connected together in a fused, bridged, or spiro fashion. Cycloalkenyls can contain 3 to 12 atoms in the ring(s) or 3 to 8 atoms in the ring(s). In some embodiments, cycloalkenyl groups can be unsubstituted or substituted. In some embodiments, cycloalkenyl groups can have 4 to 8 carbon atoms (i.e., "C4-C8 cycloalkenyl"). One example is cyclohexenyl.

[0094] The term "cycloalkyl" refers to a fully saturated all-carbon mono- or polycyclic ring system. In some embodiments, the cycloalkyl is a monocyclic ring containing from 3 to 8 carbon atoms (i.e., a "C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl is a monocyclic ring containing from 3 to 7 carbon atoms (i.e., a "C3-C7 cycloalkyl"). In some embodiments, the cycloalkyl is a monocyclic or bicyclic ring containing from 3 to 7 carbon atoms (i.e., a "C3-C7 cycloalkyl"). Some embodiments contain from 3 to 6 carbons (i.e., a "C3-C6 cycloalkyl"). Some embodiments contain from 3 to 5 carbons. Some embodiments contain from 5 to 7 carbons. Some embodiments contain from 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, and cyclohexyl. When one or more substituents are present on a cycloalkyl group, the substituent(s) may be attached at any available carbon atom. In some embodiments, the cycloalkyl group may be substituted or unsubstituted.

[0095] The term "dialkylamino" refers to an amino group (-NH2) in which the nitrogen is substituted with two alkyl groups. These two alkyl groups may be the same or different. The term "alkyl" has the same definition as described herein. A "dialkylamino" group may have 1 to 4 carbon atoms (i.e., C2-C4 dialkylamino), provided that the two alkyl groups do not exceed a total of 4 carbon atoms between the two groups. Examples include -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2CH3), and the like.

[0096] The term "dialkylsulfamoyl" refers to a sulfonamide group (-S(=O)2NH2) in which the nitrogen is substituted with two alkyl groups, which may be the same or different. The term "alkyl" has the same definition as described herein. A "dialkylsulfamoyl" group can have 1 to 4 carbon atoms (i.e., C2-C4 dialkylsulfamoyl), provided that the two alkyl groups do not exceed a total of 4 carbon atoms between the two alkyl groups. Examples include -SON(CH3)2, -SON(CH3)(CH2CH3), -SON(CH3)(CH2CH2CH3), -SON(CH2CH3)2, -SON(CH2CH3)(CH2CH2CH3), and the like.

[0097] The term "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some embodiments, a haloalkoxy group can have from 1 to 6 carbon atoms. A haloalkoxy group of a compound may be designated as "halo C1-C6 alkoxy," "halo C1-C4 alkoxy," or similar designations.

[0098] The term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). In some embodiments, a haloalkyl group can have 1 to 6 carbons (i.e., "haloC1-C6 alkyl"). A haloC1-C6 alkyl can be fully substituted, in which case it can be represented by the formula C n L 2n+1 where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. When more than one halogen is present, they may be the same or different and may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl contains 1 to 5 carbons (i.e., haloC1-C5 alkyl). In some embodiments, the haloalkyl contains 1 to 4 carbons (i.e., haloC1-C4 alkyl). In some embodiments, the haloalkyl contains 1 to 3 carbons (i.e., haloC1-C3 alkyl). In some embodiments, the haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

[0099] The term "haloalkylsulfonyl" refers to a radical consisting of a haloalkyl radical attached to the sulfur of a sulfone radical of the formula: -S(=O)2-, where haloalkyl has the same definition as described herein. The "haloalkylsulfonyl" group can have 1 to 4 carbon atoms (i.e., haloC1-C4 alkylsulfonyl). Examples include fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, chlorodifluoromethylsulfonyl, 1-fluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl, 4,4,4-trifluorobutylsulfonyl, and the like.

[0100] The term "halodialkylamino" refers to an amino group (-NH2) in which the nitrogen is substituted with either one alkyl group and one haloalkyl group, or two haloalkyl groups. When the nitrogen is substituted with two haloalkyl groups, the groups may be the same or different. The terms "alkyl" and "haloalkyl" have the same definitions as described herein. A "halodialkylamino" group may have 1 to 4 carbon atoms (i.e., haloC2-C4 dialkylamino), provided that the two groups do not exceed a total of 4 carbon atoms between the two groups. Examples include -N(CH3)(CF3), -N(CH3)(CF3), -N(CF3)2, -N(CH3)(CH2CF3), -N(CH2CF3)2, and the like.

[0101] The term "halogen" or "halo" refers to a fluoro, chloro, bromo, or iodo group. In some embodiments, the halogen or halo is fluoro, chloro, or bromo. In some embodiments, the halogen or halo is fluoro or chloro. In some embodiments, the halogen or halo is fluoro.

[0102] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system having at least one heteroatom in the ring system, i.e., an element other than carbon, including but not limited to nitrogen, oxygen, and sulfur. Some embodiments are "5-6 membered heteroaryl," which refers to an aromatic ring containing 5 or 6 ring atoms in a single ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenanthridinyl, benzimidazolyl, pyrrolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Heteroaryl groups can be substituted or unsubstituted. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5- to 7-membered heteroaryl," "5- to 10-membered heteroaryl," or similar designations. In some embodiments, heteroaryl is a substituted or unsubstituted C1-C aryl group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13In some embodiments, the heteroaryl can be a substituted or unsubstituted C1-C5 5- or 6-membered monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl can be a substituted or unsubstituted C5-C9 8-, 9-, or 10-membered bicyclic ring system containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a substituted or unsubstituted C5-C9 8-, 9-, or 10-membered heteroaryl. In some embodiments, the C5-C9 8-, 9-, or 10-membered bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrido[3,4-b]pyrazinyl, or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryl is a substituted or unsubstituted C8-C aryl containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13In some embodiments, the heteroaryl is a 13- or 14-membered tricyclic ring system. In some embodiments, the heteroaryl can be an azolyl, such as imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl, each of which may be substituted or unsubstituted. In some embodiments, the heteroaryl is a C1-C4 5-membered heteroaryl. In some embodiments, the C1-C4 5-membered heteroaryl is a furanyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, or tetrazolyl. In some embodiments, the heteroaryl is a C3-C5 6-membered heteroaryl. In some embodiments, the C3-C5 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, the "5-10-membered heteroaryl" refers to furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, triazinyl, benzofuranyl, 1H-indolyl, benzo[b]thiophenyl, and the like. In some embodiments, the "5-10-membered heteroaryl" refers to pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, and the like. In some embodiments, "5-10 membered heteroaryl" refers to pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, imidazo[4,5-c]pyridinyl, etc. In some embodiments, the heteroaryl group can be substituted or unsubstituted.

[0103] The term "heterocyclyl" refers to 3, 4, 5, 6, 7, 8, 9, 10, up to 18 membered monocyclic, bicyclic and tricyclic ring systems, where the carbon atoms together with 1 to 5 heteroatoms make up said ring system, and optionally contain one or more unsaturated bonds positioned such that a fully delocalized pi-electron system (aromatic system) does not occur in either the monocyclic ring or in at least one ring of the bicyclic or tricyclic ring system. The heteroatom(s) are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion, where the heteroatom(s) may be in either the non-aromatic or aromatic ring in the ring system. In some embodiments, "4-7 membered heterocyclyl" refers to a saturated non-aromatic ring system containing 4 to 7 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, "3- to 6-membered heterocyclyl" refers to a saturated non-aromatic ring radical containing 3 to 6 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclyl" refers to a saturated non-aromatic ring radical containing 4 to 6 ring atoms, where at least one ring atom is a heteroatom. In some embodiments, the one or two heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, the heterocyclyl may contain a carbonyl (C=O) group adjacent to the heteroatom, i.e., may be substituted with oxo at the carbon adjacent to the heteroatom, where the substituted ring system is a lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate.Examples of unsubstituted or oxo-substituted "heterocyclyl" groups are aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, and oxazolidinyl.

[0043] Examples of aryl include, but are not limited to, aryl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2.2]octane, 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, 2-oxa-6-azaspiro[3,3]heptane, and their benzo-fused analogs (e.g., benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl). Heterocyclyl groups may be designated "3- to 10-membered heterocyclyl" or similar designations. In some embodiments, heterocyclyl is a C-C group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12 In some embodiments, the heterocyclyl can be a substituted or unsubstituted C2-C6 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl can be a substituted or unsubstituted C2-C6 3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 10In some embodiments, the heterocyclyl is a substituted or unsubstituted C7-C aryl ring system containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12In some embodiments, the heteroatom(s) of a 6-membered monocyclic heterocyclyl are selected from one to three of O (oxygen), N (nitrogen) or S (sulfur), and the heteroatom(s) of a 5-membered monocyclic heterocyclyl are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). In some embodiments, the heterocyclyl is selected from aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathiyl, 1,4-oxathiyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathiyl, tetrahydro-1,4-thiol ... Azinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2.2]o 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2,6-naphthyridinyl, 1,2,3,4-tetrahydro-2,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1,2, It can be 3,4-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, [1,3]dioxolo[4,5-c]pyridinyl, [1,3]dioxolo[4,5-b]pyridinyl, [1,3]dioxolo[4,5-d]pyrimidinyl, or 3,4-methylenedioxyphenyl.In some embodiments, the unsubstituted or substituted heterocyclyl may be selected from aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 2-piperidone, 1,1-dioxidethiomorpholinyl, oxolanyl (tetrahydrofuranyl) and oxanyl (tetrahydropyranyl). When one or more substituents are present in the heterocyclyl group, the substituent(s) may be attached at any available carbon atom and / or heteroatom. In some embodiments, the heterocyclyl group may be substituted or unsubstituted.

[0104] The term "oxo" refers to a ═O substituent.

[0105] The term "nitro" refers to the group --NO.sub.2.

[0106] The term "sulfamoyl" refers to the group -S(=O)2NH2.

[0107] As used herein, "additive" refers to a substance added to a composition to provide the composition with, but not limited to, bulk, viscosity, stability, binding ability, lubrication, disintegration ability, and the like. "Diluent" is a type of additive and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmacologic necessary or desirable. For example, a diluent can be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. A diluent can also be a liquid for dissolution of a drug to be administered by injection, ingestion, or inhalation. A pharmacologic acceptable additive is a physiologically and pharmacologic suitable non-toxic and inert material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. can be provided in the pharmaceutical composition. Those skilled in the art can further formulate the compounds as disclosed and described herein in an appropriate manner according to accepted practices, such as those disclosed in Remington above.

[0108] As used herein, "dose" or "dosage" refers to a measured quantity of a drug substance taken by a subject at one time. In certain embodiments, when the drug substance is neither a free base nor a free acid, the quantity is the molar equivalent of the corresponding amount of the free base or free acid.

[0109] As used herein, "pharmaceutically acceptable salts" refers to salts of compounds that have acidic or basic moieties that are not biologically or otherwise undesirable for use in pharmaceutical products. In many cases, the compounds disclosed herein can form acid and / or base salts by virtue of the presence of acidic or basic moieties (e.g., amino and / or carboxyl groups or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining compounds that have a basic moiety with inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed by combining compounds that have an acidic moiety with inorganic and organic bases.

[0110] The compounds described herein may have one or more stereocenters. Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. In any compound provided herein with one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, it is understood that each center can be independently in the (R)-configuration or (S)-configuration, or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. The preparation of enantiomerically pure or enantiomerically enriched forms can be accomplished by resolution of racemic mixtures, or by using enantiomerically pure or enriched starting materials, or by stereoselective or stereospecific synthesis. Stereochemical definitions are available in EL Eliel, SH Wilen & LN 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 contain one or more stereocenters, the compounds may be prepared in an enantiomeric or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%.

[0111] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. An example method includes fractional recrystallization using chiral resolving organic acids with racemic compounds containing basic groups. Other chiral resolving agents suitable for fractional crystallization include stereoisomerically pure forms (e.g., S and R forms, or diastereomerically pure forms) of methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using chiral resolving bases can be utilized with racemic compounds containing basic groups.

[0112] Resolution of racemic mixtures can also be achieved by elution on a chiral column. Suitable elution solvent compositions can be determined by one skilled in the art.

[0113] In some embodiments, the compounds described herein may 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 within a range defined by any of the preceding figures. In some embodiments, the compounds described herein may 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 within a range defined by any of the preceding figures.

[0114] In some embodiments, the compounds described herein may 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 within a range defined by any of the preceding figures. In some embodiments, the compounds described herein may 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 within a range defined by any of the preceding figures.

[0115] Additionally, when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, unless otherwise specified, it is understood that the compounds include both E and Z geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds described herein may be isolated as a mixture of isomers or as separated isomeric forms.

[0116] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be sterically fixed in one form by appropriate substitution.

[0117] The compounds described herein and their pharma- ceutically acceptable salts can be found together with other substances such as water and solvent, for example, in the form of hydrate or solvate.When in solid state, the compounds described herein and their salts can appear in various forms, for example, in the form of solvate, including hydrate.The compounds can be in any solid state form, such as crystalline form, amorphous form, solvate form, and unless otherwise clearly indicated, the reference to the compounds and their salts in the specification should be understood as a reference to any solid state form of the compounds.

[0118] The compounds described herein can be used in a neutral form, such as a free acid or free base form. Alternatively, the compounds can be used in the form of a pharma- ceutically acceptable salt, such as a pharma- ceutically acceptable addition salt of an acid or base.

[0119] In some embodiments, the compounds described herein or salts thereof are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched with the compounds described herein. Substantial separation can include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or salts thereof.

[0120] Isotopes The compounds disclosed and described herein, unless the context clearly dictates otherwise, allow and include atoms at each position of the compound independently to have 1) an isotopic distribution for a chemical element in proportion to the amount normally found in nature, or 2) a proportional isotopic distribution different from that normally found in nature. A particular chemical element has an atomic number defined by the number of protons in the atomic nucleus. Each atomic number identifies a particular chemical element but not an isotope, and atoms of a given element can have neutrons whose number ranges widely. 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 for a chemical element in proportion to the amount normally found in nature are generally referred to as being isotopically labeled. Each chemical element represented in a compound structure can include any isotopic distribution of said element. For example, in a compound structure, it may be clearly disclosed or understood that a hydrogen atom is present in the compound. At any position in the compound where a hydrogen atom can be present, the hydrogen atom is present in an amount proportional to that normally found in nature and in an amount different from that normally found in nature, such as protium ( 1 H) and deuterium (2 The isotope distribution may be an isotope distribution of hydrogen, including but not limited to hydrogen (H). Thus, reference to a compound herein encompasses all possible isotope distributions of each atom, unless the context clearly dictates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine. As will be appreciated by those of skill in the art, any of the compounds as disclosed and described herein may contain radioisotopes. Thus, one or more atoms may be present in a greater proportion than found in nature. 2 H or 3 H or a large proportion 11 C. 13 C or 14 The use of compounds as disclosed and described herein that have an isotope distribution different from that typically found in nature, such as having C, is also contemplated. As a general example, and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). The carbon isotopes are carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C) and carbon-14 ( 14 The nitrogen isotopes are nitrogen-13( 13 N), nitrogen-14( 14 N) and nitrogen-15( 15 The isotope of oxygen is oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 O). The isotopes of fluorine are fluorine-17( 17 F), Fluorine-18( 18 F) and fluorine-19( 19 The isotope of phosphorus is phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34 P), phosphorus-35(35 P) and phosphorus-36( 36 The isotopes of sulfur are 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). The isotope of chlorine is chlorine-35 ( 35 Cl), Chlorine-36( 36 Cl) and chlorine-37( 37 The isotope of bromine is bromine-75( 75 Br), Bromine-76( 76 Br), Bromine-77( 77 Br), Bromine-79( 79 Br), Bromine-81( 81 Br) and Bromine-82 ( 82 The isotopes of iodine 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 all positions of the compound have an isotopic distribution for each chemical element in a proportionate amount to that normally found in nature. In some embodiments, the atoms at one position of the compound have an isotopic distribution for a chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount to that normally found in nature). In some embodiments, the atoms at at least two positions of the compound independently have an isotopic distribution for a chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount to that normally found in nature). In some embodiments, the atoms at at least three positions of the compound independently have an isotopic distribution for a chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount to that normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have an isotopic distribution for a proportional amount of chemical elements different from that normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical elements that is normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have an isotopic distribution for a proportional amount of chemical elements different from that normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical elements that is normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have an isotopic distribution for a proportional amount of chemical elements different from that normally found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical elements that is normally found in nature).

[0121] Certain compounds, e.g. 3 H and 14 Incorporating a radioactive isotope, such as C, is also useful in drug or substrate tissue distribution assays. 3H) and carbon-14 ( 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Compounds bearing isotopes such as H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by carrying out procedures 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, additional methods are available, such as radiation detectors used in conjunction with HPLC or GC.

[0122] As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound is an isotope of protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35(35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (I). 1 H), deuterium ( 2 H), Carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 In certain embodiments, an "isotopic variant" of a compound described herein is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound described herein contains an unnatural proportion of one or more isotopes, including, but not limited to, tritium ( 3 H), Carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O) and oxygen-15( 15 In the compounds as provided herein, any hydrogen may be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 2 H as the predominant isotopic form, or any carbon can be used as an example. 13Contains C as the major isotopic form, or any nitrogen as an example 15 N as the major isotopic form, any oxygen can be used as an example 18 It will be appreciated that the isotope may contain 0 as the predominant isotopic form. In certain embodiments, an "isotopic variant" of a compound may contain unnatural proportions of deuterium ( 2 H).

[0123] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor 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, in certain embodiments. Similarly, with respect to the compounds provided herein, when any atomic position is designated as a specific isotope, it is understood that the abundance of the specific isotope at that position is substantially greater than the natural abundance of that isotope. Positions designated as having a specific isotope typically have a minimum isotopic enrichment factor of incorporation of the isotope at each designated position, in certain embodiments, 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%.

[0124] 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, methods for incorporating activity levels of tritium into target molecules, are as follows: A. Catalytic reduction with tritium gas: This procedure typically yields products of high specific activity and requires halogenated or unsaturated precursors. B. Sodium borohydride [ 3 H] reduction: This procedure is fairly inexpensive and requires precursors that contain reducible functional groups such as aldehydes, ketones, lactones, esters, etc. C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure affords products of nearly theoretical specific activity. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc. D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst. E. Methyl iodide [ 3 N-Methylation using [H]: This procedure typically converts the appropriate precursor into high specific activity methyl iodide ( 3 H) to obtain O-methyl or N-methyl ( 3 H) products. This method generally allows for higher specific activities, such as, for example, about 70-90 Ci / mmol.

[0125] Activity level 125 Synthetic methods for incorporating I into target molecules include: A. Sandmeyer and similar reactions: This procedure involves converting aryl or heteroaryl amines to diazonium salts, such as diazonium tetrafluoroborate, followed by the addition of Na 125 Using I 125I-labeled compounds. A representative procedure was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948. B. Phenol ortho 125 Iodination: This procedure is used to iodinate the phenol at the ortho position as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266. 125 Allows the incorporation of I. C. 125 Aryl and heteroaryl bromide exchange with I: This method is generally a two-step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate in the presence of a trialkyltin or hexaalkylditin halide [e.g., (CH3)3SnSn(CH3)3], for example, using Pd catalysis [i.e., Pd(Ph3P)4] or via an aryl or heteroaryl lithium. A representative procedure was reported by Le Bas, M.-D. and co-workers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

[0126] The radiolabeled form of the compounds described herein can be used in screening assays to identify / assess compounds.Generally speaking, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled form of the compounds disclosed herein to VMAT2.The ability of the test compound to compete with the radiolabeled form of the compounds described herein for binding to VMAT2 correlates with its binding affinity.

[0127] compound Some embodiments include a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is R 2A , -(CH2) m -R 2B or -(CH2) n -OR 2C and R 2A are each unsubstituted or one or more R A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted with Each R A is independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, haloC1-C4 alkoxy, haloC1-C4 alkyl, haloC2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH and oxo; R 2B are each unsubstituted or one or more R B aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl substituted by Each R B is independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, haloC1-C4 alkyl, haloC1-C4 alkylsulfonyl, oxo, and -OH; R 2C are each unsubstituted or one or more R C C1-C4 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted with Each R C are independently -CN or C3-C6 cycloalkyl; m is 0, 1, 2, 3 or 4; n is 1, 2 or 3. to provide.

[0128] Some embodiments include a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is R 2A , -(CH2) m -R 2B or -(CH2) n -OR 2C and R 2A is unsubstituted or substituted with one or more R A is a C1-C4 alkyl substituted with Each R A is independently selected from the group consisting of fluoro and -OH; R 2B are each unsubstituted or one or more R B C3-C8 cycloalkyl or 4-6 membered heterocyclyl substituted with Each R B is independently selected from the group consisting of fluoro, -CN, -CHCN, and -OH; R 2C are each unsubstituted or one or more R C C1-C4 alkyl or C3-C8 cycloalkyl, substituted with Each R C are independently -CN or C3-C6 cycloalkyl; m is 0, 1, 2 or 3; n is 1, 2 or 3. to provide.

[0129] In some embodiments, the compound of formula (I) is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ia) is 2R,3R,11bR.

[0130] In some embodiments, the compound of formula (I) is a compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ic) is 2S,3R,11bR.

[0131] In some embodiments, the compound of formula (I) is a compound of formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ie) is 2R,3S,11bS.

[0132] In some embodiments, the compound of formula (I) is a compound of formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ig) is 2S,3S,11bS.

[0133] In some embodiments, R 1 is R 2A It is.

[0134] In some embodiments, R 2A are each unsubstituted or one or more R A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted with R A is as described herein above and below. In some embodiments, R 2A are each unsubstituted or one or more R AC2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl, each R A is independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, haloC1-C4 alkoxy, haloC1-C4 alkyl, haloC2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH and oxo. A It is understood that when present, they may be the same or different. In some embodiments, more than one R A When present, they are the same. In some embodiments, more than one R A If they exist, they are different.

[0135] In some embodiments, R 2A each is unsubstituted or contains one, two, three or four R A In some embodiments, R is a C2-C4 alkenyl, a C1-C6 alkyl, a C3-C8 cycloalkyl, or a 4-7 membered heterocyclyl substituted with 2A are each unsubstituted or one R A In some embodiments, R is a C2-C4 alkenyl, a C1-C6 alkyl, a C3-C8 cycloalkyl, or a 4-7 membered heterocyclyl substituted with 2A are each unsubstituted or two R A In some embodiments, R is a C2-C4 alkenyl, a C1-C6 alkyl, a C3-C8 cycloalkyl, or a 4-7 membered heterocyclyl substituted with 2A are each unsubstituted or three R A and is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 membered heterocyclyl substituted by

[0136] In some embodiments, R 2Ais unsubstituted or substituted with one or more R A C2-C4 alkenyl substituted with, where R A is as described herein above and below.

[0137] In some embodiments, R 2A is unsubstituted or substituted with one or more R A and methylallyl substituted with

[0138] In some embodiments, R 2A is prop-2-en-1-yl that is unsubstituted or substituted with one or more methyl. In some embodiments, R 2A is methylallyl.

[0139] In some embodiments, R 2A is unsubstituted or substituted with one or more R A C1-C6 alkyl substituted with, where R A is as described herein above and below.

[0140] In some embodiments, R 2A is unsubstituted or substituted with one or more R A is a C1-C6 alkyl substituted with

[0141] In some embodiments, R 2A are each unsubstituted or one or more R A substituted with n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl or n-pentyl.

[0142] In some embodiments, each R Ais independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, haloC1-C4 alkoxy, haloC2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH, and oxo. A is independently selected from the group consisting of methoxy, methylamino, methylsulfonyl, dimethylamino, N,N-dimethylsulfamoyl, chloro, fluoro, trifluoromethoxy, methyl(2,2,2-trifluoroethyl)amino, methyl(trifluoromethyl)amino, morpholino, -CN, -OH, and oxo.

[0143] In some embodiments, R 2A is one or more R independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, haloC1-C4 alkoxy, haloC2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH and oxo, each of which is unsubstituted or A substituted with n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl or n-pentyl.

[0144] In some embodiments, R 2Aare 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propan-2-yl, 1,1,1-trifluoropropan-2-yl, 2-hydroxy-2-methylpropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3-difluoro-2-hydroxypropyl, methyl, 2-hydroxypropyl, 2-hydroxybutyl, 4,4,4-trifluoro-2-hydroxybutyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl methylsulfonyl, cyanomethyl, 2-(dimethylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 2-hydroxy-3-methoxypropyl, 2-chloro-2,2-difluoroethyl, 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl, 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl, 3-(methylsulfonyl)propyl, (N,N-dimethylsulfamoyl)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-morpholinopropyl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl.

[0145] In some embodiments, R 2A is unsubstituted or has 1, 2, 3 or 4 R A C1-C4 alkyl substituted with A is independently selected from the group consisting of fluoro and -OH. 2A is unsubstituted or contains one, two or three R A C1-C4 alkyl substituted with A is independently selected from the group consisting of fluoro and -OH. 2A is C2-C4 alkyl. In some embodiments, R 2Ais -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 2A is C1-C4 alkyl substituted with 1, 2 or 3 fluoro. 2A is a C1-C4 alkyl substituted with 1, 2, or 3 groups each independently selected from a fluoro and a C-amido group. 2A is C1-C4 alkyl substituted with 1, 2 or 3 fluoro. 2A is -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CHF2, or -CH2CH2CF3. In some embodiments, R 2A is -CH2CH2CHF2 or -CH2CH2CF3.

[0146] In some embodiments, R 2A is unsubstituted or substituted with one or more R A C3-C8 cycloalkyl substituted with, where R A is as described herein above and below.

[0147] In some embodiments, R 2A is unsubstituted or substituted with one or more R A is a C3-C8 cycloalkyl substituted with

[0148] In some embodiments, R 2A are each unsubstituted or one or more R A cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl, substituted by

[0149] In some embodiments, each R A is independently selected from the group consisting of halogen and haloC1-C4 alkyl. A is independently selected from the group consisting of fluoro and trifluoromethyl.

[0150] In some embodiments, R 2A each R is unsubstituted or is one or more R independently selected from the group consisting of fluoro and trifluoromethyl; A In some embodiments, R is cyclobutyl, cyclopropyl, cyclopentyl, or cyclohexyl substituted with 2A is cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl or 3,3-difluorocyclopentyl.

[0151] In some embodiments, R 2A is unsubstituted or substituted with one or more R A 4-7 membered heterocyclyl substituted with R A is as described herein above and below.

[0152] In some embodiments, R 2A are each unsubstituted or one or more R A azetidin-3-yl, oxetan-3-yl or pyrrolidin-3-yl substituted with

[0153] In some embodiments, each R A is independently selected from the group consisting of C1-C6 alkyl, haloC1-C4 alkyl, and oxo. A is independently selected from the group consisting of methyl, 2,2,2-trifluoroethyl, and oxo.

[0154] In some embodiments, R 2A each R is unsubstituted or is one or more independently selected from the group consisting of methyl, 2,2,2-trifluoroethyl, and oxo; A In some embodiments, R is azetidin-3-yl, oxetan-3-yl, or pyrrolidin-3-yl, substituted with 2Ais oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl or 1-methylazetidin-3-yl.

[0155] In some embodiments, R 2A is methylallyl, n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl (isobutyl), methyl, n-pentyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidin-3-yl, oxetan-3-yl, or pyrrolidin-3-yl; each of which is unsubstituted or represents one or more independently selected from the group consisting of methoxy, methylamino, methylsulfonyl, dimethylamino, N,N-dimethylsulfamoyl, chloro, fluoro, trifluoromethoxy, methyl(2,2,2-trifluoroethyl)amino, methyl(trifluoromethyl)amino, morpholino, -CN, -OH, trifluoromethyl, methyl, 2,2,2-trifluoroethyl, and oxo. A has been replaced with.

[0156] In some embodiments, R 2Aare methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propan-2-yl, 1,1,1-trifluoropropan-2-yl, 2-hydroxy-2-methylpropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3-difluoro-2-hydroxypropyl, methyl, 2-hydroxypropyl, 2-hydroxybutyl, 4,4,4-trifluoro-2-hydroxybutyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, cyanomethyl, 2-(dimethylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 2-hydroxy-3-methoxypropyl, 2-chloro- 2,2-difluoroethyl, 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl, 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl, 3-(methylsulfonyl)propyl, (N,N-dimethylsulfamoyl)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-morpholinopropyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylazetidin-3-yl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl.

[0157] In some embodiments, R 2A is methylallyl. In some embodiments, R 2A is 2,2,2-trifluoroethyl. In some embodiments, R 2A is 2,2-difluoroethyl. In some embodiments, R 2A In some embodiments, R 2Ais 3,3,3-trifluoropropyl. In some embodiments, R 2A is ethyl. In some embodiments, R 2A is 2-fluoroethyl. In some embodiments, R 2A is 3-fluoropropyl. In some embodiments, R 2A is propan-2-yl. In some embodiments, R 2A is 1,1,1-trifluoropropan-2-yl. In some embodiments, R 2A is 2-hydroxy-2-methylpropyl. In some embodiments, R 2A is 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R 2A is 3,3-difluoro-2-hydroxypropyl. In some embodiments, R 2A is methyl. In some embodiments, R 2A is 2-hydroxypropyl. In some embodiments, R 2A is 2-hydroxybutyl. In some embodiments, R 2A is 4,4,4-trifluoro-2-hydroxybutyl. In some embodiments, R 2A is 3,3,3-trifluoro-2-hydroxy-2-methylpropyl. In some embodiments, R 2A is 2,3-dihydroxypropyl. In some embodiments, R 2A is 3-hydroxypropyl. In some embodiments, R 2A is 2-hydroxyethyl. In some embodiments, R 2A is cyanomethyl. In some embodiments, R 2A is 2-(dimethylamino)-2-oxoethyl. In some embodiments, R 2A is 2-(methylamino)-2-oxoethyl. In some embodiments, R 2A is 2-hydroxy-3-methoxypropyl. In some embodiments, R 2A is 2-chloro-2,2-difluoroethyl. In some embodiments, R 2Ais 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl. In some embodiments, R 2A is 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl. In some embodiments, R 2A is 3-(methylsulfonyl)propyl. In some embodiments, R 2A is (N,N-dimethylsulfamoyl)methyl. In some embodiments, R 2A is 2-methoxypropyl. In some embodiments, R 2A is 2-ethyl-2-hydroxybutyl. In some embodiments, R 2A is 3-chloro-3,3-difluoropropyl. In some embodiments, R 2A is 2-hydroxy-3-morpholinopropyl. In some embodiments, R 2A is cyclopropyl. In some embodiments, R 2A is cyclobutyl. In some embodiments, R 2A is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R 2A is 2-fluorocyclopentyl. In some embodiments, R 2A In some embodiments, R is 3,3-difluorocyclopentyl. 2A is oxetan-3-yl. In some embodiments, R 2A is oxolan-3-yl (tetrahydrofuran-3-yl). In some embodiments, R 2A is 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl. In some embodiments, R 2A is 1-methylazetidin-3-yl. In some embodiments, R 2A In some embodiments, R 2A is 4,4,4-trifluorobutyl.

[0158] In some embodiments, R 1 Ha-(CH2) m -R 2B It is.

[0159] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein m and R 2B have the same definition as described herein, and each may be independently selected from any of the embodiments as described herein above and below.

[0160] In some embodiments, the compound of Formula (I) is a compound selected from Formula (IIIa), Formula (IIIc), Formula (IIIe), or Formula (IIIg): [ka] or a pharma- ceutically acceptable salt thereof, wherein m and R 2B have the same definition as described herein, and each may be independently selected from any of the embodiments as described herein above and below.

[0161] In some embodiments, the compound of formula (I) is a compound of formula (IIIa). In some embodiments, the compound of formula (I) is a compound of formula (IIIc). In some embodiments, the compound of formula (I) is a compound of formula (IIIe). In some embodiments, the compound of formula (I) is a compound of formula (IIIg).

[0162] In some embodiments, m is 0, 1, 2, 3 or 4.

[0163] In some embodiments, m is 0, 1, 2 or 3.

[0164] In some embodiments, m is 0, 1, or 2.

[0165] In some embodiments, m is 0 or 1.

[0166] In some embodiments, m is 0.

[0167] In some embodiments, m is 1.

[0168] In some embodiments, m is 2.

[0169] In some embodiments, m is 3.

[0170] In some embodiments, m is 4.

[0171] In some embodiments, R 2B are each unsubstituted or one or more R B More than one R is aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl substituted with B It is understood that when present, they may be the same or different. In some embodiments, more than one R B When present, they are the same. In some embodiments, more than one R B If they exist, they are different.

[0172] In some embodiments, R 2B each is unsubstituted or contains one, two, three or four R B aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl substituted by

[0173] In some embodiments, R 2B are each unsubstituted or one R B In some embodiments, R is aryl, C-C cycloalkyl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl, substituted with 2B are each unsubstituted or two R BIn some embodiments, R is aryl, C-C cycloalkyl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl, substituted with 2B are each unsubstituted or three R B In some embodiments, R is aryl, C-C cycloalkyl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl, substituted with 2B Each is unsubstituted or has four R B aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl substituted by

[0174] In some embodiments, R 2B is unsubstituted or substituted with one or more R B aryl substituted with B is as described herein above and below. In some embodiments, R 2B is unsubstituted or substituted with one or more R B is phenyl substituted with

[0175] In some embodiments, each R B is independently selected from the group consisting of halogen, haloC1-C4 alkyl, haloC1-C4 alkylsulfonyl, and -CN. B is independently selected from the group consisting of fluoro, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN.

[0176] In some embodiments, R 2B is unsubstituted or is one or more R independently selected from the group consisting of fluoro, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN; B In some embodiments, R 2Bis phenyl, 4-fluorophenyl, 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-((difluoromethyl)sulfonyl)phenyl or 3-cyanophenyl.

[0177] In some embodiments, R 2B is unsubstituted or substituted with one or more R B C3-C8 cycloalkyl substituted with, where R B is as described herein above and below.

[0178] In some embodiments, R 2B are each unsubstituted or one or more R B cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or bicyclo[1.1.1]pentan-1-yl, substituted by

[0179] In some embodiments, each R B is independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, haloC1-C4 alkyl, and -OH.

[0180] In some embodiments, each R B is independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CHCN, fluoro, difluoromethyl, trifluoromethyl, and -OH.

[0181] In some embodiments, R 2B is one or more R which are each unsubstituted or independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CHCN, fluoro, difluoromethyl, trifluoromethyl, and -OH; B cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or bicyclo[1.1.1]pentan-1-yl, substituted by

[0182] In some embodiments, R 2B is 1-hydroxycyclobutyl, cyclopropyl, 1-cyanocyclopropyl, 1-fluorocyclopropyl, cyclobutyl, 1-cyanocyclobutyl, 1-(cyanomethyl)cyclopropyl, 4,4-difluoro-1-hydroxycyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 1-(difluoromethyl)cyclopropyl, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl, 3-hydroxy-3-(trifluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclopentyl, 2-ethylcyclopropyl, 1-((methylsulfonyl)oxy)cyclopropyl, 1-(methylsulfonyl)cyclopropyl or 2,2-difluorocyclopropyl.

[0183] In some embodiments, R 2B is unsubstituted or contains one or two R B and each R is a C3-C6 cycloalkyl substituted with B is independently selected from the group consisting of fluoro, CN, -CHCN, and -OH. 2B is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is unsubstituted or substituted with one or two fluoro.

[0184] In some embodiments, R 2B is unsubstituted or substituted with one or more R B is a 5-10 membered heteroaryl substituted with B is as described herein above and below.

[0185] In some embodiments, R 2B are each unsubstituted or one or more R Band 1,2,4-oxadiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-tetrazol-5-yl, furan-2-yl, imidazol-1-yl, isoxazol-3-yl, isoxazol-5-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or thiazol-4-yl, substituted with

[0186] In some embodiments, each R B is independently selected from the group consisting of C1-C4 alkyl and -CN. B is independently selected from the group consisting of methyl and -CN.

[0187] In some embodiments, R 2B each R is unsubstituted or is independently selected from methyl and -CN; B In some embodiments, R is 1,2,4-oxadiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-tetrazol-5-yl, furan-2-yl, imidazol-1-yl, isoxazol-3-yl, isoxazol-5-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or thiazol-4-yl, substituted with 2B is imidazol-1-yl, 5-methyl-1,3-oxazol-2-yl, 5-cyanofuran-2-yl, isoxazol-3-yl, oxazol-4-yl, 6-cyanopyridin-2-yl, 5-cyanopyridin-2-yl, 1,2,4-oxadiazol-5-yl, pyridin-3-yl, pyrimidin-2-yl, isoxazol-5-yl, 1H-imidazol-2-yl or 1H-tetrazol-5-yl.

[0188] In some embodiments, R 2B is unsubstituted or substituted with one or more RB 4-7 membered heterocyclyl substituted with R B is as described herein above and below.

[0189] In some embodiments, R 2B is unsubstituted or substituted with one or more R B oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidin-1-yl, piperidin-4-yl, tetrahydro-2H-pyran-4-yl, azetidin-3-yl, 1,4-dioxepan-6-yl or tetrahydro-2H-thiopyran-4-yl, substituted by

[0190] In some embodiments, each R B is independently selected from the group consisting of C1-C4 alkyl, halogen, oxo, and -CN. B is independently selected from the group consisting of methyl, fluoro, oxo, and -CN.

[0191] In some embodiments, R 2B each R is unsubstituted or is one or more independently selected from the group consisting of methyl, fluoro, oxo, and -CN; B In some embodiments, R is oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidin-1-yl, piperidin-4-yl, tetrahydro-2H-pyran-4-yl, azetidin-3-yl, 1,4-dioxepan-6-yl, or tetrahydro-2H-thiopyran-4-yl, substituted with 2B is 3-fluorooxetan-3-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 3,3-difluoropyrrolidin-1-yl, 1-cyanopiperidin-4-yl, 1-methylazetidin-3-yl, 6-fluoro-1,4-dioxepan-6-yl or 1,1-dioxidotetrahydro-2H-thiopyran-4-yl.

[0192] In some embodiments, R 2B is a 4-5 membered monocyclic heterocyclyl having one ring-forming heteroatom selected from oxygen and sulfur, wherein the 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or more R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, wherein the 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or two R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, where the 4-5 membered monocyclic heterocyclyl is unsubstituted or substituted with one or two fluoro. In some embodiments, R 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming heteroatom selected from oxygen and sulfur, wherein the C3-C4 4-5 membered monocyclic heterocyclyl is unsubstituted or is substituted with one or more R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, wherein the 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or two R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, wherein the C3-C4 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or two R B Each R Bis independently selected from the group consisting of fluoro and -OH. 2B is a 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, where the 4-5 membered monocyclic heterocyclyl is unsubstituted or substituted with one or two fluoro. In some embodiments, R 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, where the C3-C4 4-5 membered monocyclic heterocyclyl is unsubstituted or substituted with one or two fluoro. 2B is oxetan-3-yl or oxolan-3-yl, each of which is unsubstituted or substituted with one fluoro.

[0193] In some embodiments, R 2B is unsubstituted or substituted with one or more R B and each R B is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CHCN, -CHF, -CHF, -CF, -OH, -OCF, -OCH, and -OCHCH. 2B is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered monocyclic, bicyclic, or tricyclic heterocyclyl ring system having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur, where the heterocyclyl is unsubstituted or substituted with one or more R B Each R B is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CHCN, -CHF, -CHF, -CF, -OH, -OCF, -OCH, and -OCHCH. 2B is a 3-, 4-, 5-, 6-, or 7-membered monocyclic heterocyclyl ring having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur, where the heterocyclyl is unsubstituted or has one or more R B Each R Bis independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CHCN, -CHF, -CHF, -CF, -OH, -OCF, -OCH, and -OCHCH. 2B is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic heterocyclyl ring system having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur, where the heterocyclyl is unsubstituted or substituted with one or more R B Each R B is independently selected from the group consisting of fluoro, chloro, -CN, -CHF2, -CF3, -OH, and -OCH3. 2B is a 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, wherein the 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or two R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a C2-C cyclic ring having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen and sulfur; 12 and wherein the heterocyclyl is unsubstituted or substituted with one or more R B Each R B is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CHCN, -CHF, -CHF, -CF, -OH, -OCF, -OCH, and -OCHCH. 2B is a C2-C6 3-, 4-, 5-, 6-, or 7-membered monocyclic heterocyclyl ring having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur, where the heterocyclyl is unsubstituted or substituted with one or more R B Each R Bis independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CHCN, -CHF, -CHF, -CF, -OH, -OCF, -OCH, and -OCHCH. 2B is a C2-C cyclic ring having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen and sulfur; 10 wherein the heterocyclyl is unsubstituted or substituted with one or more R B Each R B is independently selected from the group consisting of fluoro, chloro, -CN, -CHF2, -CF3, -OH, and -OCH3. 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming heteroatom selected from oxygen and sulfur, wherein the C3-C4 4-5 membered monocyclic heterocyclyl is unsubstituted or is substituted with one or more R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is a C3-C4 4-5 membered monocyclic heterocyclyl having one ring-forming oxygen, wherein the C3-C4 4-5 membered monocyclic heterocyclyl is unsubstituted or has one or two R B Each R B is independently selected from the group consisting of fluoro and -OH. 2B is oxetan-3-yl or oxolan-3-yl, each of which is unsubstituted or substituted with one fluoro.

[0194] In some embodiments, R 2Bare 1,2,4-oxadiazol-5-yl, 1,3-oxazol-2-yl, 1,4-dioxepan-6-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-tetrazol-5-yl, azetidin-3-yl, bicyclo[1.1.1]pentan-1-yl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, furan-2-yl, imidazol-1-yl, isoxazol-3-yl, isoxazol-5-yl, oxazol-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydro furan-3-yl), phenyl, piperidin-4-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrrolidin-1-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, or thiazol-4-yl; each unsubstituted or substituted with one or more groups independently selected from the group consisting of -CHCN, -CN, difluoromethyl, ethyl, fluoro, methyl, methylsulfonyl, methylsulfonyloxy, -OH, oxo, phenyl, and trifluoromethyl.

[0195] In some embodiments, R 2Bare 1-((methylsulfonyl)oxy)cyclopropyl, 1-(cyanomethyl)cyclopropyl, 1-(difluoromethyl)cyclopropyl, 1-(methylsulfonyl)cyclopropyl, 1-(trifluoromethyl)cyclopentyl, 1,1-dioxidetetrahydro-2H-thiopyran-4-yl, 1,2,4-oxadiazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanopiperidin-4-yl, 1-fluorocyclobutyl, 1-fluorocyclopropyl, 1H-imidazol-2-yl, 1H-tetrazol-5-yl, 1-hydroxycyclobutyl, 1-methylazetidin-3-yl, 2-ethylcyclopropyl, 2-fluorocyclopentyl, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl, 3,3-difluorocyclopentyl, 3,3-difluoropyrrolidin-1-yl, 3-fluorobicyclo[1.1.1]pentane -1-yl, 3-fluorooxetan-3-yl, 3-fluorophenyl, 3-hydroxy-3-(trifluoromethyl)cyclobutyl, 4-((difluoromethyl)sulfonyl)phenyl, 4-(trifluoromethyl)phenyl, 4,4-difluoro-1-hydroxycyclohexyl, 4-fluorophenyl, 5-cyanofuran-2-yl, 5-cyanopyridin-2-yl, 5-methyl-1,3-oxazol-2-yl, 6-cyanopyridin-2 -yl, 6-fluoro-1,4-dioxepan-6-yl, cyclobutyl, cyclopropyl, imidazol-1-yl, isoxazol-3-yl, isoxazol-5-yl, oxazol-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), phenyl, pyridin-3-yl, pyrimidin-2-yl, 3-cyanophenyl, or 2,2-difluorocyclopropyl.

[0196] In some embodiments, R 2B is 1-((methylsulfonyl)oxy)cyclopropyl. In some embodiments, R 2B is 1-(cyanomethyl)cyclopropyl. In some embodiments, R 2Bis 1-(difluoromethyl)cyclopropyl. In some embodiments, R 2B is 1-(methylsulfonyl)cyclopropyl. In some embodiments, R 2B is 1-(trifluoromethyl)cyclopentyl. In some embodiments, R 2B is 1,1-dioxidotetrahydro-2H-thiopyran-4-yl. In some embodiments, R 2B is 1,2,4-oxadiazol-5-yl. In some embodiments, R 2B is 1-cyanocyclobutyl. In some embodiments, R 2B is 1-cyanocyclopropyl. In some embodiments, R 2B is 1-cyanopiperidin-4-yl. In some embodiments, R 2B is 1-fluorocyclobutyl. In some embodiments, R 2B In some embodiments, R 2B is 1H-imidazol-2-yl. In some embodiments, R 2B is 1H-tetrazol-5-yl. In some embodiments, R 2B is 1-hydroxycyclobutyl. In some embodiments, R 2B is 1-methylazetidin-3-yl. In some embodiments, R 2B is 2-ethylcyclopropyl. In some embodiments, R 2B is 2-fluorocyclopentyl. In some embodiments, R 2B is 2-methylthiazol-4-yl. In some embodiments, R 2B is 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl. In some embodiments, R 2B In some embodiments, R is 3,3-difluorocyclopentyl. 2B is 3,3-difluoropyrrolidin-1-yl. In some embodiments, R 2B is 3-fluorobicyclo[1.1.1]pentan-1-yl. In some embodiments, R 2Bis 3-fluorooxetan-3-yl. In some embodiments, R 2B is 3-fluorophenyl. In some embodiments, R 2B is 3-hydroxy-3-(trifluoromethyl)cyclobutyl. In some embodiments, R 2B is 4-((difluoromethyl)sulfonyl)phenyl. In some embodiments, R 2B is 4-(trifluoromethyl)phenyl. In some embodiments, R 2B In some embodiments, R is 4,4-difluoro-1-hydroxycyclohexyl. 2B is 4-fluorophenyl. In some embodiments, R 2B is 5-cyanofuran-2-yl. In some embodiments, R 2B is 5-cyanopyridin-2-yl. In some embodiments, R 2B is 5-methyl-1,3-oxazol-2-yl. In some embodiments, R 2B is 6-cyanopyridin-2-yl. In some embodiments, R 2B is 6-fluoro-1,4-dioxepan-6-yl. In some embodiments, R 2B is cyclobutyl. In some embodiments, R 2B is cyclopropyl. In some embodiments, R 2B is imidazol-1-yl. In some embodiments, R 2B is isoxazol-3-yl. In some embodiments, R 2B is isoxazol-4-yl. In some embodiments, R 2B is isoxazol-5-yl. In some embodiments, R 2B is oxazol-4-yl. In some embodiments, R 2B is oxetan-2-yl. In some embodiments, R 2B is oxetan-3-yl. In some embodiments, R 2B is oxolan-3-yl (tetrahydrofuran-3-yl). In some embodiments, R 2Bis phenyl. In some embodiments, R 2B is pyridin-3-yl. In some embodiments, R 2B is pyrimidin-2-yl. In some embodiments, R 2B is 3-cyanophenyl. In some embodiments, R 2B is 2,2-difluorocyclopropyl.

[0197] In some embodiments, R 1 Ha-(CH2) n -OR 2C It is.

[0198] In some embodiments, the compound is a compound of formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein n and R 2C have the same definition as described herein, and each may be independently selected from any of the embodiments as described herein above and below.

[0199] In some embodiments, the compound is a compound selected from Formula (Va), Formula (Vc), Formula (Ve), or Formula (Vg): [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein n and R 2C have the same definition as described herein, and each may be independently selected from any of the embodiments as described herein above and below.

[0200] In some embodiments, the compound of formula (I) is a compound of formula (Va). In some embodiments, the compound of formula (I) is a compound of formula (Vc). In some embodiments, the compound of formula (I) is a compound of formula (Ve). In some embodiments, the compound of formula (I) is a compound of formula (Vg).

[0201] In some embodiments, n is 1, 2, or 3.

[0202] In some embodiments, n is 1 or 2.

[0203] In some embodiments, n is 1.

[0204] In some embodiments, n is 2.

[0205] In some embodiments, n is 3.

[0206] In some embodiments, R 2C are each unsubstituted or one or more R C is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl or 4-7 membered heterocyclyl substituted with more than one R C It is understood that when present, they may be the same or different. In some embodiments, more than one R C When present, they are the same. In some embodiments, more than one R C If they exist, they are different.

[0207] In some embodiments, R 2C each is unsubstituted or contains one, two, three or four R C In some embodiments, R is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl, or 4-7 membered heterocyclyl substituted with 2C are each unsubstituted or one R CIn some embodiments, R is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl, or 4-7 membered heterocyclyl substituted with 2C are each unsubstituted or two R C In some embodiments, R is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl, or 4-7 membered heterocyclyl substituted with 2C are each unsubstituted or three R C In some embodiments, R is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl, or 4-7 membered heterocyclyl substituted with 2C Each is unsubstituted or has four R C and is C1-C4 alkyl, C3-C8 cycloalkyl, haloC1-C4 alkyl or 4-7 membered heterocyclyl substituted by.

[0208] In some embodiments, R 2C is unsubstituted or substituted with one or more R C C1-C4 alkyl substituted with, where R C is as described herein above and below. In some embodiments, R 2C are each unsubstituted or one or more R C ethyl, isopropyl or methyl, substituted with

[0209] In some embodiments, each R C is independently -CN or C-C cycloalkyl. C is independently selected from the group consisting of cyclopropyl and -CN.

[0210] In some embodiments, R 2C each R is unsubstituted or represents one or more independently selected from the group consisting of cyclopropyl and -CN; C In some embodiments, R is ethyl, isopropyl, or methyl, substituted with2C is methyl, cyano(cyclopropyl)methyl, 2-cyanopropan-2-yl, cyanomethyl or 1-cyanoethyl.

[0211] In some embodiments, R 2C is unsubstituted or substituted with one or more R C C3-C8 cycloalkyl substituted with, where R C is as described herein above and below.

[0212] In some embodiments, R 2C is unsubstituted or substituted with one or more R C and cyclobutyl substituted with

[0213] In some embodiments, each R C is -CN.

[0214] In some embodiments, R 2C is cyclobutyl that is unsubstituted or substituted with one or more -CN. In some embodiments, R 2C is 1-cyanocyclobutyl.

[0215] In some embodiments, R 2C is unsubstituted or substituted with one or more R C 4-7 membered heterocyclyl substituted with R C is as described herein above and below.

[0216] In some embodiments, R 2C are each unsubstituted or one or more R C In some embodiments, R is oxetan-3-yl or tetrahydro-2H-pyran-4-yl, substituted with C is -CN.

[0217] In some embodiments, R 2Cis oxetan-3-yl or tetrahydro-2H-pyran-4-yl, each of which is unsubstituted or substituted with one or more -CN. In some embodiments, R 2C is oxetan-3-yl or 4-cyanotetrahydro-2H-pyran-4-yl.

[0218] In some embodiments, R 2C , 1, 2, 3 or 4 R C is a C1-C4 alkyl or a C3-C5 cycloalkyl substituted with C is independently -CN or C-C cycloalkyl. 2C Each is one or more R C is a C1-C4 alkyl or a C3-C5 cycloalkyl substituted with C is independently -CN or C-C cycloalkyl. 2C is cyclobutyl substituted with one -CN. In some embodiments, R 2C is a C1-C3 alkyl substituted with one -CN and one C3-C5 cycloalkyl. 2C is a C1-C2 alkyl substituted with one -CN and one C3-C4 cycloalkyl. 2C is a C1-C2 alkyl substituted with one -CN and one cyclopropyl. 2C is a C1-C3 alkyl substituted with one -CN.

[0219] In some embodiments, R 2C is ethyl, isopropyl, methyl, cyclobutyl, oxetan-3-yl, or tetrahydro-2H-pyran-4-yl, each of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of cyclopropyl and -CN.

[0220] In some embodiments, R2C is methyl, cyano(cyclopropyl)methyl, 2-cyanopropan-2-yl, cyanomethyl, 1-cyanoethyl, 1-cyanocyclobutyl, oxetan-3-yl or 4-cyanotetrahydro-2H-pyran-4-yl.

[0221] In some embodiments, R 2C is methyl. In some embodiments, R 2C is cyano(cyclopropyl)methyl. In some embodiments, R 2C is 2-cyanopropan-2-yl. In some embodiments, R 2C is cyanomethyl. In some embodiments, R 2C is 1-cyanoethyl. In some embodiments, R 2C is 1-cyanocyclobutyl. In some embodiments, R 2C is oxetan-3-yl. In some embodiments, R 2C is 4-cyanotetrahydro-2H-pyran-4-yl.

[0222] R 1 base In some embodiments, R 1are methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propan-2-yl, 1,1,1-trifluoropropan-2-yl, 2-hydroxy-2-methylpropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3-difluoro-2-hydroxypropyl, methyl, 2-hydroxypropyl, 2-hydroxybutyl, 4,4,4- Trifluoro-2-hydroxybutyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, cyanomethyl, 2-(dimethylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 2-hydroxy-3-methoxypropyl, 2-chloro-2,2-difluoroethyl, 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl, 2-(methyl(2,2,2-trifluoro ethyl)amino)-2-oxoethyl, 3-(methylsulfonyl)propyl, (N,N-dimethylsulfamoyl)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-morpholinopropyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylazetidin-3-yl, (1-((methylsulfonyl)oxy)cyclopropyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (1-(methylsulfonyl)cyclopropyl)methyl, (1-(trifluoromethyl)cyclopentyl)methyl, (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methyl, (1,2,4-Oxadiazol-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (1-cyanopiperidin-4-yl)methyl, (1-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazol-2-yl)methyl, (1H-tetrazol-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylazetidin-3-yl)methyl, (2-ethylcyclopropyl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl) Methyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (3-fluorooxetan-3-yl)methyl, (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl, (4,4-difluoro-1-hydroxycyclohexyl)methyl, (5-cyanofuran-2-yl)methyl, (5-cyanopyridin-2-yl)methyl, (5-methyl-1,3-oxazol-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazole-3 -yl)methyl, (isoxazol-5-yl)methyl, (oxazol-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridin-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-(1H-imidazol-1-yl)ethyl, 2-(3,3-difluoropyrrolidin-1-yl)ethyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl cyclopropylmethyl, pyrimidin-2-ylmethyl, (2-cyanopropan-2-yl)oxy)ethyl, 2-((4-cyanotetrahydro-2H-pyran-4-yl)oxy)ethyl, 2-(1-cyanocyclobutoxy)ethyl, 2-(1-cyanoethoxy)ethyl, 2-(cyano(cyclopropyl)methoxy)ethyl, 2-(cyanomethoxy)ethyl, 2-(oxetan-3-yloxy)ethyl, 2-methoxyethyl, 5,5,5-trifluoropentyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, 4,4,4-trifluorobutyl, or (2,2-difluorocyclopropyl)methyl.

[0223] In some embodiments, R 1 are methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propan-2-yl, 1,1,1-trifluoropropan-2-yl, 2-hydroxy-2-methylpropyl, 3,3,3-trifluoro-2-hydroxypropyl, 3,3-difluoro-2-hydroxypropyl, methyl, 2-hydroxypropyl, 2-hydroxybutyl, 4,4,4-trifluoro-2-hydroxybutyl, 3,3,3-trifluoro-2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, cyanomethyl, 2-(dimethylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 2-hydroxy-3-methoxypropyl, 2-chloro- 2,2-difluoroethyl, 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl, 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl, 3-(methylsulfonyl)propyl, (N,N-dimethylsulfamoyl)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-morpholinopropyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylazetidin-3-yl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl.

[0224] In some embodiments, R 1are (1-((methylsulfonyl)oxy)cyclopropyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (1-(methylsulfonyl)cyclopropyl)methyl, (1-(trifluoromethyl)cyclopentyl)methyl, (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl, (1,2,4-oxadiazol-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, propyl)methyl, (1-cyanopiperidin-4-yl)methyl, (1-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazol-2-yl)methyl, (1H-tetrazol-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylazetidin-3-yl)methyl, (2-ethylcyclopropyl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl, (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (3-fluorooxetan-3-yl)methyl, (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl, (4,4-difluoro-1-hydroxycyclohexyl)methyl, (5-cyanofuran-2-yl)methyl, (5-cyanopyridin-2-yl)methyl, (5-methyl-1,3-oxazol-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazol-3-yl)methyl, (isoxazol-5-yl)methyl, (oxazol-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridin-3-yl)methyl, 2-(1 -cyanocyclopropyl)ethyl, 2-(1H-imidazol-1-yl)ethyl, 2-(3,3-difluoropyrrolidin-1-yl)ethyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrimidin-2-ylmethyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, or (2,2-difluorocyclopropyl)methyl.

[0225] In some embodiments, R 1 is (2-cyanopropan-2-yl)oxy)ethyl, 2-((4-cyanotetrahydro-2H-pyran-4-yl)oxy)ethyl, 2-(1-cyanocyclobutoxy)ethyl, 2-(1-cyanoethoxy)ethyl, 2-(cyano(cyclopropyl)methoxy)ethyl, 2-(cyanomethoxy)ethyl, 2-(oxetan-3-yloxy)ethyl or 2-methoxyethyl.

[0226] In some embodiments, R 1 is methylallyl. In some embodiments, R 1is 2,2,2-trifluoroethyl. In some embodiments, R 1 is 2,2-difluoroethyl. In some embodiments, R 1 In some embodiments, R 1 is 3,3,3-trifluoropropyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is 2-fluoroethyl. In some embodiments, R 1 is 3-fluoropropyl. In some embodiments, R 1 is propan-2-yl. In some embodiments, R 1 is 1,1,1-trifluoropropan-2-yl. In some embodiments, R 1 is 2-hydroxy-2-methylpropyl. In some embodiments, R 1 is 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R 1 is 3,3-difluoro-2-hydroxypropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is 2-hydroxypropyl. In some embodiments, R 1 is 2-hydroxybutyl. In some embodiments, R 1 is 4,4,4-trifluoro-2-hydroxybutyl. In some embodiments, R 1 is 3,3,3-trifluoro-2-hydroxy-2-methylpropyl. In some embodiments, R 1 is 2,3-dihydroxypropyl. In some embodiments, R 1 is 3-hydroxypropyl. In some embodiments, R 1 is 2-hydroxyethyl. In some embodiments, R 1 is cyanomethyl. In some embodiments, R 1 is 2-(dimethylamino)-2-oxoethyl. In some embodiments, R 1is 2-(methylamino)-2-oxoethyl. In some embodiments, R 1 is 2-hydroxy-3-methoxypropyl. In some embodiments, R 1 is 2-chloro-2,2-difluoroethyl. In some embodiments, R 1 is 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl. In some embodiments, R 1 is 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl. In some embodiments, R 1 is 3-(methylsulfonyl)propyl. In some embodiments, R 1 is (N,N-dimethylsulfamoyl)methyl. In some embodiments, R 1 is 2-methoxypropyl. In some embodiments, R 1 is 2-ethyl-2-hydroxybutyl. In some embodiments, R 1 is 3-chloro-3,3-difluoropropyl. In some embodiments, R 1 is 2-hydroxy-3-morpholinopropyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R 1 is 2-fluorocyclopentyl. In some embodiments, R 1 In some embodiments, R is 3,3-difluorocyclopentyl. 1 is oxetan-3-yl. In some embodiments, R 1 is oxolan-3-yl (tetrahydrofuran-3-yl). In some embodiments, R 1 is 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl. In some embodiments, R 1 is 1-methylazetidin-3-yl. In some embodiments, R 1is (1-((methylsulfonyl)oxy)cyclopropyl)methyl. In some embodiments, R 1 is (1-(cyanomethyl)cyclopropyl)methyl. In some embodiments, R 1 is (1-(difluoromethyl)cyclopropyl)methyl. In some embodiments, R 1 is (1-(methylsulfonyl)cyclopropyl)methyl. In some embodiments, R 1 is (1-(trifluoromethyl)cyclopentyl)methyl. In some embodiments, R 1 is (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl. In some embodiments, R 1 is (1,2,4-oxadiazol-5-yl)methyl. In some embodiments, R 1 is (1-cyanocyclobutyl)methyl. In some embodiments, R 1 is (1-cyanocyclopropyl)methyl. In some embodiments, R 1 is (1-cyanopiperidin-4-yl)methyl. In some embodiments, R 1 is (1-fluorocyclobutyl)methyl. In some embodiments, R 1 is (1-fluorocyclopropyl)methyl. In some embodiments, R 1 is (1H-imidazol-2-yl)methyl. In some embodiments, R 1 is (1H-tetrazol-5-yl)methyl. In some embodiments, R 1 is (1-hydroxycyclobutyl)methyl. In some embodiments, R 1 is (1-methylazetidin-3-yl)methyl. In some embodiments, R 1 is (2-ethylcyclopropyl)methyl. In some embodiments, R 1 is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1is (3-fluorooxetan-3-yl)methyl. In some embodiments, R 1 is (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl. In some embodiments, R 1 is (4,4-difluoro-1-hydroxycyclohexyl)methyl. In some embodiments, R 1 is (5-cyanofuran-2-yl)methyl. In some embodiments, R 1 is (5-cyanopyridin-2-yl)methyl. In some embodiments, R 1 is (5-methyl-1,3-oxazol-2-yl)methyl. In some embodiments, R 1 is (6-cyanopyridin-2-yl)methyl. In some embodiments, R 1 is (6-fluoro-1,4-dioxepan-6-yl)methyl. In some embodiments, R 1 is (isoxazol-3-yl)methyl. In some embodiments, R 1 is (isoxazol-5-yl)methyl. In some embodiments, R 1 is (oxazol-4-yl)methyl. In some embodiments, R 1 is (oxetan-2-yl)methyl. In some embodiments, R 1 is (oxetan-3-yl)methyl. In some embodiments, R 1 is (pyridin-3-yl)methyl. In some embodiments, R 1 is 2-(1-cyanocyclopropyl)ethyl. In some embodiments, R 1 is 2-(1H-imidazol-1-yl)ethyl. In some embodiments, R 1 is 2-(3,3-difluoropyrrolidin-1-yl)ethyl. In some embodiments, R 1 is 3-fluorobenzyl. In some embodiments, R 1 is 4-((difluoromethyl)sulfonyl)benzyl. In some embodiments, R 1 is 4-(trifluoromethyl)benzyl. In some embodiments, R 1is 4-(trifluoromethyl)phenethyl. In some embodiments, R 1 is 4-fluorobenzyl. In some embodiments, R 1 is benzyl. In some embodiments, R 1 is cyclopropylmethyl. In some embodiments, R 1 is pyrimidin-2-ylmethyl. In some embodiments, R 1 In some embodiments, R is (2-cyanopropan-2-yl)oxy)ethyl. 1 is 2-((4-cyanotetrahydro-2H-pyran-4-yl)oxy)ethyl. In some embodiments, R 1 is 2-(1-cyanocyclobutoxy)ethyl. In some embodiments, R 1 is 2-(1-cyanoethoxy)ethyl. In some embodiments, R 1 is 2-(cyano(cyclopropyl)methoxy)ethyl. In some embodiments, R 1 is 2-(cyanomethoxy)ethyl. In some embodiments, R 1 is 2-(oxetan-3-yloxy)ethyl. In some embodiments, R 1 is 2-methoxyethyl. In some embodiments, R 1 In some embodiments, R 1 is 3-cyanobenzyl. In some embodiments, R 1 is 4-fluorophenethyl. In some embodiments, R 1 is cyclobutylmethyl. In some embodiments, R 1 is 4,4,4-trifluorobutyl. In some embodiments, R 1 is (2,2-difluorocyclopropyl)methyl. 1 It is understood that when a group has a chiral carbon, that chiral carbon can be either (R) or (S). In some embodiments, R 1 When a group has a chiral carbon, the chiral carbon is (R). In some embodiments, R 1When the group has a chiral carbon, the chiral carbon is (S). 1 It is understood that when a group has two chiral carbons, these chiral carbons may, independently, be (R) or (S). In some embodiments, R 1 When a group has two chiral carbons, both chiral carbons are (R). In some embodiments, R 1 When a group has two chiral carbons, both chiral carbons are (S). 1 When a group has two chiral carbons, one chiral carbon is (R) and the other is (S).

[0227] In some embodiments, R 1 is -CH3. In some embodiments, R 1 In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 In some embodiments, R 1 is -CH2CH2OCH3, -CH2CH(OH)CH3, -CH2CH(OH)CF3, -CH2CF3, -CH2CF2H, -CH2CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, or -CH(CH3)(CF3). 1 is -CH2CF3, -CH2CF2H, -CH2CH2CF3 or -CH2CH2CHF2.

[0228] In some embodiments, R 1 -CH2CH3, -CH(CH3)2, -CH2CN, -CH2CF3, -CH(CH3)(CF3), -CH2CF2H, -CH2CF2H, -CH2CF2CH3, -CH2CH2CF3, -CH2CH2CH2H, -CH2CH2OCH3, [ka] [ka] It is.

[0229] In some embodiments, R 1 -CH2CH3, -CH(CH3)2, -CH2CF3, -CH(CH3)(CF3), -CH2CF2H, -CH2CF2H, -CH2CF2CH3, -CH2CH2CF3, -CH2CH2CH2H, -CH2CH2OCH3, [ka] It is.

[0230] In some embodiments, R 1 -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, [ka] It is.

[0231] Some embodiments include all combinations of one or more compounds selected from the following group shown in Table A, and pharma- ceutically acceptable salts thereof. Some embodiments include all combinations of one or more compounds selected from the following group shown in Table A. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

[0232] Any and all compounds, methods, compositions or uses of formula (I) described herein also include the optional limitation that the compound of formula (I) is not one or more compounds selected from the group consisting of Compound 4-33, Compound 4-34, Compound 4-35, Compound 4-37, Compound 4-95, Compound 4-96, Compound 4-97, Compound 4-100, Compound 4-101, Compound 4-102, Compound 4-103, Compound 4-104, Compound 4-105, Compound 4-106, Compound 4-107, Compound 4-108, Compound 4-109, Compound 4-110, Compound 4-111, Compound 4-112, Compound 4-113 and Compound 5-4.

[0233] Some embodiments provide a compound of Table 10A and / or Table 10B, or a pharma- ceutically acceptable salt thereof. Some embodiments provide a compound of the structure: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0234] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0235] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0236] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0237] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0238] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0239] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0240] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0241] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0242] Some embodiments have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0243] Intermediates useful in preparing compounds of formula (I) Certain intermediates as described herein above and below are novel and useful in the preparation of compounds of formula (I).

[0244] In some embodiments, the compound is 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (Compound 1-B), 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1-C). , 10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 1-D), and 9-hydroxy-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (Compound 2-B), or a salt thereof.

[0245] In some embodiments, the compound is 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 1-B), or a salt thereof. In some embodiments, the compound is selected from the group consisting of (3R,11bR)-9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 1-B(3R,11bR)) and (3S,11bS)-9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 1-B(3S,11bS)), or a salt thereof. In some embodiments, the compound is (3R,11bR)-9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 1-B(3R,11bR)), or a salt thereof. In some embodiments, the compound is [ka] It is.

[0246] In some embodiments, the compound is 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1-C), or a salt thereof. In some embodiments, the salt is DPTTA. In some embodiments, the compound is (2R,3R,11bR)-9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1-C(2R,3R,11bR)), or a salt thereof. In some embodiments, the salt is DPTTA. In some embodiments, the compound is [ka] It is.

[0247] In some embodiments, the compound is 10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D), or a salt thereof. In some embodiments, the compound is (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)), (2S,3S,11bS)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)), ( or a salt thereof. In some embodiments, the compound is (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)), or a salt thereof. [ka] It is.

[0248] In some embodiments, the compound is 9-hydroxy-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (compound 2-B), or a salt thereof. In some embodiments, the compound is selected from the group consisting of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)) and (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)), or a salt thereof. In some embodiments, the compound is (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)), or a salt thereof. [ka] It is.

[0249] It will be further appreciated that certain features that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0250] Pharmaceutical Compositions, Formulations and Dosage Forms The disclosure further provides pharmaceutical products, such as pharmaceutical compositions, formulations, unit dosage forms and kits, each of which comprises a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0251] The present disclosure further provides a pharmaceutical composition comprising any one of the compounds described herein (e.g., compounds of formula (I), including the specific compounds described herein) that are VMAT2 inhibitors, and at least one pharma- ceutically acceptable excipient, for use in the methods described herein, such as for treating hyperkinetic movement disorder. A pharma- ceutically acceptable excipient is a physiologically and pharma- ceutically suitable non-toxic and inert material or ingredient that does not interfere with the activity of the drug substance, and an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and not limiting in any way. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005).

[0252] Composition can be formulated as pills, capsules, granules or tablets, which contain diluent, dispersing and surfactant, binder and lubricant in addition to VMAT2 inhibitor.Those skilled in the art can further formulate VMAT2 inhibitor in a suitable manner according to accepted practice, such as the one disclosed in Remington above.

[0253] The administration method includes systemic administration of the VMAT2 inhibitor described herein, preferably in the form of pharmaceutical composition as discussed above.As used herein, systemic administration includes oral and parenteral administration methods.For oral administration, suitable pharmaceutical compositions include powder, granule, pill, tablet and capsule, as well as liquid, syrup, suspension and emulsion.

[0254] Pharmaceutical preparations for oral administration may be obtained by any suitable method, typically by uniformly mixing the compound(s) with a liquid or finely divided solid carrier, or both, in the required proportions, then processing the mixture, if necessary after adding suitable auxiliaries, and, if desired, forming the resulting mixture into the desired shape to obtain tablets or dragee cores.

[0255] Conventional additives such as binder, filler, adjuvant, carrier, acceptable wetting agent, tableting lubricant and disintegrant can be used in tablets and capsules for oral administration.Liquid preparations for oral administration can be in the form of solution, emulsion, aqueous or oily suspension and syrup.Alternatively, oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use.Non-oral dosage forms can be prepared by dissolving compound in a suitable liquid vehicle and filter-sterilizing the solution before lyophilization, or simply filling and sealing suitable vials or ampoules.

[0256] Some embodiments provide a method for preparing a pharmaceutical composition comprising admixing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0257] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the pharmaceutical agent, such carriers as are known in the art to be appropriate.

[0258] When preparing a pharmaceutical composition, the drug substance is typically mixed (i.e. blended) with an excipient, diluted by an excipient, or enclosed in a carrier, such as, for example, in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the drug substance. Thus, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsule, suppository, sterile injectable solution, and sterile packaged powder.

[0259] For preparing solid form pharmaceutical compositions such as powders, tablets, capsules, cachets, suppositories and dispersible granules, additives can be one or more substances that can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.Also included are solid form preparations that are intended to be converted immediately before use into liquid form preparations for oral administration.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. in addition to the active ingredient.

[0260] For preparing suppositories, a low melting wax, such as a blend of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0261] Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents.

[0262] The pharmaceutical compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the pharmaceutical compositions can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

[0263] The pharmaceutical composition may be formulated as an aqueous solution, an aqueous alcoholic solution, a solid suspension, an emulsion, a liposomal suspension, or a freeze-dried powder for reconstitution. Such pharmaceutical compositions may be administered directly or as an admixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and drip.

[0264] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

[0265] Aqueous suspensions suitable for oral use may be made by dispersing finely divided drug substance in water containing a viscous material.

[0266] For topical administration to the epidermis, the compounds described herein, or pharma- ceutically acceptable salts thereof, can be formulated as gels, ointments, creams or lotions, or as transdermal patches.Formulations suitable for topical administration in the mouth also include lozenges containing the active pharmaceutical ingredient in a flavored base.

[0267] The solution or suspension is directly applied to the nasal cavity by conventional means, for example, by using a dropper, pipette or spray.The formulation can be provided in single or multiple dose form.In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of a spray, this can be achieved, for example, by utilizing a metered atomizing spray pump.

[0268] Administration to the respiratory tract can also be achieved by utilizing an aerosol formulation provided in a pressurized pack with the addition of a suitable propellant.When the compounds described herein or pharma-ceutically acceptable salts thereof or pharmaceutical compositions containing them are administered as an aerosol, for example as a nasal aerosol or by inhalation, this can be done, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation device, a metered dose inhaler or a dry powder inhaler.

[0269] Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base, such as lactose, starch, starch derivatives, etc. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges of, for example, gelatin, or blister packs from which the powder may be administered with the aid of an inhaler.

[0270] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, may also be administered via a fast dissolving or slow release composition, wherein the composition comprises a biodegradable fast dissolving or slow release carrier.

[0271] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or any of these in the appropriate number of packaged forms. In some embodiments, the pharmaceutical preparation is a tablet or capsule for oral administration. In some embodiments, the pharmaceutical preparation is a liquid formulated for intravenous administration.

[0272] The compositions may be formulated in unit dosage forms, each dosage containing the drug substance or an equivalent mass of the drug substance. The term "unit dosage form" refers to physically discrete units of a formulation suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, together with suitable excipients as described herein.

[0273] Liquid forms containing the drug substance that may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils.

[0274] The pharmaceutical compositions described herein may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or may be lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier prior to administration.

[0275] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable additives as described herein. In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered orally or intranasally from a device that delivers the formulation in an appropriate manner.

[0276] The composition may be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the drug substance, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of the drug for human or veterinary administration. Such notice may, for example, be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compound described herein, formulated in a compatible pharmaceutical carrier, and may be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition.

[0277] To prepare solid compositions such as tablets, the drug substance can be mixed with excipients to form a solid preformulated composition containing a homogenous mixture of the ingredients. When these preformulated compositions are referred to as homogenous, the drug substance is typically evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets and capsules.

[0278] Kits are provided with unit doses of one or more of the compounds described herein or their pharma-ceutically acceptable salts, usually in oral or injectable doses.Such kits can include a container that contains unit doses, an information package insert that describes the use of the drug in treating the pathology of interest and the associated benefits, and optionally the instrument or device for delivering the composition.

[0279] The compounds described herein, or their pharma-ceutically acceptable salts, can be effective over a wide dosage range and are generally administered in a therapeutically effective amount.However, it is understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0280] The amount of compound or composition administered to a subject will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the subject, the mode of administration, etc. In therapeutic applications, the compositions may be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the condition being treated and on the judgment of the attending clinician depending on factors such as the severity of the disease, the age, weight, and general condition of the subject.

[0281] The desired dose can be conveniently presented in a single dose or in divided doses, which are administered at appropriate intervals, for example, 2, 3, 4 or more subdoses per day.The subdoses themselves can be further divided, for example, into a number of discrete loosely spaced administrations.The daily dose can be divided into several, for example, 2, 3 or 4 administrations, especially when relatively large amounts are administered as deemed appropriate.In appropriate cases, depending on the behavior of the individual, it may be necessary to deviate upwards or downwards from the daily dose indicated.

[0282] It will be apparent to one of ordinary skill in the art that the dosage forms described herein can contain a compound described herein or a pharma- ceutically acceptable salt thereof.

[0283] preparation As used herein, a "preparation" is the product of a process used to make or isolate a compound as disclosed and described herein, where the preparation contains at least one other component in addition to the compound. In some embodiments, the preparation includes a chemical entity.

[0284] As used herein, a "chemical entity" defined in the context of a "preparation" refers to a compound as disclosed and described herein, and in addition to this compound, at least one other component. For example, the chemical entity can be a co-crystal or a salt of a compound as disclosed and described herein.

[0285] Some embodiments provide a preparation comprising a compound as disclosed and described herein. In some embodiments, the compound is a component of a chemical entity. In some embodiments, the chemical entity is a salt of a compound as disclosed and described herein. In some embodiments, the chemical entity is a (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt of a compound as disclosed and described herein.

[0286] In some embodiments, the compounds of the preparation are in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or 99.9% enantiomeric excess, or within a range defined by any of the preceding figures. In some embodiments, the compounds of the preparation are in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% enantiomeric excess, or within a range defined by any of the preceding figures.

[0287] In some embodiments, the compounds of the preparation are in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 99.9% diastereomeric excess, or within a range defined by any of the preceding figures. In some embodiments, the compounds of the preparation are in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% diastereomeric excess, or within a range defined by any of the preceding figures.

[0288] In some embodiments, the preparation comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 93% by weight of the compound, or a weight percentage within a range defined by any of the preceding figures. In some embodiments, the preparation comprises at least 50%, 60%, 70%, 80%, 90% or 93% by weight of the compound, or a weight percentage within a range defined by any of the preceding figures. In some embodiments, the preparation comprises at most 50%, 60%, 70%, 80%, 90%, 93% or 95% by weight of the compound, or a weight percentage within a range defined by any of the preceding figures.

[0289] In some embodiments, the preparation comprises at least 50% by weight of the compound. In some embodiments, the preparation is a solid, i.e., in the form of a solid preparation. In some embodiments, the preparation is used to prepare a pharmaceutical composition.

[0290] How to use The compound of formula (I) as disclosed and described herein is an inhibitor of VMAT2. Thus, the present disclosure includes a method of inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing the expression of VMAT2) by contacting VMAT2 with a compound as disclosed and described herein, or a pharma-ceutically acceptable salt thereof. In some embodiments, contacting can occur in vitro, such as when VMAT2 is located in a purified preparation or in a cell outside a living organism (e.g., in a tissue sample or cell preparation). In some embodiments, contacting can occur in vivo, such as when VMAT2 is located in a living organism.

[0291] The VMAT2 inhibitor described herein can reduce the level of monoamine in central nervous system.Therefore, the present disclosure includes the method of reducing the level of monoamine in central nervous system of a subject, comprising administering to the subject the compound of formula (I) or its pharmacologic acceptable salt in an amount sufficient to reduce the level of monoamine compared to the level before administration.

[0292] VMAT2 inhibitors as disclosed and described herein are believed to have utility across a wide range of therapeutic applications, and can be used to treat or prevent a variety of disorders caused by or related to the inhibition of human vesicular monoamine transporter isoform 2. These disorders include neurological and psychiatric disorders, such as hyperkinetic movement disorders, schizophrenia, and mood disorders. Compounds of formula (I), or pharmacologic acceptable salts thereof, can be used in any of the therapeutic methods disclosed and described herein. Also, (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A(3R,11bR)) or a pharma- ceutically acceptable salt thereof, or (3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A(3S,11bS)) or a pharma- ceutically acceptable salt thereof, or an isotopic variant of compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may be used in any of the methods of treatment disclosed and described herein. In some embodiments, an isotopic variant of compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may have deuterium at three or more positions with a proportional amount of isotopic distribution different from that normally found in nature. In some embodiments, compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may have at least 95%, 97%, 99%, 99.5% or 99.9% deuterium incorporation at three or more positions, or deuterium incorporation at three or more positions within a range defined by any of the preceding numbers.

[0293] Thus, in various embodiments as disclosed herein, there is provided a method for treating or preventing a neurological and / or psychiatric disease or disorder in a subject in need thereof by administering to the subject a pharma- ceutical effective amount of a VMAT2 inhibitor as described herein, or a pharma- ceutical acceptable salt thereof. The neurological and / or psychiatric disease or disorder can be, for example, hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, 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 (e.g., focal and repetitive behaviors associated with autism spectrum disorder (ASD)), Rett syndrome, or acanthocyocytosis.

[0294] In various other embodiments as disclosed herein, a method is provided for treating or preventing vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, by administering to the subject a pharmacologic effective amount of a VMAT2 inhibitor as described herein, or a pharmacologic acceptable salt thereof.VMAT2 disease or disorder can be, for example, ataxia or spinal muscular atrophy; chorea; congenital malformation, deformity or abnormality; dementia; oral cavity, salivary gland or jaw disease; dyskinesia; dystonia; endocrine, nutritional or metabolic disease; epilepsy; habit or impulsive disorder; Huntington's disease or related disorder; mood or psychotic disorder; neurotic, stress-related and somatoform disorder; degenerative disease of the basal ganglia; extrapyramidal and movement disorder; neurological or psychiatric disease or disorder; nervous system or motor dysfunction disorder; Parkinson's disease / parkinsonism disorder; childhood onset behavioral and affective disorder; pervasive developmental disorder; and substance abuse or dependency disorder.

[0295] Therefore, in various embodiments as disclosed herein, there is provided a method for treating or preventing hyperkinetic movement disorder in a subject in need thereof, by administering to the subject in need thereof a pharmacologic effective amount of the VMAT2 inhibitor described herein or its pharmacologic acceptable salt.In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia, Tourette's syndrome, Huntington's disease, chorea associated with Huntington's disease, or tic.In other embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, or tremor.

[0296] In some embodiments, provided herein is a method for treating or preventing mood disorder in a subject in need thereof, by administering to the subject in need thereof a pharmacologic effective amount of the VMAT2 inhibitor described herein or its pharmacologic acceptable salt.In some embodiments, the mood disorder is bipolar disorder, major depressive disorder, mania in mood disorder, or depression in mood disorder.

[0297] In some embodiments as disclosed herein, there is provided a method for treating or preventing schizophrenia or schizoaffective disorder in a subject in need thereof by administering to the subject in need thereof a pharma- ceutical effective amount of a VMAT2 inhibitor described herein, or a pharma- ceutical acceptable salt thereof.

[0298] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

[0299] In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia.

[0300] In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome.

[0301] In some embodiments, the hyperkinetic movement disorder is Huntington's disease.

[0302] In some embodiments, the hyperkinetic movement disorder is a tic.

[0303] In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0304] In some embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

[0305] In some embodiments, the neurological or psychiatric disease or disorder is restricted and repetitive behaviors associated with autism spectrum disorder (ASD).

[0306] In some embodiments, the neurological or psychiatric disease or disorder is obsessions and compulsions in partial and non-responders (or completely resistant) with obsessive-compulsive disorder (OCD). In some embodiments, the neurological or psychiatric disease or disorder is obsessions and compulsions in partial and non-responders (or completely resistant) with obsessive-compulsive disorder (OCD), and the compounds described herein are administered as adjunctive therapy. In some embodiments, the compounds described herein are administered as adjunctive therapy with a primary therapy that is treatment with an antidepressant.

[0307] In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder type I. In some embodiments, the compound described herein is administered as monotherapy for the treatment of bipolar disorder type I. In some embodiments, the compound described herein is administered as maintenance therapy for the treatment of bipolar disorder type I. In some embodiments, the compound described herein is administered as monotherapy maintenance therapy for the treatment of bipolar disorder type I.

[0308] In some embodiments, the VMAT2 inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered to a subject to treat or prevent a disease or disorder selected from the following: Ataxia or spinal muscular atrophy, for example, spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia; Chorea, for example, benign hereditary chorea, chorea, chorea associated with mitochondrial disease / causes, chorea associated with Wilson's disease, chorea of ​​pregnancy, acanthocytic chorea, drug-induced chorea, hemiballismus, rheumatic / Sydenham chorea, and thyrotoxic / hyperthyroid chorea; Congenital malformations, deformities or abnormalities, such as Angelman syndrome, congenital neuropathy, Aicardi syndrome, neurofibromatosis, congenital facial nerve hypoplasia, Moebius syndrome II, Cockayne syndrome, Sjögren-Larsson syndrome, Laurence-Moon-Bardet-Biedl syndrome, Fragile X syndrome, and Prader-Willi syndrome; Dementia, such as AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, Lewy body dementia, microinfarct dementia, presenile dementia, senile dementia, and vascular dementia; Diseases of the oral cavity, salivary glands and jaw bones, e.g. glossodynia / burning mouth syndrome and temporomandibular joint disorders; Dyskinesias, such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and respiratory dyskinesia; Dystonia, for example, blepharospasm, buccoglossal 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 disease, laryngeal dystonia, oromandibular dystonia, and spasmodic torticollis / cervical dystonia; Endocrine, nutritional and metabolic disorders, such as Wilson's disease, diabetes mellitus, obesity, Syndrome X, and Lesch-Nyhan syndrome; Epilepsy, for example, Baltic myoclonic epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, Lafora myoclonic epilepsy, severe myoclonic epilepsy of infancy, and convulsions; Habitual and impulsive disorders, such as binge eating disorder, kleptomania, impulse control disorders, trichotillomania, intermittent explosive disorder, pathological gambling, and pyromania; Huntington's disease or related disorders, such as Huntington's disease, Huntington-like syndromes 1-3, Huntington's chorea, and X-linked McLeod neuroacanthocytic syndrome; Mood or psychotic disorders, for example, schizophrenia, psychosis, mania, bipolar disorder, depression, and mood disorders; Other diseases or disorders, such as fumbling, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit syndrome, spasticity, up-and-down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders, and rheumatoid arthritis; Neurotic, stress-related and somatoform disorders, for example social phobia, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and psychogenic movement disorder; Other degenerative diseases of the basal ganglia, such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglia degeneration, and neuroferritinopathy; Other extrapyramidal and movement disorders, such as hemiballismus, extrapyramidal disorders, essential tremor, geniospasm, hyperalgesia, akathisia, ballismus / hemiballismus, myoclonus, and restless legs syndrome / Willis-Ekbom syndrome; other nervous system or motor functions, such as sleep-related bruxism, abnormal involuntary movement disorders, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, clonic hemifacial spasms, olfactory agenesis, congenital cranial nerve palsies, exercise 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 developmental delay, cerebral palsy, athetoid cerebral palsy, posturing, pseudoparesis, psychomotor hyperactivity, bradykinesia, synkinesis, akinesia, Riley-Day syndrome, and athetosis; Parkinson's disease / parkinsonism, for example, parkinsonism, drug-induced parkinsonism, micrographia, and parkinsonism; childhood-onset behavioral and emotional disorders, such as attention deficit hyperactivity disorder, attention deficit disorder, hyperkinesia, hyperkinesia (neonatal), oppositional defiant disorder, provisional tic disorder, persistent (chronic) motor or vocal tic disorder, stereotypy, stereotypy, and Tourette's syndrome; Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger syndrome, pervasive developmental disorder (NOS), and dyslexia; and Substance abuse or dependence, including, for example, addictive disorders, alcoholism, cocaine dependence, illegal drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine-like substance abuse, nicotine dependence, polydrug abuse, and prescription drug abuse.

[0309] In some embodiments, the patient being treated has been determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having 22q11.2 deletion syndrome. In some embodiments, the patient is determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having COMT haploinsufficiency.

[0310] In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in a mammalian body to compounds that can inhibit human vesicular monoamine transporter isoform 2. As such, these VMAT2 inhibitors can have additional utility in modifying the in vivo properties of metabolites in a mammal, such as maximum concentration or duration of action.

[0311] Characterizing any of the VMAT2 inhibitors described herein can be determined using the methods described herein and those in the art.For example, dopamine depletion can be determined using the locomotor activity (LMA) assay.Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has been shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds.

[0312] Combination therapy The compounds of the present disclosure, or their pharmaceutically acceptable salts, can be used as monotherapy or in combination with one or more other pharmaceutical agents.In some embodiments, the compounds of formula (I), or their pharmaceutically acceptable salts, are administered together (simultaneously or sequentially) with one or more pharmaceutical agents selected from antidepressants, antipsychotics (typical or atypical), antiepileptics, antimicrobials, antiarrhythmics, mood stabilizers and gastrointestinal agents.In some embodiments, the compounds of formula (I), or their pharmaceutically acceptable salts, are used in adjunctive therapy, which refers to a treatment used in conjunction with a primary treatment, and the purpose of which is to support the primary treatment.Adjunctive therapy is typically a co-administration therapy.As an example of adjunctive therapy, when obsessive-compulsive disorder is being treated, the primary therapy may be, for example, an antidepressant, and the co-administration of the compounds described herein would be considered as adjunctive therapy.

[0313] compound synthesis Detailed compound synthesis methods are described in the Examples herein. In general, 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 compounds described in the chemical literature.

[0314] Generally, the compounds used in the reactions described herein can be made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. Methods known to those skilled in the art can be identified through various reference books and databases. Suitable reference books and treatises detailing the synthesis or providing references to articles describing the preparation of reactants useful in the preparation of the compounds of the present disclosure include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992.

[0315] Specific and similar reactants may be identified through indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries, and through online databases (for further details contact the American Chemical Society, Washington, DC). Chemicals that are known but not commercially available in catalogs may be prepared according to known methods by custom chemical synthesis houses, and many of the standard chemical supply houses (e.g., those listed above) offer custom synthesis services.

[0316] The term "reducing agent" refers to a compound that provides a hydride to an electrophilic position of a reactant compound, such as an unsaturated carbon (e.g., a carbon of a carbonyl moiety), such as to convert a ketone-containing reactant compound to an alcohol-producing compound or an ester-containing reactant compound to an alcohol-producing compound. The reducing agent can be a hydride reducing agent. Examples of hydride reducing agents include diborane, borane (e.g., borane tetrahydrofuran complex), 9-borabicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminum hydride, lithium diisobutyl-tert-butoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tris[(3-ethyl-3-pentyl)oxy]alumino hydride, sodium bis(2-methoxyethoxy)aluminum dihydride, sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, water, and the like. These include, but are not limited to, tetramethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, lithium 9-borabicyclo[3.3.1]nonane hydride, sodium triacetoxyborohydride, potassium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tricyamylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidinoborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium borohydride, and the like.

[0317] The term "halogenating agent" refers to a compound that donates a halogen atom to a reactant compound, such as converting an alcohol reactant compound to an alkyl halide product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonyl chloride and NaI, p-toluenesulfonyl chloride and NaI, phosphorus tribromide, triphenylphosphine dibromide, phosphorus pentabromide, or thionyl bromide, and the like.

[0318] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0319] The base may be an inorganic base or an organic base.

[0320] The term "organic base" refers to a base that contains at least one C-H bond (e.g., an amine base). In some embodiments, the amine base can be a primary, secondary, or tertiary amine.

[0321] The term "inorganic base" refers to a base that does not contain at least one C-H bond and that contains at least one alkali metal or alkaline earth metal.

[0322] The term "acid" refers to a compound that is an electron pair acceptor in an acid-base reaction.

[0323] The acid may be an inorganic acid or an organic acid.

[0324] The term "inorganic acid" refers to an acid that does not contain a carbon bond. Inorganic acids can be strong or weak acids.

[0325] The term "organic acid" refers to an acid that contains at least one C-H, C-F, or C-C bond.

[0326] Certain abbreviations This specification contains a number of abbreviations, the definitions of which are set out in the table below. [Table 18] EXAMPLES

[0327] The following examples are included to demonstrate embodiments of the present disclosure, however, those of skill in the art will recognize in light of the present disclosure that many changes can be made in the specific embodiments that are disclosed and still obtain a similar or similar result without departing from the spirit and scope of the disclosure.

[0328] Analytical HPLC analysis was performed on an LC-MS system with a UV detector (Dionex™ UVD 170u UV / VIS detector), a Corona array detector (Thermo™ Veo™ RS) and a mass spectrometer (Dionex MSQ Plus™). Reverse-phase preparative HPLC purification was performed on a Phenomenex Liquid Chromatography-Mass Spectrometry (LCMS) system C18 Kinetics 5μ 100A 150×21.2 mm column using an ACN / water gradient containing 0.05% TFA, run at 1.1 mL / min and 50° C. Supercritical fluid chromatography purification (SFC) was performed using a Waters™ Prep 100q™ system with a UV detector (Waters™ 2998 Photodiode Array Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Waters™ Viridis™ BEH 2-ethylpyridine 130Å 5 μm, 30 mm×100 mm column was used with a gradient of 0.3% NHOH in CO2 and MeOH, run at 100 mL / min, 40° C. and 105 bar backpressure regulator. All final compounds were analyzed by analytical HPLC-MS and peaks were monitored for purity at UV 220, 212, 270 and 254 nm, by mass spectrometer and via charged aerosol detector. 1H was recorded in an appropriate NMR solvent such as dimethylsulfoxide-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 using Z gradients. 1 H chemical signals are reported in parts per million (ppm) and residual solvent signals are used as reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in Hertz (Hz). Reactions were carried out under an atmosphere of dry nitrogen unless otherwise noted.

[0329] I. A general synthetic scheme for the preparation of compounds of formula (I) is shown in FIG. 6, where X is halo (e.g., I, Cl, or Br), OS(O)OR 1 or OS(O)2R z where R z is C1-C6 alkyl, haloC1-C6 alkyl or phenyl, said phenyl being unsubstituted or substituted with one or more halo, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy or haloC1-C6 alkoxy. Alternatively, commercially available HO-R 1 is reacted with a halogenating agent to give R 1 -X, where X is I, Cl or Br, can be prepared.

[0330] According to Figure 6, compounds of general formula (I) as described herein can be synthesized in several steps from compound 1-A. In one case, the sequence for the formation of compounds of general formula (I) includes the condensation of compound 1-A with 3-[(dimethylamino)methyl]-5,5-dimethylhexan-2-one in a solvent or solvent mixture such as i-PrOH / water, optionally in the presence of an acid and additives such as NaI, to obtain compound 1-B. Examples of suitable hydrides include sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, tetramethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, lithium 9-borabicyclo[3.3.1]nonane hydride, sodium triacetoxyborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, tri-sec-butylborohydride, and the like. Reduction of compound 1-B in the presence of a reducing agent such as sodium borohydride, potassium tricyamylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidineborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium borohydride, in a solvent or mixture of solvents such as methanol, MTBE, and optionally in the presence of an additive such as acetic acid, gives compound 1-C. Preparation of compound 1-D can be accomplished by hydrogenolysis or solvolysis, for example, by treating compound 1-C with an acid in a solvent such as methanol. Finally, compound 1-D can be converted to R 1 Treatment with -X, where X is a leaving group such as I, Br, Cl, triflate, or an epoxide in the presence of a base in a solvent such as DMF, acetone, etc., can provide compounds of general formula (I).

[0331] Example 1A Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)), see FIG. 7. [ka]

[0332] Step 1: Synthesis of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 1-B).

[0333] A suspension of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (compound 1-A, 25 g, 93.5 mmol, 1.2 equiv.) in water (63 mL) was prepared and cooled to 0° C. Then, aqueous HCl (6.7 mL, 12.1 N, 1.05 equiv.) was added, followed by sodium iodide (5.83 g, 38.9 mmol, 0.5 equiv.), and the resulting mixture was allowed to warm to room temperature. Finally, a solution of 3-[(dimethylamino)methyl]-5,5-dimethylhexan-2-one (14.4 g, 77.9 mmol, 1.0 equiv.) in i-PrOH (22 mL) was added, and the reaction mixture was stirred vigorously at 45° C. for 3 days. The resulting suspension was cooled, the precipitate collected, and the filtrate extracted into DCM. The collected precipitate was dissolved in DCM and added to the combined organic layers, dried over MgSO4, filtered to remove solids, and concentrated in vacuo. DCM was used to load onto a silica gel column (220 g × 2, 120 g × 1) and run with an increasing gradient of EtOAc in hexanes (0 to 40% over 20 min) to give 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 1-B, 22.6 g, 55.5 mmol, 71%).

[0334] Step 2: Synthesis of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C).

[0335] To a solution of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 1-B, 22.6 g, 55.5 mmol, 1.0 equiv.) in MTBE:MeOH (4:1, 113 mL) and acetic acid (3.2 mL, 55.5 mmol, 1.0 equiv.), solid sodium borohydride (2.3 g, 61.0 mmol, 1.1 equiv.) was carefully added in small portions. The reaction progress was monitored hourly by LC / MS. Then, 4:1 MTBE:MeOH (56 mL), 0.5 equiv. of acetic acid, and an additional 2.0 equiv. of sodium borohydride were added to the stirred mixture. After stirring at room temperature overnight, 1N NaOH (180 mL) was added and the resulting mixture was heated to 50° C. for 3 h. The mixture was cooled to room temperature and allowed to stand for 1 h. The resulting precipitate was collected by vacuum filtration, rinsed with excess water (approximately 600 mL) until pH<10, and finally washed with MTBE. The filter cake was dried to give 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C, 18.7 g, 42.1 mmol, 76%).

[0336] Step 3: Synthesis of (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C(2R,3R,11bR) also referred to as compound 4-60 in Table A).

[0337] To a suspension of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C, 18.7 g, 42.1 mmol, 1.0 equiv.) in MeOH (150 mL) was added (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA, 17.9 g, 46.3 mmol, 1.1 equiv.) in small portions. Additional MeOH (100 mL) and heat (65° C.) were required to dissolve the solid. The resulting solution was cooled to 60° C., seeded with previously prepared compound 1-C(2R,3R,11bR)·(DPTTA) (138 mg, see, e.g., Example 1B), and stirred at 60° C. for 30 min. The mixture was then cooled to room temperature at a rate of 4° C. / h and then stirred at room temperature overnight. The resulting precipitate was collected by vacuum filtration and dried to obtain compound 1-C (2R,3R,11bR) (DPTTA) (14.7 g, 18.5 mmol, 44%) as a white solid. The optical purity of 100% ee as a single diastereomer was determined by chiral supercritical fluid chromatography (SFC) analysis. Chiral purity analysis was performed using a Waters™ Ultra-Performance Convergence Chromatography (UPC2)™ supercritical fluid chromatography (SFC) system equipped with a UV detector (Waters™ Acquity UPC2 PDA Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Chiral Technologies Inc™ ChiralPak™ IC / SFC 1.6 μm, 2.1 mm×50 mm column was used with an isocratic gradient of 0.5% DMEA in 85% CO2 and 15% MeOH at 1.5 mL / min, 55° C. and 1500 psi backpressure regulator. An extracted wavelength of 285 nm was used for %ee quantification and analysis.

[0338] The chiral salt pair was suspended in DCM and water was added. The mixture was basified with saturated aqueous NH4OH until pH was about 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-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C(2R,3R,11bR), 7.41 g, 18.1 mmol, 43%).

[0339] Step 4: Synthesis of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)).

[0340] To a solution of (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C (2R,3R,11bR), 6.9 g, 16.8 mmol, 1.0 equiv) in MeOH (68 mL) cooled to 0° C. was added 37% aqueous HCl (34 mL) dropwise over 30 min. The resulting mixture was stirred at 0° C. for 30 min, warmed to room temperature, stirred for 30 min, and finally stirred at 80° C. overnight. The mixture was transferred to a 2 L flask, diluted with water (60 mL) and DCM (100 mL), and cooled to 0° C. Saturated aqueous NaHCO3 was then added dropwise until a pH of approximately 8 was reached, with additional DCM added as needed to aid stirring. The resulting precipitate was collected by vacuum filtration, rinsed with water and MTBE, dried, and set aside. The filtrate was extracted with 5:1 DCM:i-PrOH. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. The resulting solid was combined with the filter cake to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 5.5 g, 17.2 mmol) in nearly quantitative yield.

[0341] Example 1B Preparation of (2R,3R,11bR)-9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol and the salt of (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (compound 1-C(2R,3R,11bR)(DPTTA)), see FIG. 8. [ka]

[0342] To a suspension of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 1-C, 506 mg, 1.24 mmol, 1.0 equiv.) in MeOH (7 mL) was added (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA, 494 mg, 1.24 mmol, 1.0 equiv.) in small portions. The resulting mixture was heated to reflux with stirring until a clear solution was achieved. The mixture was cooled to room temperature without stirring and allowed to stand at room temperature for 16 h. The resulting precipitate was collected by vacuum filtration, rinsed with methanol (1 mL), and dried to give compound 1-C·(2R,3R,11bR) (DPTTA) (365 mg, 37%) as a white solid. An optical purity of 90% ee was determined by chiral SFC analysis. Chiral purity analysis was performed using a Waters™ Ultra-Performance Convergence Chromatography (UPC2)™ supercritical fluid chromatography (SFC) system equipped with a UV detector (Waters™ Acquity UPC2 PDA Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Chiral Technologies Inc™ ChiralPak™ IC / SFC 1.6 μm, 2.1 mm×50 mm column was used with an isocratic gradient of 0.5% DMEA in 85% CO2 and 15% MeOH at 1.5 mL / min, 55° C. and 1500 psi backpressure regulator. An extracted wavelength of 285 nm was used for %ee quantification and analysis. A 20 mg sample of the solid was set aside for further recrystallization, and the mother liquor and remaining white solid were recombined and concentrated in vacuo. This mixture was suspended in MeOH (5 mL) and heated to reflux to achieve a clear solution. Stirring was discontinued and the mixture was cooled to 60° C. and seeded with 2 mg of the previous 90%ee compound 1-C·(2R,3R,11bR)(DPTTA) solid. The mixture was allowed to stand at 60° C. for 1 hour, then the temperature was reduced by 5° C. per hour until room temperature and then allowed to stand for 16 hours.The resulting precipitate was collected by vacuum filtration, rinsed with methanol (1 mL), and dried to give compound 1-C·(2R,3R,11bR) (DPTTA) (200 mg, 20%) with an optical purity of 100% ee as a single diastereomer as determined by chiral SFC analysis.

[0343] Example 2 Preparation of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)) and (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)), see FIG. 9.

[0344] Step 1: Synthesis of 3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B).

[0345] To a solution of 7-methoxy-3,4-dihydroisoquinolin-6-ol (compound 2-A, 7.2 g, 40.7 mmol, 1.2 equiv.) in EtOH (66 mL) was added [2-(2,2-dimethylpropyl)-3-oxobutyl]trimethylazanium iodide (11.1 g, 33.9 mmol, 1.0 equiv.) and the resulting mixture was stirred at reflux for 3 days. The mixture was cooled, diluted with aqueous NaHCO3, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dry loaded onto Celite and chromatographed on a silica gel column (220 g) with an increasing gradient of EtOAc in hexanes (0-60% over 20 min). Due to co-eluting impurities, the material was dry loaded onto Celite and rechromatographed on a silica gel column (80 g) using a shallow gradient of EtOAc in hexanes (0 to 45% over 20 min) to give 3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B, 4.2 g, 13.3 mmol, 39%) as a 7:1 mixture of racemic diastereomers.

[0346] Step 2: Isolation of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)) and (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)).

[0347] Separation of 3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B) enantiomers was achieved by preparing a solution in MeOH in a minimal volume and subjecting it to preparative chiral SFC. Chiral compound separation was performed using a Pic Solution™ SFC-PICLAB-Prep 200™ supercritical fluid chromatography (SFC) system equipped with a UV detector and an Advion™ mass spectrometer. A Chiral Technologies Inc™ ChiralPak™ IG / SFC 5 μm, 20 mm×250 mm column was used with an isocratic gradient of 0.5% DMEA in 80% CO2 and 20% MeOH at 150 mL / min, 55° C. and 100 bar backpressure regulator. After purification, 1.6 g each of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3R,11bR)) (99% ee) and (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)) (100% ee) were isolated.

[0348] Suitable crystals were generated by slow evaporation of a solution of compound 2-B (3S,11bS) in acetone. The absolute stereochemistry was confirmed by obtaining a small molecule crystal structure of compound 2-B (3S,11bS).

[0349] Single crystal X-ray structure of compound 2-B (3S,11bS).

[0350] The single crystal structure of (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)) was determined. The absolute configuration parameters (Flack parameters) are near zero when the configuration assignment is correct and near +1 when the configuration is incorrect. For this data set, the Flack parameters for the assignment shown in Figure 1A are 0.06(3). The crystallographic information is shown in Table 1. [Table 1]

[0351] Example 3 Alternative preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)) and preparation of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)), see FIG. 10. [ka]

[0352] Synthesis of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)).

[0353] To a solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B (3R,11bR), 733 mg, 2.31 mmol, 1.0 equiv.) in MeOH (5 mL) was added sodium borohydride (131 mg, 3.46 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 16 h, at which point additional sodium borohydride was added (44 mg, 1.16 mmol, 0.5 equiv.). The mixture was stirred at room temperature for an additional 3 h. The excess reagent was quenched with water, and the resulting mixture was extracted three times with 5:1 DCM:i-PrOH. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. The resulting solid was suspended in MTBE (5.9 mL) and MeOH (1.5 mL) and the resulting mixture was heated to 50° C. with stirring for 1 h. The suspension was cooled to room temperature and the solid was collected by filtration. The filter cake was rinsed with MTBE (2.2 mL) and the solid was collected to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 567 mg, 1.77 mmol, 35:1 dr, 77%).

[0354] Single crystal X-ray structure of compound 1-D (2R,3R,11bR).

[0355] Crystals of compound 1-D (2R,3R,11bR) were grown using a CrystalBreeder system. Approximately 5 mg of compound 1-D (2R,3R,11bR) in 0.25 mL of DMF (approximately 20 mg / mL) was subjected to slow thermal cycling from 5°C to 80°C several times. Multiple vials were utilized. After thermal cycling, large needle-like crystals formed on the side of the vial. The solvent was decanted and the crystals were analyzed. Suitable crystals were selected for single crystal X-ray structure determination. Although a similar preparation using ACN also provided crystals, the crystals grown from DMF provided better crystals more suitable for further analysis.

[0356] The crystal structure of compound 1-D (2R,3R,11bR) was solved. The structure was determined to be anhydrous and unsolvated, and the three chiral centers at C2, C3, and C11b were all determined to have the R configuration. See FIG. 1B for the asymmetric unit of the crystal structure. The crystal data, unit system, and space group for compound 1-D (2R,3R,11bR) are shown in Table 2. The data collection and refinement parameters for compound 1-D (2R,3R,11bR) are shown in Table 3. [Table 2] [Table 3]

[0357] Synthesis of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)).

[0358] (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)) was prepared in a manner similar to that for preparing compound 1-D(2R,3R,11bR) using (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)) as the starting material and sodium borohydride as the reducing agent.

[0359] Example 4 Preparation of (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3R,11bR)) and (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3S,11bS)), see FIG. 11. [ka]

[0360] Synthesis of (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3R,11bR)).

[0361] A solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B (3R,11bR), 48 mg, 0.15 mmol, 1.0 equiv.) in THF (0.75 mL) was cooled to 0° C. Then a solution of lithium tri-sec-butylborohydride (1 M THF, 0.30 mL, 0.30 mmol, 2.0 equiv.) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 3 h. The mixture was concentrated in vacuo, diluted with water, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (4 g) was loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0-60% over 30 min). Fractions were split between the pure product (compound 1-D (2S,3R,11bR), 16 mg) and the product with the minor diastereomer (28 mg, 10:1 diastereomeric ratio between compound 1-D (2S,3R,11bR):compound 1-D (2R,3R,11bR)). Combined, (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol was isolated in a combined yield of 91% (compound 1-D (2S,3R,11bR), 44 mg).

[0362] Synthesis of (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3S,11bS)).

[0363] (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3S,11bS)) was prepared in a manner similar to that for preparing compound 1-D(2S,3R,11bR) using (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B(3S,11bS)) as the starting material and lithium tri-sec-butylborohydride as the reducing agent.

[0364] Example 5A Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1), see FIG. 12. [ka]

[0365] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.20 g, 0.63 mmol, 1.0 equiv.) in acetone (6.3 mL), cesium carbonate (0.61 g, 1.9 mmol, 3.0 equiv.) was added and the resulting mixture was stirred at room temperature for 10 min. Then, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.19 g, 0.82 mmol, 1.3 equiv.) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with 5:1 DCM:i-PrOH. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (40 g) was loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0 to 50% over 25 min) to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1, 0.19 g, 0.47 mmol, 75%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 6.81 (s, 1H), 6.79 (s, 1H), 4.63 (q, J = 8.9 Hz, 2H), 4.56 (d, J = 6.4 Hz, 1H), 3.76 (s, 3H), 3.13 - 3.00 (m, 2H), 2.99 - 2.83 (m, 3H), 2.57 - 2.44 (m, 2H), 2.32 - 2.26 (m, 1H), 1.94 (t, J = 11.2 Hz, 1H), 1.70 (d, J = 13.6 Hz, 1H), 1.48 - 1.40 (m, 1H), 1.27 (q, J = 11.5 Hz, 1H), 0.91 (s, 9H), 0.81 (dd, J = 14.0, 7.6 Hz, 1H).

[0366] Example 5B Preparation of (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-27). [ka]

[0367] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.80 g, 2.50 mmol, 1.0 equiv.) in DMF (40 mL) was added cesium carbonate (2.44 g, 7.50 mmol, 3.0 equiv.) at 50° C. A solution of cyclopropyl trifluoromethanesulfonate (0.60 g, 3.13 mmol, 1.25 equiv.) in DMF (3 mL) was added via syringe pump over 6 h. The resulting mixture was stirred at 50° C. for an additional 10 h. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed five times with water, 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 in hexanes (0-100% over 25 min) to give impure (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-27, 0.83 g, 2.31 mmol) as an off-white solid. To remove trace impurities, crude compound 4-27 (0.83 g, 2.31 mmol, 1.0 equiv) was dissolved in anhydrous THF (14 mL) under nitrogen atmosphere with stirring at 0 °C. A 2M solution of lithium aluminum hydride in THF (2.3 mL, 4.62 mmol, 2.0 equiv) was added dropwise over 10 min. The temperature was raised to 60° C. and stirred for 16 h. The mixture was cooled to 0° C. and then sodium sulfate dodecahydrate (0.65 g, 2.02 mmol, 0.9 equiv) was added during 10 min and then allowed to stir for 20 min. The mixture was filtered through Celite and the filter cake was rinsed with acetone, MeOH and DCM. The filtrate was concentrated in vacuo and then redissolved in 1:1 DCM / EtOAc and washed three times with 1M aqueous NaOH. The organic layer was dried over MgSO4, filtered and concentrated in vacuo.The crude material was submitted to three chromatographic separations: a silica gel column (12 g) loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0-75% over 25 min), a basic alumina column (24 g) run with an increasing gradient of EtOAc in hexanes (0-75% over 25 min), and a reversed-phase C18 column (30 g) loaded with DMSO and run with an increasing gradient of MeCN in water (10-70% over 20 min) to afford (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-27, 0.40 g, 1.11 mmol, 44% over two steps) as a white solid. 1 H NMR (500 MHz, DMSO-d6): δ (ppm) 6.89 (s, 1H), 6.71 (s, 1H), 4.55 (d, J = 6.3 Hz, 1H), 3.75 (tt, J = 6.0, 3.0 Hz, 1H), 3.69 (s, 3H), 3.11 - 3.04 (m, 1H), 3.00 (br d, J = 11.2 Hz, 1H), 2.94 (dd, J = 11.8, 4.4 Hz, 1H), 2.92 - 2.86 (m, 2H), 2.55 (dd, J = 14.3, 3.8 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.33 - 2.25 (m, 1H), 1.92 (t, J = 11.5 Hz, 1H), 1.69 (d, J = 12.9 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.25 (q, J = 11.5 Hz, 1H), 0.90 (s, 9H), 0.80 (dd, J = 13.8, 7.5 Hz, 1H), 0.75 - 0.70 (m, 2H), 0.64 - 0.60 (m, 2H).

[0368] Example 5C Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetan-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-30). [ka]

[0369] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.20 g, 0.63 mmol, 1.0 equiv.) in DMF (6 mL), cesium carbonate (0.61 g, 1.88 mmol, 3.0 equiv.) was added and the resulting mixture was stirred at room temperature for 10 min. Then, 3-bromooxetane (0.12 mL, 1.56 mmol, 2.5 equiv.) was added and the mixture was stirred at 60° C. for 6 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was submitted to two chromatographic separations: a silica gel column (4 g) loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0-100% over 30 min), and a reversed-phase C18 column (16 g) loaded with DMSO and run with an increasing gradient of MeCN in water (10-100% over 25 min) to afford (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetan-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-30, 0.15 g, 0.41 mmol, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 6.77 (s, 1H), 6.31 (s, 1H), 5.15 (quin, J = 5.5 Hz, 1H), 4.88 (t, J = 6.7 Hz, 2H), 4.57 - 4.51 (m, 3H), 3.75 (s, 3H), 3.12 - 3.04 (m, 1H), 3.04 - 2.91 (m, 2H), 2.90 - 2.79 (m, 2H), 2.46 - 2.42 (m, 1H), 2.31 - 2.23 (m, 1H), 1.92 (br t, J = 11.3 Hz, 1H), 1.70 (d, J = 13.6 Hz, 1H), 1.47 - 1.38 (m, 1H), 1.25 (q, J = 1.0 Hz, 1H), 0.90 (s, 9H), 0.81 (dd, J = 13.8, 7.5 Hz, 1H).

[0370] Example 5D Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-50). [ka]

[0371] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.20 g, 0.63 mmol, 1.0 equiv.) in DMF (6 mL) was added cesium carbonate (0.61 g, 1.88 mmol, 3.0 equiv.) and the resulting mixture was stirred at room temperature for 10 min. Then, (2S)-2-(trifluoromethyl)oxirane (72 μL, 0.94 mmol, 1.5 equiv.) was added and the mixture was stirred at room temperature for 6 h. An additional portion of (2S)-2-(trifluoromethyl)oxirane (24 μL, 0.31 mmol, 0.5 equiv.) was added and the mixture was stirred for an additional hour at room temperature. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was submitted to two chromatographic separations: a silica gel column (12 g) loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0-65% over 20 min), and a reversed-phase C18 column (16 g) loaded with DMSO and run with an increasing gradient of MeCN in water (10-40% over 25 min, then 40%-90% over 15 min) to afford (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-50, 0.13 g, 0.31 mmol, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 6.76 (s, 1H), 6.72 (s, 1H), 6.60 (d, J = 6.2 Hz, 1H), 4.55 (d, J = 6.5 Hz, 1H), 4.41 - 4.30 (m, 1H), 4.12 (dd, J = 10.5, 4.0 Hz, 1H), 3.98 (dd, J = 10.3, 6.7 Hz, 1H), 3.74 (s, 3H), 3.12 - 2.83 (m, 5H), 2.59 - 2.54 (m, 1H), 2.46 - 2.43 (m, 1H), 2.32 - 2.23 (m, 1H), 1.93 (br t, J = 11.2 Hz, 1H), 1.70 (bd, J = 14.1 Hz, 1H), 1.48 - 1.38 (m, 1H), 1.26 (q, J = 11.5 Hz, 1H), 0.91 (s, 9H), 0.81 (br dd, J = 13.8, 7.5 Hz, 1H).

[0372] Example 5E Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxolan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-53). [ka]

[0373] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.30 g, 0.94 mmol, 1.0 equiv.) in DMF (3 mL) was added cesium carbonate (0.92 g, 2.82 mmol, 3.0 equiv.) and the resulting mixture was stirred at room temperature for 10 min. Then, (3S)-3-iodooxolane (0.15 mL, 1.41 mmol, 1.5 equiv.) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was subjected to four chromatographic separations: a dry-loaded (Celite) basic alumina column (24 g) run with an increasing gradient of MeOH in DCM (0-5% over 10 min, then 100% over 10 min); a dry-loaded (Celite) silica column (4 g) run with an increasing gradient of EtOAc in hexanes (0-100% over 20 min); a reversed-phase C18 column (30 g) loaded with DMSO and run with an increasing gradient of MeCN in water (10-50% over 20 min); and submitted to a dry-loaded (Celite) silica column (4 g) run with an increasing gradient of EtOAc in hexanes (0 to 100% over 20 min) to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxolan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-53, 0.14 g, 0.35 mmol, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 6.74 (s, 1H), 6.62 (s, 1H), 4.95 - 4.89 (m, 1H), 4.55 (d, J = 6.5 Hz, 1H), 3.86 - 3.73 (m, 4H), 3.72 (s, 3H), 3.13 - 3.04 (m, 1H), 3.01 (br d, J = 11.5 Hz, 1H), 2.95 (dd, J = 11.7, 4.2 Hz, 1H), 2.92 - 2.82 (m, 2H), 2.58 - 2.53 (m, 1H), 2.49 - 2.44 (m, 1H), 2.32 - 2.24 (m, 1H), 2.19 - 2.08 (m, 1H), 1.99 - 1.88 (m, 2H), 1.70 (d, J = 13.1 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.26 (q, J = 11.4 Hz, 1H), 0.91 (s, 9H), 0.81 (dd, J = 13.9, 7.4 Hz, 1H).

[0374] Example 5F Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55), see FIG. 12. [ka]

[0375] To a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 1.00 g, 3.13 mmol, 1.0 equiv.) in DMF (28 mL) was added cesium carbonate (3.06 g, 9.39 mmol, 3.0 equiv.) and the resulting mixture was stirred at room temperature for 10 min. Then (R)-2-methyloxirane (0.31 mL, 6.26 mmol, 2 equiv.) was added and the mixture was stirred at 80° C. for 16 h. An additional portion of (R)-2-methyloxirane (0.16 mL, 3.13 mmol, 1 equiv.) was added and the mixture was stirred at 80° C. for an additional 4 h. A third additional portion of (R)-2-methyloxirane (39 μL, 0.78 mmol, 0.25 equiv) was added and the mixture was stirred at 80 °C for an additional 3 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with 5:1 DCM:i-PrOH. The combined organic extracts were washed five times with water, 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 in hexanes (0-100% over 20 min) to give impure (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55, 0.95 g) as an off-white solid. The crude white solid was recrystallized from 1:1 hexanes / EtOAc to give crude 4-55 (0.70 g) as an off-white solid. A reverse-phase C18 column (100 g) was loaded with DMSO and run with an increasing gradient of MeCN in water (10-70% over 25 min) to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55, 0.59 g, 1.55 mmol, 50%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ (ppm) 6.71 (s, 1H), 6.63 (s, 1H), 4.77 (d, J = 4.4 Hz, 1H), 4.54 (d, J = 6.6 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.77 (dd, J = 9.3, 6.3 Hz, 1H), 3.72 (s, 3H), 3.68 (dd, J = 9.5, 5.5 Hz, 1H), 3.11 - 3.05 (m, 1H), 2.99 (br d, J = 11.0 Hz, 1H), 2.94 (dd, J = 11.8, 4.1 Hz, 1H), 2.90 - 2.83 (m, 2H), 2.55 - 2.51 (m, 1H), 2.47 - 2.42 (m, 1H), 2.30 - 2.24 (m, 1H), 1.91 (t, J = 11.2 Hz, 1H), 1.69 (d, J = 12.6 Hz, 1H), 1.47 - 1.40 (m, 1H), 1.25 (q, J = 11.5 Hz, 1H), 1.13 (d, J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.80 (dd, J = 13.7, 7.7 Hz, 1H).

[0376] Representative reagents (i.e., R 1 -X) include those shown in Table 8. [Table 8]

[0377] Representative epoxide reagents used to synthesize the compounds shown in Tables 10A and 10B include those shown in Table 9. [Table 9]

[0378] Tables 10A and 10B, shown below, provide the observed (Obs) ion m / z ratios for Compound 4-1, Compound 4-27, Compound 4-30, Compound 4-50, Compound 4-55, and other representative compounds made similarly to the procedures described in the Examples above. In many cases, dialkyl sulfates, bromides, chlorides, or iodides, as shown in Table 8, were used in place of the triflates. In other cases, epoxides, as shown in Table 9, were used in place of the triflates. Also frequently, the final compounds were submitted directly to purification by preparative HPLC. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0379] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12]

[0380] A summary of representative physical properties for compound 4-1 prepared according to the methods disclosed herein is provided in Tables 11 and 12, and a summary of representative physical properties for compounds 4-15 prepared according to the methods disclosed herein is provided in Tables 13 and 14.

[0381] Example 6 Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetry (TGA) analyses for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-1) and (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-15). [ka]

[0382] Powder X-ray Diffraction (PXRD) Powder X-ray powder diffraction (PXRD) analysis was performed on a Rigaku Corporation powder X-ray diffractometer Miniflex 600 serial number BD66000190-01. For analysis, approximately 0.5-1 mg of sample was added to a zero background sample holder. The powder was gently pressed down with a piece of weighing paper and the sample holder was placed into the sample changer. Run parameters: Miniflex counter detector, Kb filter (×2), scan axis theta / 2-theta, continuous mode, start (deg) 2.0, stop (deg) 45.0, step (deg) 0.020, speed (deg / min) 10.0, spin-on, voltage (kV) 40, current (mA) 15. Reported 2θ values ​​may vary by plus or minus 0.2° (i.e., ±0.2°).

[0383] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation technique, sample mounting procedure, instrumentation used, sample purity, etc. One of skill in the art will understand that despite differences in peak intensities, a particular crystalline form may be identified by its characteristic peak(s).

[0384] Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA): DSC and TGA analyses were performed on a TA Instruments Discovery 2500 calorimeter (DSC) with serial number: 2500-00547 and a Discovery 5500 (TGA) with serial number: 5500-0126. For the DSC analysis, the weights of the Tzero pan and Tzero lid were obtained and recorded. Approximately 1-3 mg of material was weighed into the Tzero pan and the Tzero lid was squeezed with tweezers. The pan was transferred to the DSC autosampler for analysis. The method for analysis was a ramp to 275°C at 10°C / min. A reference pan was prepared without material by the same procedure.

[0385] For TGA analysis, standard aluminum sample pans were placed into platinum TGA pans and blanks were tared on the instrument. Approximately 1-5 mg of material was added to the standard aluminum pans and analyzed at 10°C / min up to approximately 400°C. For TGA and DSC, temperature signatures reported herein may vary by plus or minus 3°C (i.e., ±3°C).

[0386] Table 11 provides selected powder X-ray diffraction (PXRD) diffractogram peak positions in 2θ, DSC and TGA data for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-1) free base crystalline Form I. [Table 11]

[0387] Table 12 provides the powder X-ray diffraction (PXRD) diffractogram peak positions in 2θ for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-1) free base crystalline Form I. [Table 12-1] [Table 12-2]

[0388] Table 13 provides selected powder X-ray diffraction (PXRD) diffractogram peak positions in 2θ, DSC and TGA data for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-15) free base crystalline Form I. [Table 13]

[0389] Table 14 provides the powder X-ray diffraction (PXRD) diffractogram peak positions in 2θ for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-15) free base crystalline Form I. [Table 14-1] [Table 14-2]

[0390] Example 7 Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-1), see FIG. 13. [ka]

[0391] Step 1: Synthesis of (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A (3R,11bR)).

[0392] To a solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 2-B (3R,11bR), 95 mg, 0.30 mmol, 1.0 equiv.) in acetone (1.5 mL), cesium carbonate (0.19 g, 0.60 mmol, 2.0 equiv.) was added and the mixture was stirred at room temperature for 10 min. Dimethyl sulfate (17 μL, 0.18 mmol, 0.6 equiv.) was then added and the mixture was stirred at room temperature for 1 h. An additional 0.1 equiv. of dimethyl sulfate was added and the mixture was stirred for an additional 30 min. The resulting suspension was filtered to remove solids and concentrated in vacuo. The crude material was redissolved in DCM, quenched with 1M aqueous NaOH, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (12 g) was loaded with DCM and run with an increasing gradient of EtOAc in hexanes (0-40% over 25 min) to give (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A (3R,11bR), 75 mg, 0.23 mmol, 77%).

[0393] Step 2: Synthesis of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-1).

[0394] To a solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A (3R,11bR), 33 mg, 0.10 mmol, 1.0 equiv.) in EtOH (0.6 mL) cooled to 0° C. was added sodium borohydride (7.4 mg, 0.20 mmol, 2.0 equiv.). The resulting mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 1 h. The mixture was diluted with DCM, washed twice with saturated aqueous K2CO3, and the aqueous layer was further extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (12 g) was loaded with DCM and run with an increasing gradient of EtOAc (0-60%) in hexanes over 15 min to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-1, 20 mg, 0.06 mmol, 60%) as a white solid. 10 mg was dissolved in MeOH (1 mL) and submitted for further purification by preparative HPLC. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 6.72 (s, 1H), 6.64 (s, 1H), 4.55 (d, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.13 - 3.05 (m, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.95 (dd, J = 11.8, 4.2 Hz, 1H), 2.91 - 2.82 (m, 2H), 2.58 - 2.54 (m, 1H), 2.48 - 2.43 (m, 1H), 2.33 - 2.25 (m, 1H), 1.93 (t, J = 11.4 Hz, 1H), 1.70 (d, J = 12.8 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.25 (q, J = 12.8 Hz, 1H), 0.91 (s, 9H), 0.81 (dd, J = 13.6, 7.6 Hz, 1H). The observed (Obs) ion m / z ratio for compound 5-1 was 334.2.

[0395] Example 8 Preparation of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-3), see FIG. 13. [ka]

[0396] Step 1: Synthesis of (3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A (3S,11bS)).

[0397] Compound 5-A (3S,11bS) was prepared following the same procedure used to prepare compound 5-A (3R,11bR) (see Example 7, step 1), using compound 2-B (3S,11bS) instead of compound 2-B (3R,11bR). See FIG. 13.

[0398] Step 2: Synthesis of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-3).

[0399] Compound 5-3 was prepared according to the same procedure used to prepare compound 5-1 (see Example 7, step 2), using compound 5-A (3S,11bS) instead of compound 5-A (3R,11bR). The observed (Obs) ion m / z ratio for compound 5-3 was 334.2.

[0400] Example 9 Preparation of (2S,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-2), see FIG. 14. [ka]

[0401] A solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one (compound 5-A (3R,11bR), 27 mg, 0.08 mmol, 1.0 equiv) in THF (0.6 mL) was prepared and cooled to 0° C. Then, lithium tri-sec-butylborohydride (1 M THF, 0.16 mL, 0.16 mmol, 2.0 equiv) was added dropwise. The excess reagent was quenched with water. The resulting aqueous mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (4 g) was loaded with DCM and run with an increasing gradient of EtOAc in hexanes to give (2S,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-2, 17 mg, 0.05 mmol, 63%). 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 6.64 (s, 1H), 6.63 (s, 1H), 4.46 (d, J = 4.0 Hz, 1H), 3.84 - 3.80 (m, 1H), 3.70 (s, 6H), 3.38 (d, J = 11.2 Hz, 1H), 2.94 - 2.83 (m, 2H), 2.56 - 2.46 (m, 2H), 2.41 - 2.26 (m, 3H), 1.72 - 1.65 (m, 1H), 1.50 - 1.43 (m, 2H), 0.90 (s, 9H), 0.84 (dd, J = 14.2, 4.6 Hz, 1H). The observed (Obs) ion m / z ratio for compound 5-2 was 334.2.

[0402] Example 10 Preparation of (2R,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-4), see FIG. 14. [ka]

[0403] (2R,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 5-4) was prepared according to the same procedure as for preparing compound 5-2 (see Example 9), using compound 5-A (3S,11bS) instead of compound 5-A (3R,11bR). The observed (Obs) ion m / z ratio for compound 5-4 was 334.2.

[0404] Example 11 Methods for determining the VMAT2 inhibitory activity of a compound.

[0405] The following provides an example of the technique for determining the ability of a compound to inhibit VMAT2. The procedure is adapted from that described previously (see, for example, Near, (1986), Mol. Pharmacol. 30: 252-57; Teng, et al., J. Neurochem. 71, 258-65, 1998). The homogenate from human platelets is prepared by homogenization, and then washed by centrifugation as previously described (see, for example, Hoare et al., (2003) Peptides 24:1881-97).

[0406] Human VMAT2 Ki values ​​for the compounds listed in Tables 15A and 15B were determined using the following procedure: Compound dilution series in DMSO were generated either by hand from powder stocks or from DMSO stocks using serial dilution in a Vantage (Hamilton) or direct dilution using an Echo655 (Beckman). Twelve concentrations of test compounds were diluted from 10 nM in human platelet homogenate (30 μg membrane protein per well) in VMAT2 binding buffer (Dulbecco's phosphate buffered saline, 1 mM EDTA, pH 7.4) in a total volume of 0.145 to 0.150 mL in low binding 96-well plates (Corning #3605). 3 H-Dihydrotetrabenazine ( 3 H-dihydrotetrabenezine (American Radiolabeled Chemicals). After 90 min of incubation at 25°C, bound radioligand was harvested by rapid filtration onto either GF / B or GF / C glass fiber filters pretreated with 0.1% polyethyleneimine using either a Unifilter-96 harvester (PerkinElmer) or a MicroLabstar (Hamilton). After harvesting, filter plates were washed with 0.8 mL of VMAT2 binding buffer and bound radioligand was quantified by scintillation counting using a TopCount NXT or microplate counter MicroBeta (PerkinElmer). Data from 12-point concentration-response curves were analyzed to determine IC using a four-parameter logistic regression algorithm. 50 where the top was constrained to 100 and the bottom was constrained to 0. The K values ​​for each compound were calculated using the Cheng-Prusoff equation and depending on the batch of platelets and radiolabel used in each experiment, 3 A Kd of 2.5 nM or 4.06 nM was calculated for H-dihydrotetrabenazine.

[0407] Compound K i Values ​​(in nM) are provided in Tables 15A and 15B.

[0408] [Table 15-1] [Table 15-2] [Table 15-3]

[0409] 15 to 21 show the VMAT2 K values ​​for representative compounds of formula (I) and comparative compounds. i Values ​​(nM) are provided. i Values ​​were determined according to Example 11. Comparative compounds were prepared as described in International Publication No. WO2018 / 195121A1, which is incorporated by reference in its entirety. Representative compounds of formula (I) are VMAT2 K i In terms of potency, the compounds are more potent than the comparator compounds (eg, 4.1-fold to 20.9-fold).

[0410] Example 12 VMAT2 Inhibitor-Induced Reduction of Open Field Hypolocomotor Activity.

[0411] The effect of VMAT2 inhibitors on dopamine depletion was measured using a locomotor activity (LMA) assay. After a pretreatment period of 60 or 120 min, male Sprague-Dawley rats (200–250 g) were placed in a transparent cage surrounded by a photoelectric detector (San Diego Instruments). Locomotor activity of the rats was detected by breaks in a photoelectric beam, and activity was defined as the number of beam breaks in a 30 min period. Data were analyzed for significance by one-way analysis of variance (ANOVA; Sigmastat version 3.0.1, SPSS, Chicago, IL) followed by a Student-Newman-Keuls post-hoc test. ED 50was calculated for Compound 4-1 (0.24 mg / kg, see FIG. 22), Compound 4-15 (0.18 mg / kg, see FIG. 22), Compound 4-27 (0.14 mg / kg, see FIG. 23), Compound 4-31 (0.31 mg / kg, see FIG. 24), Compound 4-50 (0.21 mg / kg, see FIG. 23) and Compound 4-55 (0.29 mg / kg, see FIG. 23).

[0412] Example 13A Conditioned avoidance response assay of antipsychotic activity.

[0413] The conditioned avoidance response (CAR) test has been shown to be a valid and reliable preclinical model for assessing the antipsychotic activity of compounds. In the CAR paradigm, rats are trained to respond to a conditioned stimulus (auditory) by negative reinforcement in a two-chamber shuttle box. If the animal fails to move to the other chamber upon presentation of the auditory stimulus, a mild foot shock is administered on the side where the rat is located. Rats learn to avoid the mild foot shock by moving to the other chamber at the onset of the auditory signal, which is called the conditioned avoidance response. Crossing to the other chamber during the delivery of the shock is called an escape response. If the rat fails to move to the other chamber even upon delivery of the foot shock, the rat is considered to have made an escape failure. Numerous studies have shown that typical and atypical antipsychotic drugs selectively suppress the CAR, thus making it an ideal assay for screening potential antipsychotic compounds (see, e.g., Wadenberg et al., Biobehav. Rev. (1999) 23: 851-62).

[0414] Male Wistar rats are trained daily for 3 to 4 weeks. Training sessions involve placing rats in a CAR bidirectional shuttle box followed by a training period of 20 trials. A trial consisted of a 10 s presentation of 80 dB white noise followed by a coded 0.6 mA foot shock lasting up to 20 s. Intertrial intervals ranged from 20 to 60 s. Rats learn to avoid the shock by moving from one compartment to the other when the conditioned stimulus is presented (conditioned avoidance response). Rats are considered sufficiently trained if they avoid the shock when the conditioned stimulus is presented in at least 19 out of 20 trials. Rats not meeting these criteria are not used.

[0415] On the day of testing, trained animals are allowed to acclimate to the testing room for 30 minutes prior to testing. They are then dosed with compound and placed in the CAR bidirectional shuttle box. For testing, 20 trials are performed for each rat. In each trial, a conditioned stimulus (10 s presentation of 80 dB white noise) is administered, followed by a foot shock (coded 0.6 mA foot shock lasting up to 20 s). If the animal moves to the other room upon presentation of the conditioned stimulus, it is scored as a conditioned avoidance response. If the animal moves upon presentation of the foot shock, it is scored as an escape. If the animal is unable to move upon presentation of the foot shock, it is scored as an escape failure. Antipsychotic efficacy is evident by an increase in the number of escapes. Data are analyzed by way of way analysis of variance (ANOVA), followed by post-hoc comparisons with Bonferroni tests, where appropriate. Effects are considered significant if p<0.05. Outliers, defined as 2 standard deviations above or below the mean, are detected and removed from all analyses.

[0416] Example 13B Conditioned avoidance response (CAR) assay of antipsychotic activity. material and method

[0417] Animals: Adult male Wistar rats from Envigo (Indianapolis, IN) were used in this study. Rats were received at approximately 150 g, assigned unique identification numbers, and group-housed in ventilated cages, 2-3 per cage. Prior to the start of the study, all rats were inspected, handled, and weighed to ensure adequate health and fitness. A 12 / 12 light / dark cycle was maintained during the course of the study. Room temperature was maintained between 20°C and 23°C, with relative humidity around 50%. Chow diet and water were provided ad libitum throughout the study period. All testing was performed during the rats' light cycle.

[0418] Compound Formulation Compound 4-1 (0.03, 0.1, 0.3 and 1 mg / kg) was formulated in 0.25% methylcellulose and administered orally 120 minutes prior to testing in a dose volume of 3 mL / kg.

[0419] Compounds 4-15 (0.03, 0.1, 0.3 and 1 mg / kg) were formulated in 0.25% methylcellulose and administered orally 120 minutes prior to testing in a dose volume of 3 mL / kg.

[0420] Behavioral Testing - Conditioned Avoidance Response The conditioned avoidance response (CAR) test has been shown to be a highly reliable animal model for screening antipsychotic drugs (see Wadenberg & Hicks, Neuroscience and Biobehavioral Reviews, (1999) 23:851-862). In the CAR paradigm, animals are trained to respond to a conditioned stimulus (auditory and visual) with negative reinforcement (foot shock). Numerous studies have shown that typical and atypical antipsychotic drugs selectively suppress the CAR, thus making it an ideal assay for screening potential antipsychotic compounds (Wadenberg & Hicks, Neuroscience and Biobehavioral Reviews, (1999) 23:851-862).

[0421] Rats were placed into the CAR bidirectional shuttle box and a training period of 20 trials followed. A trial consisted of a 10 s presentation of 80 dB white noise followed by a coded 0.6 mA foot shock lasting up to 20 s. The inter-trial interval ranged from 20 to 60 s. Rats learned to avoid the shock by moving from one compartment to the other when the cue was presented. If they were unable to do so, they received a foot shock during which they most likely crossed the compartment to escape the shock. Finally, if they were unable to exit the compartment, they endured the full 20 s of foot shock. The following measurements were captured from the assay:

[0422] Avoidance response: when the rat moves from one compartment to the other during the presentation of a cue stimulus (CS). A reduction in avoidance responses is a typical sign of an effective dose of an antipsychotic drug.

[0423] Escape failure: if the rat failed to move to the other compartment during the 20 sec foot shock.

[0424] Data analysis Avoidance response data were expressed as the number of avoidance responses and the percentage of avoidance responses based on three baseline responses prior to drug testing. Escape failures were expressed as the total number of failures during the test session.

[0425] Body weight and avoidance data were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett's post hoc comparisons when appropriate. Escape failures were analyzed by Kruskal-Wallis nonparametric analysis followed by Dunn's post hoc comparisons when appropriate. Results are reported as mean ± SEM. Effects were considered statistically significant if p<0.05.

[0426] ED for compound 4-1 (0.55 mg / kg) 50 The ED was also calculated for compound 4-15 (0.44 mg / kg). 50(mg / kg) was calculated. In addition, it was observed that rats treated with either Compound 4-1 or Compound 4-15 showed reduced avoidance without a significant increase in escape failure at 0.3 mg / kg.

[0427] Example 14 A method for determining the stability of a compound in human liver microsomes.

[0428] Test compounds (0.5 μM) were incubated with pooled mixed-gender liver microsomes from humans (0.5 mg / mL total protein) at 37°C in the presence of an NADPH-generating system containing 50 mM potassium phosphate buffer, pH 7.4, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate and 1 unit / mL glucose-6-phosphate dehydrogenase. All concentrations were for a final incubation volume of 125 μL. Incubations were performed in a water bath at 37°C for 0, 5, 10, 20, 40 and 60 minutes and terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing internal standard. Precipitated proteins were removed by centrifugation prior to LC-MS / MS analysis. Aliquots of the resulting supernatant fractions were analyzed for parent compound depletion by LC-MS / MS monitoring. The resulting peak area ratio versus time data were fitted to a nonlinear regression using XLfit scientific curve fitting software (IDBS Ltd., Surrey, UK) and the elimination half-life (t 1 / 2 , min) were calculated. Pharmacokinetic parameters were predicted using the method described by Obach et al. (J. Pharmcol. Exp. Ther. 1997; 283: 46.58). Briefly, intrinsic clearance values ​​were calculated from the elimination half-life data and then scaled to represent the expected clearance in whole animals, see Table 16 (human). Additional values ​​calculated included the predicted extraction fraction and the predicted maximum bioavailability.

[0429] For very stable compounds, the in vitro half-life calculated by the HLM method is at most 420 minutes. Therefore, for these stable compounds, the in vitro half-life is at least 420 minutes but may be greater. Furthermore, for these stable compounds, the predicted total body clearance and scaled intrinsic clearance may be at least 2.59 and 2.97, respectively, but may be lower, and the predicted maximum bioavailability (%F) may be at least 87 but may be higher. [Table 16-1] [Table 16-2]

[0430] The above-mentioned various embodiments can be combined to provide further embodiments.All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety.The aspects of the embodiments can be modified, if necessary, to use the concepts of various patents, applications and publications to provide further embodiments.

[0431] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.

Claims

1. A compound of formula (Ia): 【Chemistry 48】 or a pharma- ceutically acceptable salt thereof, R 1 is -CH 2 CF 3 , -CH 2 CF 2 H, -CH 2 CF 2 CH 3 , 【Chemistry 53】 is.]

2. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-1) 2. The compound of claim 1, wherein:

3. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 4-1) 2. The compound of claim 1,

4. (2R,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-13) 2. The compound of claim 1, wherein:

5. (2R,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-13) 2. The compound of claim 1,

6. (2R,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-14) 2. The compound of claim 1, wherein:

7. (2R,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-14) 2. The compound of claim 1,

8. (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-27) 2. The compound of claim 1, wherein:

9. (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-27) 2. The compound of claim 1 ,

10. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetan-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-30) 2. The compound of claim 1, wherein:

11. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetan-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-30) 2. The compound of claim 1 ,

12. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-31) 2. The compound of claim 1, wherein:

13. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-31) 2. The compound of claim 1 ,

14. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-hydroxy-2-methylpropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-47) 2. The compound of claim 1, wherein:

15. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-hydroxy-2-methylpropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-47) 2. The compound of claim 1 ,

16. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2R)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-49) 2. The compound of claim 1, wherein:

17. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2R)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-49) 2. The compound of claim 1 ,

18. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-50) 2. The compound of claim 1, wherein:

19. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-50) 2. The compound of claim 1 ,

20. (2R,3R,11bR)-9-(3,3-difluoro-2-hydroxypropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-51) 2. The compound of claim 1, wherein:

21. (2R,3R,11bR)-9-(3,3-difluoro-2-hydroxypropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-51) 2. The compound of claim 1 ,

22. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55) 2. The compound of claim 1, wherein:

23. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-55) 2. The compound of claim 1 ,

24. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-114) 2. The compound of claim 1, wherein:

25. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 4-114) 2. The compound of claim 1 ,

26. A pharmaceutical composition, formulation, Unit dosage forms, and A pharmaceutical product selected from a kit, comprising: each of which is a compound according to any one of claims 1 to 25; or a pharma- ceutically acceptable salt thereof, Pharmaceutical products.

27. A pharmaceutical composition, formulation, Unit dosage forms, and A pharmaceutical product selected from a kit, comprising: each of which is a compound according to any one of claims 1 to 25; or a pharma- ceutically acceptable salt thereof; and at least one pharma- ceutically acceptable excipient. Pharmaceutical products.

28. A compound according to any one of claims 1 to 25. or a pharma- ceutically acceptable salt thereof; and at least one pharma- ceutically acceptable excipient. Pharmaceutical compositions.

29. A method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vesicular monoamine transporter-2 (VMAT2) disease or disorder. A composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28.

30. A method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vesicular monoamine transporter-2 (VMAT2) disease or disorder. A composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28, wherein the VMAT2 disease or disorder is The composition, pharmaceutical product, or pharmaceutical composition is selected from ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jaw diseases; dyskinesia; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson's disease / parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders.

31. The method of claim 30, for treating a neurological or psychiatric disease or disorder in a subject in need thereof. A composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28.

32. A method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to claim 31. A composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28, wherein the neurological or psychiatric disease or disorder is Hyperkinetic movement disorder, 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 acanthocyocytosis 20. A composition, pharmaceutical product, or pharmaceutical composition selected from the group consisting of:

33. The neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

34. The hyperkinetic movement disorder is tardive dyskinesia.

34. The composition, pharmaceutical product, or pharmaceutical composition of claim 33.

35. The method of claim 35, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

34. The composition, pharmaceutical product, or pharmaceutical composition of claim 33.

36. The method of claim 30, wherein the neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

37. The method of claim 37, wherein the neurological or psychiatric disease or disorder is schizophrenia.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

38. The neurological or psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

39. The method of claim 39, wherein the neurological or psychiatric disease or disorder is an autism spectrum disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

40. The neurological or psychiatric disease or disorder is a mood disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

41. The neurological or psychiatric disease or disorder is a mood disorder selected from bipolar disorder, major depressive disorder, mania in a mood disorder, or depression in a mood disorder.

33. A composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

42. A composition, pharmaceutical product, or pharmaceutical composition described in any one of claims 32 to 41, characterized in that the composition, pharmaceutical product, or pharmaceutical composition is for use in adjunctive therapy for the treatment of a neurological or psychiatric disease or disorder.

43. In the manufacture of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder, 26. A compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28. Use of.

44. Ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jaw diseases; dyskinesia; dystonia; endocrine, nutritional or metabolic diseases; epilepsy; habit or impulse disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related and somatoform disorders; degenerative diseases of the basal ganglia; extrapyramidal and movement disorders; neurological or psychiatric diseases or disorders; nervous system or motor dysfunction disorders; Parkinson's disease / parkinsonism disorders; childhood-onset behavioral and emotional disorders; pervasive developmental disorders; and substance abuse or dependence disorders. In the manufacture of a medicament for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder selected from 26. A compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28. Use of.

45. In the manufacture of a medicament for treating a neurological or psychiatric disease or disorder, 26. A compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28. Use of.

46. Hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, mood disorder, 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 acanthocyocytosis. In the manufacture of a medicament for treating a neurological or psychiatric disease or disorder selected from the group consisting of:

26. A compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28. Use of.

47. The neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

47. The use according to claim 46.

48. The hyperkinetic movement disorder is tardive dyskinesia.

48. The use according to claim 47.

49. The method of claim 49, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

48. The use according to claim 47.

50. The neurological or psychiatric disease or disorder is schizophrenia or schizoaffective disorder.

47. The use according to claim 46.

51. The neurological or psychiatric disease or disorder, wherein the disease or disorder is schizophrenia.

47. The use according to claim 46.

52. The neurological or psychiatric disease or disorder is treatment-resistant obsessive-compulsive disorder.

47. The use according to claim 46.

53. The method of claim 53, wherein the neurological or psychiatric disease or disorder is an autism spectrum disorder.

47. The use according to claim 46.

54. The neurological or psychiatric disease or disorder is a mood disorder.

47. The use according to claim 46.

55. The neurological or psychiatric disease or disorder is a mood disorder selected from bipolar disorder, major depressive disorder, mania in a mood disorder, or depression in a mood disorder.

47. The use according to claim 46.

56. The use described in any one of claims 46 to 55, characterized in that the medicament is for use in adjunctive therapy for treating a neurological or psychiatric disease or disorder.

57. For use in a method of treatment of the human or animal body by therapy, 26. A composition comprising a compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical product according to claim 26 or 27, or 29. The pharmaceutical composition of claim 28.

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