VMAT2 inhibitor and method of use

Abstract

To provide a VMAT2 inhibitor compound of formula (I), a composition, and a related method. [Solution] Also provided herein is a method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject requiring such treatment, comprising the step of administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof; a pharmaceutical product containing a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. TIFF2026139830000104.tif2944

Description

[Technical Field]

[0001] background Technical field This disclosure generally relates to VMAT2 inhibitor compounds, compositions, and related methods. [Background technology]

[0002] Description of related technologies Abnormal regulation of the dopaminergic system is essential for several central nervous system (CNS) disorders, including neurological and psychiatric disorders. These neurological and psychiatric disorders include conditions such as hyperactivity disorder, as well as schizophrenia and mood disorders. The transporter protein vesicular monoamine transporter-2 (VMAT2) plays a crucial 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 =3.2nM) (see, for example, Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8), currently used in the treatment of various ADHDs. It is used in [location]. Inhibition of VMAT2 by (±)-TBZ leads to depletion of brain monoamines in vivo (e.g., Pettibone et al., Eur. J. Pharmacol.). (See (1984) 102:431-6). (±)-TBZ is found in the presynaptic and rat brains. It also inhibits postsynaptic dopamine receptors (see, for example, Login et al., (1982) Ann. Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521). (±)-TBZ undergoes extensive first-pass metabolism after oral administration to humans. (±)-TBZ exhibits these characteristics, and is rarely or never observed in systemic circulation. Therefore, the pharmacological activity of (±)-TBZ is thought to be mainly mediated by its active metabolite. Since (±)-TBZ has two chiral centers, it is a racemic mixture of two stereoisomers. (±)-TBZ is rapidly and extensively metabolized in vivo by carbonyl reductase to four metaboloidal stereoisomers, including 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-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) exhibit significant efficacy as VMAT2 inhibitors. [Table 17]

[0004] In patients administered (±)-TBZ, [-]-alpha-DHTBZ (2S,3S,11bS-DHTBZ) and [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) are the most abundant DHTBZ isomers, while [-]-beta-DHTBZ (2R,3S,11bS-DHTBZ) and [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) exist as secondary metabolites. The [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) isomer was determined to be present in the smallest amount among all four isomers. Therefore, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) is considered to be the major DHTBZ isomer that contributes to the pharmacological activity of (±)-TBZ. Once formed, [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) has a relatively short half-life (approximately 5 hours), which requires (±)-TBZ to have a three-times-daily (TID) dosage regimen.

[0005] (±)-TBZ has a narrow therapeutic window, and its clinical use requires careful dose titration. Adverse effects associated with (±)-TBZ and / or its metabolites include neuroleptic malignant syndrome, somnolence, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia and parkinsonism. Generally speaking, the probability of observing adverse effects is a function of the plasma concentration achieved with a given dosage regimen. A longer half-life (t 1 / 2 ) and a compound with lower clearance will have lower peak-to-trough variation in plasma exposure when equivalent dosing intervals are considered. These longer half-life compounds may exhibit improved tolerability by maintaining drug concentrations at the level required for efficacy but below the level at which adverse effects are likely to be induced.

[0006] A fundamental and effective strategy for improving drug half-life is to reduce clearance. The term clearance describes the process of drug elimination from the body or from a single organ, which is defined as the volume of fluid containing drug that is removed from the body per unit time. Clearance is a fundamental pharmacokinetic parameter, and since this parameter affects drug properties such as half-life and ultimately dosing regimens, it is commonly measured in drug research and development. Where compound and dose selection has been optimized, the benefits of smaller plasma concentration fluctuations seen for compounds with low clearance include the prospect of improved patient compliance due to potentially reduced steady-state peak concentrations, increased trough concentrations, and possibly an improved risk-benefit profile.

[0007] Notwithstanding the progress that has been made in this field, there remains a need in the art for improved VMAT2 inhibitors, including compounds, compositions and related methods thereto. Identification of long half-life / low clearance small molecule VMAT2 inhibitors is advantageous for drug development, particularly where such drugs are being developed for chronic administration. In certain patient populations where patient compliance and pill burden are ongoing challenges, reduced dosing frequency is highly desirable and provides increased patient benefit. The present disclosure meets these and other needs, including improved in vitro VMAT2 potency, improved pharmacokinetics, or both, as will be apparent upon reference to the following disclosure. PRIOR ART DOCUMENTS NON-PATENT LITERATURE

[0008] NON-PATENT LITERATURE 1 Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8 NON-PATENT LITERATURE 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 Problems]

[0009] Summary Some embodiments provide a compound of formula (I): [Chemical Formula] or a pharmaceutically acceptable salt thereof, wherein in the formula: R 1 is R 2A , -(CH2) m -R 2B or -(CH2) n -OR 2C , R 2A is each C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4- to 7-membered heterocyclyl, each of which is unsubstituted or substituted with one or more R A , 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, halo C1-C4 alkoxy, halo C1-C4 alkyl, halo C2-C4 dialkylamino, 4- to 7-membered heterocyclyl, -CN, -OH and oxo, R 2B is aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 7-membered heterocyclyl, each of which is unsubstituted or substituted with one or more R B , each R BThese are independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halo-C1-C4 alkyl, halo-C1-C4 alkylsulfonyl, oxo, and -OH. R 2C Each of these is either unsubstituted or one or more R C A C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 member heterocycline that is substituted with Each R C These are independently -CN or C3-C6 cycloalkyl groups. m is 0, 1, 2, 3, or 4. n is 1, 2, or 3. To provide.

[0010] Pharmaceutical products comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, are also provided herein.

[0011] Pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, are also provided herein.

[0012] Pharmaceutical products comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient are also provided herein.

[0013] Pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, are also provided herein.

[0014] Pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable additive are also provided herein.

[0015] Also provided herein is a compound of formula (I), or a pharmaceutically 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 the step of contacting said VMAT2 with a compound of formula (I).

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

[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 the step of administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof; a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically 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 the step of administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof; a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

[0021] Also provided herein are methods for treating neurological or psychiatric disorders or conditions in subjects requiring such treatment, comprising the step of administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a further pharmaceutically active substance selected from antidepressants, antipsychotics (typical or atypical), antiepileptics, antimicrobial agents, antiarrhythmics, mood stabilizers, and gastrointestinal agents.

[0022] A method for relieving one or more symptoms of a neurological or psychiatric disorder or condition, comprising the step of administering to a subject in need thereof an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the neurological or psychiatric disorder or condition is selected from the group consisting of hyperactivity 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 acanthocyanotic chorea is also provided herein.

[0023] The use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating vesicular monoamine transporter-2 (VMAT2) diseases or disorders; pharmaceutical products containing compounds of formula (I) or pharmaceutically acceptable salts thereof; and pharmaceutical compositions containing compounds of formula (I) or pharmaceutically acceptable salts thereof is also provided herein.

[0024] The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for treating a neurological or psychiatric disorder or condition, is also provided herein.

[0025] The use of compounds of formula (I), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of neurological or psychiatric disorders or conditions is also provided herein.

[0026] The use of compounds of formula (I) or pharmaceutically acceptable salts thereof for treating neurological or psychiatric disorders or conditions, wherein the neurological or psychiatric disorder or condition is selected from the group consisting of hyperactivity 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 acanthocyanotic chorea, is also provided herein.

[0027] Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods of treating the human or animal body by therapy; pharmaceutical products containing compounds of formula (I) or pharmaceutically acceptable salts thereof; and pharmaceutical compositions containing compounds of formula (I) or pharmaceutically acceptable salts thereof are also provided herein.

[0028] Compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in methods of treating the human or animal body by therapy are also provided herein.

[0029] Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for treating vesicular monoamine transporter-2 (VMAT2) diseases or disorders; pharmaceutical products comprising compounds of formula (I) or pharmaceutically acceptable salts thereof; and pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof are also provided herein.

[0030] Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in methods for treating neurological or psychiatric disorders or conditions; pharmaceutical products comprising compound (I) or pharmaceutically acceptable salts thereof; and pharmaceutical compositions comprising compound (I) or pharmaceutically acceptable salts thereof are also provided herein.

[0031] Compounds of formula (I), or pharmaceutically acceptable salts thereof, for the treatment of neurological or psychiatric disorders or conditions are also provided herein.

[0032] In some embodiments, the neurological or psychiatric disorder or condition is selected from the group consisting of hyperactivity 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 acanthocyanotic chorea.

[0033] In some embodiments, vesicular monoamine transporter-2 (VMAT2) disease or disorder may include ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; and cognitive impairment. A selection of the following conditions may be present: oral, salivary gland, or jawbone disorders; dyskinesia; dystonia; endocrine, nutritional, or metabolic disorders; epilepsy; habitual or impulsivity disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related, and somatoform disorders; degenerative disorders of the basal ganglia; extrapyramidal and motor disorders; neurological or psychiatric disorders or conditions; nervous system or motor dysfunction; Parkinson's disease / parkinsonist disorders; childhood-onset behavioral and affective disorders; pervasive developmental disorders; and substance abuse or addiction disorders. [Brief explanation of the drawing]

[0034] [Figure 1A] Figure 1A shows the single crystal structure representation of (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)).

[0035] [Figure 1B]Figure 1B shows the single crystal structure representation 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] [Figure 2] Figure 2 shows the powder X-ray diffraction (PXRD) diffraction pattern 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]isoquinoline-2-ol (compound 4-1) free base crystalline form I.

[0037] [Figure 3] Figure 3 shows the DSC and TGA thermograms of the free base crystalline form I 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]isoquinoline-2-ol (compound 4-1).

[0038] [Figure 4] Figure 4 shows the powder X-ray diffraction (PXRD) diffraction pattern 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]isoquinoline-2-ol (compound 4-15) free base crystalline form I.

[0039] [Figure 5] Figure 5 shows the DSC and TGA thermograms of the free base crystalline form I 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]isoquinoline-2-ol (compound 4-15).

[0040] [Figure 6] Figure 6 shows a general synthetic scheme for the preparation of the compound of formula (I) and its associated intermediates, where R1 has the same meaning as described herein, and X is a leaving group such as a halo (e.g., I, Cl, and Br) or OS(O)2Rz (e.g., mesylates (-OMs), triflates (-OTf), and tosylates (-OTs), where Rz has the same meaning as described herein). As shown in Figure 6, the intermediates, compound 1-B, compound 1-C, and compound 1-D (including their corresponding stereoisomers) are novel and useful in the preparation of the compound of formula (I) and its pharmaceutically acceptable salts as described herein.

[0041] [Figure 7] Figure 7 shows the resolution step of 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C) with (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanediic acid (DPTTA), which is used to resolve (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6 A general synthetic scheme for the preparation of compound 1-D(2R,3R,11bR) is shown, which involves obtaining H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C(2R,3R,11bR)), then deprotecting it to obtain (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 typical reactions for the preparation of salts of (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C(2R,3R,11bR)) and (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanediic acid (DPTTA). See Example 1B.

[0043] [Figure 9] Figure 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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3S,11bS)) using chiral supercritical fluid chromatography (SFC). See Example 2.

[0044] [Figure 10]Figure 10 shows a representative image 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 (9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3R,11bR)) A typical reduction step is shown; and a representative reduction step for the preparation of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-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)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3S,11bS)) is shown.

[0045] [Figure 11]Figure 11 shows a representative diagram 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 (9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3R,11bR)) A typical reduction step is shown; and a representative reduction step 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)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2R,3S,11bS)) is shown.

[0046] [Figure 12]Figure 12 shows a typical 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-trifluoroethyltrifluoromethanesulfonate (CF3CH2OTf) in the presence of cesium carbonate and acetone, for the 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]isoquinoline-2-ol (compound 4-1). See Example 5A. Figure 12 also shows a typical 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 (R)-2-methyloxirane in the presence of cesium carbonate and DMF. See Example 5F.

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

[0048] [Figure 14] Figure 14 shows typical reduction reactions 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]isoquinoline-2-ol (compound 5-2), see Example 9; and typical reduction reactions 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]isoquinoline-2-ol (compound 5-4), see Example 10. In both reactions, lithium tri-sec-butylboron hydride is used as the reducing agent in THF.

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

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

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

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

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

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

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

[0056] [Figure 22] Figure 22 shows the in vivo pharmacology of compounds 4-1 and 4-15 in Sprague-Dolly rats in an open-field hypocomotion model as described in Example 12.

[0057] [Figure 23] Figure 23 shows the in vivo pharmacology of compounds 4-27, 4-50, and 4-55 in Sprague-Dolly rats in an open-field model of reduced spontaneous movement as described in Example 12.

[0058] [Figure 24] Figure 24 shows the in vivo pharmacology of compound 4-31 in Sprague-Dolly rats in an open-field model of reduced spontaneous movement, as described in Example 12. [Modes for carrying out the invention]

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

[0060] As used herein, "approximately" 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, “administer” means providing 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, and suspensions; injectable dosage forms such as IV, IM, and IP; transdermal dosage forms including creams, jellies, powders, and patches; oral dosage forms; inhalation powders, sprays, and suspensions; and rectal suppositories.

[0062] Healthcare professionals may provide the compounds described herein directly to a subject in the form of a sample, or indirectly to a subject by providing an oral or written prescription for the compound. Alternatively, for example, a subject may obtain the compound on their own without the involvement of a healthcare professional. When a compound is administered to a subject, the body is transformed by the compound in some way. When a compound described herein is provided in combination with one or more other active agents, “administration” is understood to include the administration of the compound and the other active agents simultaneously or at different times. When the combined active agents are administered simultaneously, they may be administered together in a single composition or separately. Preferred methods of administration may vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

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

[0064] The term “compound,” as used herein, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopic variants of the structure described. The term also refers to the compounds described herein, regardless of how they are prepared, for example, synthetically, through biological processes (e.g., metabolism or enzymatic transformation), or by a combination thereof. All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. In the solid state, the compounds and salts described herein may appear in various forms, for example, cocrystals or solvates containing hydrates. Since compounds can be any solid state form, such as polymorphs or solvates, unless otherwise explicitly indicated, references to compounds and salts in the specification should be understood to encompass all solid state forms of the compounds. In some embodiments, the compounds or salts described herein are substantially isolated. "Substantially isolated" means that the compound is separated at least partially or substantially from the environment in which it was formed or detected. Partial isolation may include, for example, a composition enriched with the compounds described herein. Substantial isolation may include a composition containing 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 a salt thereof.

[0065] The term "solvate," as used herein, refers to the solid state form of any compound described herein, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of solvent constrained by non-covalent intermolecular forces. If the solvent is water, the solvate is a hydrate.

[0066] As used herein, the term “hydrate” refers to a compound or salt thereof described herein, further comprising stoichiometric or nonstoichiometric amounts of water constrained by non-covalent intermolecular forces.

[0067] The terms “requiring treatment” and, when referring to treatment, “requiring it” are used interchangeably to mean a judgment made by a care provider (e.g., a physician, nurse, or caregiver in the case of humans; a veterinarian in the case of animals, including non-human mammals) that a subject or animal requires treatment or would benefit from it. This judgment is based on a variety of factors within the scope of the care provider’s expertise, but includes knowledge that the subject or animal is or will become ill as a result of a disease, condition, or disorder treatable by the compounds described herein. Accordingly, the compounds described herein may be used in a protective or preventive manner, or they may be used to alleviate, inhibit, or induce remission of 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, cattle, sheep, horses, primates, and humans. In the context of clinical trials, screenings, or activity studies, subjects may be healthy volunteers or participants without underlying VMAT2-mediated disorders or conditions, or volunteers or participants diagnosed with a disorder or condition requiring medical treatment as determined by a healthcare professional. Outside of clinical trials, subjects receiving care from a healthcare professional who have been diagnosed with a disorder or condition are typically described as subjects.

[0069] The term "pediatric subjects" refers to subjects who are under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (from birth to 1 month old); infants (1 month to 2 years old); children (2 years to 12 years old); and adolescents (12 years to 21 years old (up to their 22nd birthday, but not the day of their 22nd birthday)), e.g., Berhman et al. See also: 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 term "pharmaceutically acceptable" means a compound (and its salts), composition, and / or dosage form that is suitable for use in contact with human and animal tissues without any excessive toxicity, irritation, allergic response, or other problems or complications, within reasonable limits of medical judgment, and that meets a reasonable benefit-to-risk ratio.

[0071] The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient, including but not limited to salts, solvates, and hydrates of the compounds described herein, thereby making the composition suitable for investigation of a specified effective outcome in mammals (e.g., humans, but not limited to humans). Those skilled in the art will understand and recognize the appropriate techniques for determining, based on the needs of the artisans, whether the active ingredient has the desired effective outcome.

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

[0073] The terms “to treat,” “to treat,” and “treatment” refer to the medical management of a disease, disorder, or condition in a subject (e.g., subject) (see, for example, Stedman's Medical Dictionary). Generally, an appropriate dose and treatment regimen will provide a sufficient amount of VMAT2 inhibitor to provide a therapeutic benefit. The therapeutic benefit for a subject to whom the VMAT2 inhibitor compound(s) described herein is administered includes, for example, improved clinical outcomes, the objective of which is to prevent, slow, or delay (reduce) undesirable physiological changes associated with the disease, or to prevent, slow, or delay (reduce) the progression or severity of such disease. The efficacy of one or more VMAT2 inhibitors may include, but is not limited to, improvement, reduction, or mitigation of symptoms caused by or associated with the treated disease, whether detectable or undetectable; a decrease in the occurrence of symptoms; an improvement in quality of life; a longer period of disease-free status (i.e., a reduction in the likelihood or tendency of the subject to present the symptoms on which the diagnosis of the disease was made); a reduction in the severity of the disease; a stable (i.e., non-worsening) state of the disease; a delay or slowing of disease progression; remission or mitigation of the disease state; and remission (whether partial or total); and / or overall survival. In some embodiments, the subject may be a pediatric subject.

[0074] The term “therapeutic dose” means the amount of a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof, that elicits one or more of the following biological or pharmaceutically acceptable responses in a tissue, system, animal, or human, as requested by a subject, researcher, veterinarian, physician, or other clinician or caregiver: (1) To prevent disability, for example, in persons who may have a predisposition to a disease, condition or disability but have not yet experienced or shown any associated pathology or symptoms; (2) inhibiting the disorder, for example, inhibiting the disease, condition or disorder in an object experiencing or exhibiting the associated pathology or symptom (i.e., halting the further development of the pathology and / or symptom); and (3) To induce remission of a disorder, for example, to induce remission of a disease, condition or disorder in an object experiencing or exhibiting a related pathology or symptom (i.e., to reverse the pathology and / or symptom).

[0075] As used herein, the term “contact” refers to bringing together the indicated portions in an in vitro or in vivo system. For example, “contact” the VMAT2 protein with the compound provided herein includes administering the compound provided herein (or a pharmaceutically acceptable salt thereof) to a subject such as a human having the VMAT2 protein, and introducing the compound provided herein into a sample containing cells or a purified preparation containing the VMAT2 protein, for example.

[0076] chemical group Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the field to which this disclosure pertains. All patents, applications, published applications and other publications are incorporated in their entirety by reference. If there are multiple definitions of a term herein, the definitions in this section shall prevail unless otherwise noted.

[0077] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a part, where n is the number of ring-forming atoms. 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-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0078] In compounds of formula (I) and pharmaceutically acceptable salts thereof in which a variable group appears more than once, each variable group can be a distinct part selected independently of the group defining that variable group. For example, when describing a structure having, for example, two R groups present simultaneously in the same compound, these two R groups can represent distinct parts selected independently of the group defining R, or these two R groups can be the same.

[0079] Whenever a group is described as "substituted," that group may be substituted with one or more of the indicated substituents. Similarly, if a group is described as "unsubstituted or substituted," and is substituted, then this substituent(s) may be selected from one or more of the indicated substituents. It should be understood that substitutions in a given atom are limited by their valence.

[0080] As used herein, "a" and "b" are integers. a ~C b "C1-C4 alkyl" refers, for example, to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or to 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, including the boundary. Therefore, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, namely methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl (CH3CH2CH(CH3)-), and tert-butyl ((CH3)3C-). If "a" and "b" are not specified for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl groups, the broadest range described in these definitions should be inferred.

[0081] In addition to the foregoing, where used in the specification and the attached claims, the following terms have the meanings indicated therein, unless otherwise specified.

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

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

[0084] The term "alkyl" refers to a fully saturated linear or branched hydrocarbon radical. Alkyl groups may have 1 to 20 carbon atoms (wherever they appear herein, numerical ranges such as "1 to 20" refer to each integer within a given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 20 or fewer carbon atoms, including 1, 2, 3, etc. In some embodiments, alkyl groups may have 1 to 6 carbon atoms (i.e., "C1-C6 alkyl"). Some embodiments have 1 to 5 carbon atoms (i.e., C1-C5 alkyl), some embodiments have 1 to 4 carbon atoms (i.e., C1-C4 alkyl), some embodiments have 1 to 3 carbon atoms (i.e., C1-C3 alkyl), and some embodiments have 1 or 2 carbon atoms. As just one example, "C1-C4 alkyl" means that 1 carbon atom is present in the alkyl chain. This indicates that there are four carbon atoms, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, etc. If one or more substituents are present in the alkyl group, these substituents may be bonded to any available carbon atoms. In some embodiments, the alkyl group may be substituted or unsubstituted.

[0085] The term "alkylamino" refers to an amino group (-NH2) in which one nitrogen atom is replaced by an alkyl group. The term "alkyl" has the same definition as described herein. An alkylamino group may have one to four carbon atoms (i.e., C1-C4 alkylamino). Examples of alkylamino groups include -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), etc.

[0086] The term "alkynyl" refers to an alkyl group containing one or more triple bonds in a linear or branched hydrocarbon chain. Examples of alkynyls include ethynyl and propynyl. The alkynyl group may be unsubstituted or substituted. In some embodiments, the alkynyl group may be unsubstituted or substituted. In some embodiments, the alkynyl group may have two to six carbon atoms. The alkenyl group of a compound may be designated as "C2-C6 alkynyl" or a similar designation.

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

[0088] The term "alkylsulfonyloxy" refers to a radical consisting of an alkyl radical bonded 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 may have 1 to 4 carbon atoms (i.e., C1-C4 alkylsulfonyloxy). Examples include methylsulfonyloxy (CH3S(=O)2O-), ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, sec-butylsulfonyloxy, isobutylsulfonyloxy, t-butylsulfonyloxy, etc.

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

[0090] The term "aryl" refers to aromatic ring systems containing 6, 10, or 14 carbon atoms, which may include a single ring, two fused rings, or three fused rings, such as phenyl, naphthalenyl, and phenantrenyl. In some embodiments, the aryl group may have 6 or 10 carbon atoms (i.e., C6 or C6). 10 (aryl). In some embodiments, the aryl group is phenyl. If one or more substituents are present in the "aryl" ring, these substituents may be bonded to any available ring carbon. In some embodiments, the aryl group may be substituted or unsubstituted.

[0091] The "C-amide" group is connected to the rest of the molecule via carbon atoms, and is a "-C(=O)N(R)" group. A R B )" refers to the group, where R A and R B These 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 monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but if there are more than one, the double bonds cannot form a completely delocalized pi-electron system (i.e., an aromatic system) throughout all rings, otherwise the group would be “aryl” as defined herein. If it consists of two or more rings, the rings may be joined together in the form of condensation, bridging, or spiro. Cycloalkenyls may contain 3 to 12 atoms in the ring(s) or 3 to 8 atoms in the ring(s). In some embodiments, the cycloalkenyl group may be unsubstituted or substituted. In some embodiments, the cycloalkenyl group may have 4 to 8 carbon atoms (i.e., “C4-C8 cycloalkenyl”). One example is cyclohexenyl.

[0094] The term "cycloalkyl" refers to a monocyclic or polycyclic ring system in which all carbon atoms are completely saturated. In some embodiments, a cycloalkyl is a monocyclic ring containing 3 to 8 carbon atoms (i.e., "C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., "C3-C7 cycloalkyl"). In some embodiments, a cycloalkyl is a monocyclic or bicyclic ring containing 3 to 7 carbon atoms (i.e., "C3-C7 cycloalkyl"). In some embodiments, it contains 3 to 6 carbon atoms (i.e., "C3-C6 cycloalkyl"). In some embodiments, it contains 3 to 5 carbon atoms. In some embodiments, it contains 5 to 7 carbon atoms. In some embodiments, it contains 3 to 4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentane, and cyclohexyl. If one or more substituents are present in the cycloalkyl group, these substituents may be bonded to 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 atom is replaced by 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 one to four carbon atoms (i.e., C2-C4 dialkylamino), provided that the two alkyl groups do not exceed a total of four carbon atoms between the two groups. Examples include -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2CH3), etc.

[0096] The term “dialkylsulfamoyl” refers to a sulfonamide group (-S(=O)2NH2) in which the nitrogen atom 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 may have one to four carbon atoms (i.e., C2-C4 dialkylsulfamoyl), provided that the two alkyl groups do not exceed a total of four carbon atoms between them. Examples include -SO2N(CH3)2, -SO2N(CH3)(CH2CH3), -SO2N(CH3)(CH2CH2CH3), -SO2N(CH2CH3)2, -SO2N(CH2CH3)(CH2CH2CH3), etc.

[0097] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some embodiments, the haloalkoxy group may have one to six carbon atoms. The haloalkoxy group of a compound may be designated as "haloC1-C6 alkoxy," "haloC1-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 may have one to six carbon atoms (i.e., “haloC1-C6 alkyl”). A haloC1-C6 alkyl group may be completely substituted, in which case the formula C n L 2n+1 Haloalkyls can be represented by the formula, where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. If 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 carbon atoms (i.e., halo C1-C5 alkyl). In some embodiments, the haloalkyl contains 1 to 4 carbon atoms (i.e., halo C1-C4 alkyl). In some embodiments, the haloalkyl contains 1 to 3 carbon atoms (i.e., halo C1-C3 alkyl). In some embodiments, the haloalkyl contains 1 or 2 carbon atoms. Examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, etc.

[0099] The term "haloalkylsulfonyl" refers to a radical consisting of a haloalkyl radical bonded to the sulfur of a sulfone radical of the formula: -S(=O)2-, where haloalkyl has the same definition as described herein. A "haloalkylsulfonyl" group may 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, etc.

[0100] The term "halodialkylamino" refers to an amino group (-NH2) in which nitrogen is substituted with either one alkyl group and one haloalkyl group, or two haloalkyl groups. When nitrogen is substituted with two haloalkyl groups, these groups may be the same or different. The terms "alkyl" and "haloalkyl" have the same definitions as described herein. A "halodialkylamino" group may have one to four carbon atoms (i.e., haloC2-C4dialkylamino), provided that two groups do not exceed a total of four carbon atoms between the two groups. Examples include -N(CH3)(CF3), -N(CH3)(CF3), -N(CF3)2, -N(CH3)(CH2CF3), -N(CH2CF3)2, etc.

[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 heteroaryls," referring to an aromatic ring containing 5 or 6 ring atoms in the monocyclic ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, prinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenantridinyl, benzimidazolyl, pyrrolyl, quinolinyl, isoquinolinyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, etc. The heteroaryl group may be substituted or unsubstituted. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as a "5-7 membered heteroaryl," a "5-10 membered heteroaryl," or similar designations. In some embodiments, the heteroaryl is a substituted or unsubstituted C1-C group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13The heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system with 5, 6, 7, 8, 9, 10, or up to 14 members. In 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 8, 9, or 10-membered bicyclic heteroaryls of C5-C9 are imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxazolyl, indazolyl, prinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrido[3,4-b]pyradinyl, or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryls are substituted or unsubstituted C8-C9 containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13It 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 5-membered heteroaryl with 1 to 4 C1. In some embodiments, the 5-membered heteroaryl with 1 to 4 C1 is 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 6-membered heteroaryl with 3 to 5 C3. In some embodiments, the C3-C5 six-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, or triazinyl. In some embodiments, "five- to ten-membered heteroaryl" refers to furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinoxalinyl, triazinyl, benzofuranyl, 1H-indolyl, benzo[b]thiophenyl, etc. In some embodiments, "five- to ten-membered heteroaryl" refers to pyrazinyl, pyridadinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, etc. In some embodiments, "5-10 membered heteroaryl" refers to pyrazinyl, pyridadinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, imidazo[4,5-c]pyridinyl, etc. In some embodiments, the heteroaryl group may be substituted or unsubstituted.

[0103] The term “heterocyclyl” refers to monocyclic, bicyclic, and tricyclic ring systems of 3, 4, 5, 6, 7, 8, 9, 10, and up to 18 members, where a carbon atom, together with 1 to 5 heteroatoms, constitutes the ring system and optionally contains one or more unsaturated bonds positioned such that a completely delocalized pi-electron system (aromatic system) does not appear in either the monocyclic ring or at least one of the rings in the bicyclic or tricyclic ring system. Heteroatoms 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 the form of condensation, bridging, or spiro, where the heteroatoms may be present in either the non-aromatic or aromatic rings in the ring system. In some embodiments, “4- to 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, a "3- to 6-membered heterocyclil" 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, a "4- to 6-membered heterocyclil" 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, one or two heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, the heterocyclil may contain a carbonyl (C=O) group adjacent to the heteroatom, i.e., the carbon adjacent to the heteroatom may be substituted with an oxo, where the substituted ring system is a lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate.Examples of unsubstituted or oxosubstituted "heterocyclyl" groups include azilidinyl, azetidinyl, tetrahydrofuranil, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiadinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, oxazolidinino This includes, but is not limited to, thiazolinyl, thiazolidinyl, morpholinyl, oxylanyl, 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-condensed analogs (e.g., benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl). The heterocyclyl group may be designated as a "3- to 10-membered heterocyclyl" or similar designation. In some embodiments, the heterocyclyl is a C2-C group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12 The heterocyclyl can be a monocyclic, bicyclic, or tricyclic ring system of 3, 4, 5, 6, 7, 8, 9, 10, or up to 13 members. In some embodiments, the heterocyclyl can be a substituted or unsubstituted C2-C6 monocyclic ring of 3, 4, 5, 6, or 7 members containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl can be a substituted or unsubstituted C2-C6 ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 10It can be a bicyclic ring system with 4, 5, 6, 7, 8, 9, 10, or 11 members. In some embodiments, the heterocyclil is a substituted or unsubstituted C7-C ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12It can be a 12 or 13-membered tricyclic ring system. In some embodiments, the heteroatoms of a 6-membered monocyclic heterocyclil are selected from one to three of O (oxygen), N (nitrogen), or S (sulfur), and the heteroatoms of a 5-membered monocyclic heterocyclil are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur). In some embodiments, the heterocyclil is aziridinyl, azetidinyl, tetrahydrofuranil, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-dithiolanyl Adinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morpholinyl, oxylanil, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranil, tetrahydrothiopyranil, 1,4-diazabicyclo[2.2.2]o Cutane, 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-naphthilidinyl, 1,2,3,4-tetrahydro-2,7-naphthilidinyl, 1,2,3,4-tetrahydro-1,7-naphthilidinyl, 1,2, It can be 3,4-tetrahydro-1,6-naphthilidinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, [1,3]dioxolo[4,5-c]pyrimidinyl, [1,3]dioxolo[4,5-b]pyrimidinyl, [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, oxolanil (tetrahydrofuranil), and oxanil (tetrahydropyranil). If one or more substituents are present on the heterocyclyl group, these substituents may be bonded to any available carbon atoms and / or heteroatoms. In some embodiments, the heterocyclyl group may be substituted or unsubstituted.

[0104] The term "oxo" refers to an =O substituent.

[0105] The term "nitro" refers to the -NO2 group.

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

[0107] As used herein, “additive” refers to a substance added to a composition that provides the composition with, but not limited to, bulk, viscosity, stability, binding ability, lubricity, disintegration ability, etc. “Diluent” refers to a type of additive, which may be pharmaceutically necessary or desirable, but lack pharmacological activity, as a raw material in a pharmaceutical composition. 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 may also be a liquid for dissolving a drug administered by injection, ingestion, or inhalation. A pharmaceutically acceptable additive is a physiologically and pharmaceutically suitable, non-toxic, and inert material or raw material that does not interfere with the activity of the active pharmaceutical ingredient. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc., may be provided in pharmaceutical compositions. Those skilled in the art will be able to appropriately provide these in accordance with accepted practices, such as those disclosed in Remington, as described above. The compounds can be further formulated as disclosed and described in the details.

[0108] As used herein, “dose” or “dosage” refers to the measured amount of the active pharmaceutical ingredient to be taken at one time by the subject. In certain embodiments, if the active pharmaceutical ingredient is neither a free base nor a free acid, the amount is the molar equivalent of the corresponding amount of the free base or free acid.

[0109] As used herein, “pharmaceutically acceptable salt” means a salt of a compound having an acidic or basic moiety that is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds disclosed herein can form acidic and / or base salts thanks to the presence of an acidic or basic moiety (e.g., an amino and / or carboxyl group or similar group). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with an inorganic or organic acid. Pharmaceutically acceptable base addition salts can be formed by combining a compound having an acidic moiety with an inorganic or organic base.

[0110] The compounds described herein may have one or more stereocenters. Unless otherwise indicated, all stereoisomers, including enantiomers and diastereomers, are intended. In any compound provided herein having one or more chiral centers, unless absolute stereochemistry is explicitly indicated, each center is understood to be independently in the (R)-configuration, the (S)-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or stereoisomerically mixed. Preparation of enantiomerically pure or enantiomerically enriched forms may be carried out by the division of racemic mixtures, by using enantiomerically pure or enriched starting materials, or by stereoselective or stereospecific synthesis. A stereochemical definition is 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, where the compounds described herein are chiral or otherwise contain one or more stereocenters, the compounds may be prepared with enantiomer or diastereomer excesses 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 separation of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. An example of such a method involves fractional recrystallization using a chiral-resolving organic acid together with a racemic compound containing a basic group. Other chiral-resolving agents suitable for fractional crystallization include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using chiral-resolving bases can be used with racemic compounds containing basic groups.

[0112] Racemic mixtures can also be separated by elution using a chiral column. Suitable eluent compositions can be determined by those 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 the range defined by any of the aforementioned 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 the range defined by any of the aforementioned figures.

[0114] In some embodiments, the compounds described herein may be prepared with a diastereomer 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 the range defined by any of the aforementioned figures. In some embodiments, the compounds described herein may be prepared with a diastereomer 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 the range defined by any of the aforementioned figures.

[0115] In addition, if a compound described herein contains one or more double bonds (e.g., C=C, C=N, etc.) or other geometrically asymmetric centers, it is understood that, unless otherwise specified, the compound contains 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 mixtures of isomers or as separate isomeric forms.

[0116] The compounds described herein also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond and the accompanying transfer of a proton. Tautomers include prototropic tautomers, which are isomer-protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers can be in equilibrium or can be sterically fixed into one form by appropriate substitution.

[0117] The compounds described herein and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents, for example, in the form of hydrates or solvates. In the solid state, the compounds and their salts described herein may appear in various forms, for example, in the form of solvates including hydrates. The compounds may be in any solid state, such as crystalline, amorphous, or solvated forms, and unless otherwise explicitly indicated, references to the compounds and their salts in this specification should be understood as views relating to all solid states of the compounds.

[0118] The compounds described herein may be used in neutral forms, such as free acids or free bases. Alternatively, the compounds may be used in the form of pharmaceutically acceptable salts, such as pharmaceutically acceptable addition salts of acids or bases.

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

[0120] Isotopes The compounds disclosed and described herein allow and contain atoms at each position of the compound independently to have either 1) an isotopic distribution of a chemical element in proportion to that commonly found in nature, or 2) an isotopic distribution of a chemical element different from that commonly found in nature, unless the context explicitly indicates otherwise. A particular chemical element has an atomic number, defined by the number of protons in its nucleus. Each atomic number identifies a particular chemical element but not an isotope, and an atom of a given element can have neutrons, the number of which varies 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. A compound in which one or more atoms have an isotopic distribution of a chemical element in proportion to that which is different from that commonly found in nature is generally referred to as isotopically labeled. Each chemical element represented in a compound structure can include any isotopic distribution of that element. For example, in a compound structure, the presence of hydrogen atoms in that compound may be clearly disclosed or understood. At any position in a compound where a hydrogen atom may exist, the hydrogen atom may be present in amounts proportional to those commonly found in nature and in amounts proportional to those not commonly found in nature ( 1 H) and Deuterium (2 This can be an isotopic distribution of hydrogen, including but not limited to H). Therefore, references to compounds herein encompass all potential isotopic distributions of each atom unless the context explicitly indicates otherwise. Examples of isotopes include those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As those skilled in the art will know, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, one or more atoms may contain radioactive isotopes in a proportion greater than that found in nature. 2 H or 3 H or a large proportion 11 C, 13 C or 14 The use of compounds disclosed and described herein, which have isotopic distributions different from those commonly found in nature, such as those containing 1C, is also intended. As a general example, but not limited to, hydrogen isotopes include protium ( 1 H), Deuterium ( 2 H) and tritium ( 3 It contains H). The carbon isotope is carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C) and carbon-14 ( 14 Contains C). The isotope of nitrogen is nitrogen-13 ( 13 N), Nitrogen-14( 14 N) and nitrogen-15( 15 It contains N). 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 It contains fluorine-17(O). 17 F), Fluorine-18( 18 F) and fluorine-19 ( 19 It contains F). The isotope of phosphorus is phosphorus-31( 31 P), phosphorus-32( 32 P), Lin-33( 33 P), phosphorus-34( 34 P), phosphorus-35(35 P) and phosphorus-36( 36 It contains P). The sulfur isotope is sulfur-32( 32 S), sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), sulfur-36( 36 S) and sulfur-38( 38 Contains S). The isotope of chlorine is chlorine-35( 35 Cl), Chlorine-36( 36 Cl) and chlorine-37( 37 Contains Cl). 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 Contains Br). The isotope of iodine is iodine-123( 123 I) Iodine-124 124 I) Iodine-125 125 I) Iodine-131( 131 I) and Iodine-135 135I) is included. In some embodiments, atoms at all positions of the compound have an isotopic distribution for each chemical element in amounts proportional to those commonly found in nature. In some embodiments, an atom at one position of the compound has an isotopic distribution for a chemical element in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution for a chemical element in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution for a chemical element in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution for a chemical element in amounts proportional to those commonly found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution for a chemical element in amounts different from those commonly found in nature (the remaining atoms have an isotopic distribution for a chemical element in amounts proportional to those commonly 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 element that differs from that commonly found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical element that differs from that commonly 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 element that differs from that commonly found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical element that differs from that commonly 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 element that differs from that commonly found in nature (the remaining atoms have an isotopic distribution for a proportional amount of chemical element that differs from that commonly found in nature).

[0121] A certain compound, for example, 3 H and 14 Products incorporating radioactive isotopes such as 13C are also useful in drug or substrate tissue distribution assays. Tritium ( 3H) and carbon-14 ( 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Compounds comprising isotopes such as deuterium ( 2 H) that are present in a proportionally larger amount than that normally found in nature can provide certain therapeutic advantages resulting from, for example, improved metabolic stability such as increased in vivo half-life or reduced required dosage. Isotope-labeled compounds can generally be prepared by carrying out procedures conventionally practiced in the chemical art. Methods for measuring such isotope perturbation or enrichment are readily available, such as mass spectrometry; and for isotopes that are radioisotopes, additional methods such as radiation detectors used in connection with HPLC or GC are available.

[0122] As used herein, "isotopic variant" means a compound that contains an unnatural proportion of an isotope at one or more of the atoms constituting such compound. In certain embodiments, the "isotopic variant" of a compound contains 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 It contains one or more isotopes in unnatural proportions, including but not limited to I). In certain embodiments, the “isotope variant” of the compound is in a stable form, i.e., non-radioactive. In certain embodiments, the “isotope variant” of the compound is hydrogen ( 1 H), Deuterium ( 2 H), carbon-12 ( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), Nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 It contains one or more isotopes in unnatural proportions, including but not limited to O). In certain embodiments, the “isotope variant” of the compound is an unstable form, i.e., radioactive. In certain embodiments, the “isotope variant” of the compound described herein is tritium ( 3 H), carbon-11 ( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O) and oxygen-15( 15 It contains one or more isotopes in unnatural proportions, including but not limited to O). In the compounds provided herein, any hydrogen is, for example, 2 H may be included as the primary isotopic form, or any carbon may be included as an example. 13It contains 1C as the primary isotopic form, or any nitrogen as an example. 15 It can contain N as the primary isotope form, and any oxygen can be an example. 18 It will be understood that O may be included as the primary isotopic form. In certain embodiments, the "isotope variant" of the compound is an unnatural proportion of deuterium ( 2 Contains H).

[0123] With respect to the compounds provided herein, if a particular atomic position is designated to have 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 approximately 0.015%. The positions designated as having deuterium typically have, in a particular embodiment, minimum isotope enrichment factors of at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion) at each designated deuterium position. Similarly, with respect to the compounds provided herein, if any atomic position is designated as having a particular isotope, it is understood that the abundance of that particular isotope at that position is substantially greater than the natural abundance of that isotope. Positions designated as having a particular isotope typically have, at each designated position, minimum isotope enrichment factors 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% isotope incorporation at a given location in a particular embodiment.

[0124] Synthetic methods for incorporating radioactive isotopes into organic compounds are applicable to the compounds described herein and are well known in the art. These synthetic methods, for example, for incorporating active levels of tritium into a target molecule, are as follows: A. Catalytic reduction with tritium gas: This procedure typically produces high specific activity products and requires halogenated or unsaturated precursors. B. Sodium borohydride [ 3 Reduction by [H]: This procedure is considerably inexpensive and requires a precursor containing a reducible functional group such as an aldehyde, ketone, lactone, or ester. C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure yields a product with nearly theoretical specific activity. This also requires a precursor containing a reducible functional group such as an aldehyde, ketone, lactone, or ester. D. Tritium gas exposure labeling: This procedure involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst. E. Methyl iodide [ 3 N-methylation using H]: This procedure typically involves using a suitable precursor with high specific radioactivity methyl iodide ( 3 By treating with H, O-methyl or N-methyl ( 3 This method is used to prepare the H) product. This method generally allows for higher specific energies, such as about 70-90 Ci / mmol.

[0125] Activity level 125 Synthetic methods for incorporating I into a target molecule include the following: A. Sandmeyer and similar reactions: This procedure involves converting an arylamine or heteroarylamine to a diazonium salt such as diazonium tetrafluoroborate, and then adding Na 125 I GET 125The compound is converted to an I-labeled compound. A typical procedure was reported by Zhu, GD. and co-workers in J. Org. Chem., 2002, 67, 943-948. B. Ortho phenol 125 Iodination: This procedure is performed at the ortho position of phenol, as reported by Collier, TL and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266. 125 Enables the incorporation of I. C. 125 Aryl bromide and heteroaryl bromide exchange by I: This method is generally a two-step process. The first step is the conversion of aryl bromide or heteroaryl bromide to the corresponding trialkyltin intermediate, for example, using a Pd-catalyzed reaction [i.e., Pd(Ph3P)4] in the presence of trialkyltin halide or hexaalkyldisin [e.g., (CH3)3SnSn(CH3)3] or via aryllithium or heteroaryllithium. A typical procedure is reported by Le Bas, M.-D. and co-workers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282. I was told.

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

[0127] compound Some embodiments involve compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 R 2A ,-(CH2) m -R 2B or -(CH2) n -OR 2C And, R 2A Each of these is either unsubstituted or one or more R A A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl that is substituted with Each R A These are 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, halo-C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH, and oxo. R 2B Each of these is either unsubstituted or one or more R B These are substituted with aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl compounds. Each R B These are independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halo-C1-C4 alkyl, halo-C1-C4 alkylsulfonyl, oxo, and -OH. R 2C Each of these is either unsubstituted or one or more R C A C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 member heterocycline that is substituted with Each R C These are independently -CN or C3-C6 cycloalkyl groups. m is 0, 1, 2, 3, or 4. n is 1, 2, or 3. To provide.

[0128] Some embodiments involve compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 R 2A ,-(CH2) m -R 2B or -(CH2) n -OR 2C And, R 2A is either unsubstituted or one or more R A These are C1-C4 alkyl groups that are substituted with Each R A These are independently selected from the group consisting of fluoro and -OH, R 2B Each of these is either unsubstituted or one or more R B A C3-C8 cycloalkyl or 4-6 member heterocycline that is substituted with Each R B These are independently selected from the group consisting of fluoro, -CN, -CH2CN, and -OH. R 2C Each of these is either unsubstituted or one or more R C It is a C1-C4 alkyl or C3-C8 cycloalkyl that is substituted with Each R C These are independently -CN or C3-C6 cycloalkyl groups. 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 the compound of formula (Ia): [ka] Or a pharmaceutically 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 the compound of formula (Ic): [ka] Or a pharmaceutically 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 the compound of formula (Ie): [ka] Or a pharmaceutically 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 the compound of formula (Ig): [ka] Or a pharmaceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ig) is 2S,3S,11bS.

[0133] In some embodiments, R 1 is R 2A That is the case.

[0134] In some embodiments, R 2A Each of these is either unsubstituted or one or more R A A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl substituted with, where R A This is as described above and below in this specification. In some embodiments, R 2A Each of these is either unsubstituted or one or more R AA C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocycline substituted with each R A R 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, halo-C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C2-C4 dialkylamino, 4-7 member heterocyclyl, -CN, -OH, and oxo. A If R exists, it is understood that they may be the same or different. In some embodiments, there are more than one R A If present, they are the same. In some embodiments, there are more than one R A If they exist, they are different.

[0135] In some embodiments, R 2A Each of these is either unsubstituted or has one, two, three, or four Rs. A It is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl that is substituted with R. 2A Each is either unsubstituted or one R A It is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl that is substituted with R. 2A These are either unsubstituted or two R's A It is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl that is substituted with R. 2A Each is either unsubstituted or one of the three R A These are C2-C4 alkenyls, C1-C6 alkyls, C3-C8 cycloalkyls, or 4-7 member heterocyclines that are substituted with a specific compound.

[0136] In some embodiments, R 2Ais either unsubstituted or one or more R A These are C2-C4 alkenyls that are substituted with R, where R A This is as described above and below in this specification.

[0137] In some embodiments, R 2A is either unsubstituted or one or more R A It is a methyl allyl substituted with [a specific compound].

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

[0139] In some embodiments, R 2A is either unsubstituted or one or more R A These are C1-C6 alkyl groups substituted with R, where R A This is as described above and below in this specification.

[0140] In some embodiments, R 2A is either unsubstituted or one or more R A These are C1-C6 alkyl groups that are substituted with [a specific compound].

[0141] In some embodiments, R 2A Each of these is either unsubstituted or one or more R A The substitutions are n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl, or n-pentyl.

[0142] In some implementations, each R AThe group is independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, halo-C1-C4 alkoxy, halo-C2-C4 dialkylamino, 4-7 member heterocyclyl, -CN, -OH, and oxo. In some embodiments, each R A The following are 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 Each R is either unsubstituted or 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, halo-C1-C4 alkoxy, halo-C2-C4 dialkylamino, 4-7 member heterocyclyl, -CN, -OH, and oxo. A The substitutions are n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl, or n-pentyl.

[0144] In some embodiments, R 2AThese include 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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 These are 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 either unsubstituted or has 1, 2, 3 or 4 R A These are C1-C4 alkyl groups that are substituted with R, and each R A R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2A is either unsubstituted or has one, two, or three R's. A These are C1-C4 alkyl groups that are substituted with R, and each R A R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2A R is a C2-C4 alkyl group. In some embodiments, R 2Ais -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 2A is a C1-C4 alkyl group substituted with one, two, or three fluoropolymers. In some embodiments, R 2A is a C1-C4 alkyl group substituted with one, two, or three groups independently selected from fluoro and C-amide groups. In some embodiments, R 2A is a C1-C4 alkyl group substituted with one, two, or three fluoropolymers. In some embodiments, R 2A These are -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CHF2, or -CH2CH2CF3. In some embodiments, R 2A This is either -CH2CH2CHF2 or -CH2CH2CF3.

[0146] In some embodiments, R 2A is either unsubstituted or one or more R A It is a C3-C8 cycloalkyl substituted with, where R A This is as described above and below in this specification.

[0147] In some embodiments, R 2A is either unsubstituted or one or more R A These are C3-C8 cycloalkyl groups that are substituted with [a specific compound].

[0148] In some embodiments, R 2A Each of these is either unsubstituted or one or more R A It is substituted with cyclobutyl, cyclopropyl, cyclopentyl, or cyclohexyl.

[0149] In some implementations, each R A The R is independently selected from the group consisting of halogens and C1-C4 alkyls. In some embodiments, each R A This is independently selected from the group consisting of fluoromethyl and trifluoromethyl compounds.

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

[0151] In some embodiments, R 2A is either unsubstituted or one or more R A It is a 4-7 member heterocyclyl substituted with, where R A This is as described above and below in this specification.

[0152] In some embodiments, R 2A Each of these is either unsubstituted or one or more R A It is substituted with azetidine-3-yl, oxetan-3-yl, or pyrrolidine-3-yl.

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

[0154] In some embodiments, R 2A Each of these is either unsubstituted or one or more R independently selected from the group consisting of methyl, 2,2,2-trifluoroethyl, and oxo. A It is substituted with azetidine-3-yl, oxetan-3-yl, or pyrrolidine-3-yl. In some embodiments, R 2AThese are oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl, or 1-methylazetidine-3-yl.

[0155] In some embodiments, R 2A R is methylallyl, n-butyl, ethyl, 2-ethylbutyl, n-propyl, propane-2-yl, 2-methylpropyl(isobutyl), methyl, n-pentyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine-3-yl, oxetane-3-yl, or pyrrolidine-3-yl; each is unsubstituted or one or more R 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 It has been replaced with.

[0156] In some embodiments, R 2AThis includes methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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- These are 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)pyrrolidine-3-yl, 1-methylazetidine-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 is 2,2-difluoropropyl. In some embodiments, R 2Ais 3,3,3-trifluoropropyl. In some embodiments, R 2A is ethyl. In some embodiments, R 2A R is 2-fluoroethyl. In some embodiments, 2A is 3-fluoropropyl. In some embodiments, R 2A is propane-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 R is 2-hydroxypropyl. In some embodiments, 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 R is 3-hydroxypropyl. In some embodiments, 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 R 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 R is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R 2A is 2-fluorocyclopentyl. In some embodiments, R 2A is 3,3-difluorocyclopentyl. In some embodiments, R 2A R is oxetane-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)pyrrolidine-3-yl. In some embodiments, R 2A is 1-methylazetidine-3-yl. In some embodiments, R 2A is 5,5,5-trifluoropentyl. In some embodiments, R 2A It is 4,4,4-trifluorobutyl.

[0158] In some embodiments, R 1 ha-(CH2) m -R 2B That is the case.

[0159] In some embodiments, the compound of formula (I) is the compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, where m and R 2B Each has the same definition as described herein and can be independently selected from any of the embodiments described above and below herein.

[0160] In some embodiments, the compound of formula (I) is a compound selected from formulas (IIIa), (IIIc), (IIIe), or (IIIg): [ka] or a pharmaceutically acceptable salt thereof, where m and R 2B Each has the same definition as described herein and can be independently selected from any of the embodiments described above and below herein.

[0161] In some embodiments, the compound of formula (I) is the compound of formula (IIIa). In some embodiments, the compound of formula (I) is the compound of formula (IIIc). In some embodiments, the compound of formula (I) is the compound of formula (IIIe). In some embodiments, the compound of formula (I) is the 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 Each of these is either unsubstituted or one or more R B It is an aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocycline that is substituted with R. B If R exists, it is understood that they may be the same or different. In some embodiments, there are more than one R B If present, they are the same. In some embodiments, there are more than one R B If they exist, they are different.

[0172] In some embodiments, R 2B Each of these is either unsubstituted or has one, two, three, or four Rs. B These are aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl compounds that are substituted with aryl.

[0173] In some embodiments, R 2B Each is either unsubstituted or one R B The substituted elements are aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl. In some embodiments, R 2B These are either unsubstituted or two R's BThe substituted elements are aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl. In some embodiments, R 2B Each is either unsubstituted or one of the three R B The substituted elements are aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl. In some embodiments, R 2B Each is either unsubstituted or one of the four R B These are aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl compounds that are substituted with aryl.

[0174] In some embodiments, R 2B is either unsubstituted or one or more R B It is an aryl that is substituted with, where R B This is as described above and below in this specification. In some embodiments, R 2B is either unsubstituted or one or more R B It is a phenyl compound that is substituted with [a specific compound].

[0175] In some implementations, each R B The elements are independently selected from the group consisting of halogens, halo C1-C4 alkyls, halo C1-C4 alkylsulfonyls, and -CN. In some embodiments, each R B The compound is independently selected from the group consisting of fluoromethyl, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN.

[0176] In some embodiments, R 2B R is either unsubstituted or one or more R independently selected from the group consisting of fluoromethyl, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN. B It is a phenyl substituted with R. In some embodiments, 2BThese are phenyl, 4-fluorophenyl, 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-((difluoromethyl)sulfonyl)phenyl, or 3-cyanophenyl.

[0177] In some embodiments, R 2B is either unsubstituted or one or more R B It is a C3-C8 cycloalkyl substituted with, where R B This is as described above and below in this specification.

[0178] In some embodiments, R 2B Each of these is either unsubstituted or one or more R B The substituted elements are cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, or bicyclo[1.1.1]pentan-1-yl.

[0179] In some implementations, each R B The following are independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halo-C1-C4 alkyl, and -OH.

[0180] In some implementations, each R B The compound is independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CH2CN, fluoro, difluoromethyl, trifluoromethyl, and -OH.

[0181] In some embodiments, R 2B Each of these is either unsubstituted or one or more R independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CH2CN, fluoro, difluoromethyl, trifluoromethyl, and -OH. B The substituted elements are cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, or bicyclo[1.1.1]pentan-1-yl.

[0182] In some embodiments, R 2B These are 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 either unsubstituted or has one or two R B It is a C3-C6 cycloalkyl substituted with each R B R is independently selected from the group consisting of fluoro, CN, -CH2CN, and -OH. In some embodiments, R 2B These are cyclopropyl, cyclobutyl, or cyclopentyl, which are either unsubstituted or substituted with one or two fluoropolymers, respectively.

[0184] In some embodiments, R 2B is either unsubstituted or one or more R B It is a 5-10 member heteroaryl substituted with, where R B This is as described above and below in this specification.

[0185] In some embodiments, R 2B Each of these is either unsubstituted or one or more R BThese are substituted with 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,3-oxazole-4-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazol-5-yl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, or thiazole-4-yl.

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

[0187] In some embodiments, R 2B Each is either unsubstituted or one or more R selected independently from methyl and -CN. B Substituted with 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,3-oxazole-4-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazol-5-yl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, or thiazole-4-yl. In some embodiments, R 2B These are imidazole-1-yl, 5-methyl-1,3-oxazole-2-yl, 5-cyanofuran-2-yl, isoxazole-3-yl, oxazole-4-yl, 6-cyanopyridine-2-yl, 5-cyanopyridine-2-yl, 1,2,4-oxadiazole-5-yl, pyridine-3-yl, pyrimidine-2-yl, isoxazole-5-yl, 1H-imidazole-2-yl, or 1H-tetrazole-5-yl.

[0188] In some embodiments, R 2B is either unsubstituted or one or more RB It is a 4-7 member heterocyclyl substituted with, where R B This is as described above and below in this specification.

[0189] In some embodiments, R 2B is either unsubstituted or one or more R B These are oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidine-1-yl, piperidine-4-yl, tetrahydro-2H-pyran-4-yl, azetidine-3-yl, 1,4-dioxepan-6-yl, or tetrahydro-2H-thiopyran-4-yl, which are substituted with .

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

[0191] In some embodiments, R 2B Each of these is either unsubstituted or one or more R independently selected from the group consisting of methyl, fluoro, oxo, and -CN. B These are substituted with oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidine-1-yl, piperidine-4-yl, tetrahydro-2H-pyran-4-yl, azetidine-3-yl, 1,4-dioxepan-6-yl, or tetrahydro-2H-thiopyran-4-yl. In some embodiments, R 2B These are 3-fluorooxetan-3-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 3,3-difluoropyrrolidine-1-yl, 1-cyanopiperidine-4-yl, 1-methylazetidine-3-yl, 6-fluoro-1,4-dioxepane-6-yl, or 1,1-dioxidetetrahydro-2H-thiopyran-4-yl.

[0192] In some embodiments, R 2B A is a 4-5 member monocyclic heterocyclil having one ring-forming heteroatom selected from oxygen and sulfur, where the 4-5 member monocyclic heterocyclil is unsubstituted or has one or more R B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B This is a C3-C4 4-5 member monocyclic heterocyclil having one ring-forming oxygen atom, where the 4-5 member monocyclic heterocyclil is unsubstituted or has one or two R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B R is a 4-5 member monocyclic heterocyclyl having one ring-forming oxygen, where the 4-5 member monocyclic heterocyclyl is unsubstituted or substituted with one or two fluorocarbons. In some embodiments, R 2B A is a C3-C4 4-5 member monocyclic heterocycline having one ring-forming heteroatom selected from oxygen and sulfur, where the C3-C4 4-5 member monocyclic heterocycline is unsubstituted or has one or more R B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B This is a 4-5 member monocyclic heterocyclyl having one ring-forming oxygen atom, where the 4-5 member monocyclic heterocyclyl is unsubstituted or has one or two R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B This is a C3-C4 4-5 member monocyclic heterocycline having one ring-forming oxygen, where the C3-C4 4-5 member monocyclic heterocycline is unsubstituted or has one or two R atoms. B It is replaced by each R BR is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B R is a 4-5 member monocyclic heterocyclyl having one ring-forming oxygen, where the 4-5 member monocyclic heterocyclyl is unsubstituted or substituted with one or two fluorocarbons. In some embodiments, R 2B This is a C3-C4 4-5 member monocyclic heterocycline having one ring-forming oxygen, where the C3-C4 4-5 member monocyclic heterocycline is unsubstituted or substituted with one or two fluorocarbons. In some embodiments, R 2B These are oxetan-3-yl or oxolan-3-yl, which are either unsubstituted or substituted with one fluoropolymer, respectively.

[0193] In some embodiments, R 2B is either unsubstituted or one or more R B It is a heterocycline that is substituted with each R B R is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R 2B A 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 has one or more R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R 2B A 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 atoms. B It is replaced by each R BR is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R 2B A 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 has one or more R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro, chloro, -CN, -CHF2, -CF3, -OH, and -OCH3. In some embodiments, R 2B This is a 4-5 member monocyclic heterocyclyl having one ring-forming oxygen atom, where the 4-5 member monocyclic heterocyclyl is unsubstituted or has one or two R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B It is a C2-C atom having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur. 12 These are monocyclic, bicyclic, or tricyclic heterocyclyl ring systems with 3, 4, 5, 6, 7, 8, 9, 10, or up to 13 members, where the heterocyclyl is unsubstituted or has one or more R groups. B It is replaced by each R B R is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R 2B A 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 has one or more R atoms. B It is replaced by each R BR is independently selected from the group consisting of fluoro, chloro, bromo, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R 2B It is a C2-C atom having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen, and sulfur. 10 A bicyclic heterocyclyl ring system of 4, 5, 6, 7, 8, 9, 10, or 11 members, where the heterocyclyl is unsubstituted or has one or more R B It is replaced by each R B R is independently selected from the group consisting of fluoro, chloro, -CN, -CHF2, -CF3, -OH, and -OCH3. In some embodiments, R 2B A is a C3-C4 4-5 member monocyclic heterocycline having one ring-forming heteroatom selected from oxygen and sulfur, where the C3-C4 4-5 member monocyclic heterocycline is unsubstituted or has one or more R B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B This is a C3-C4 4-5 member monocyclic heterocycline having one ring-forming oxygen, where the C3-C4 4-5 member monocyclic heterocycline is unsubstituted or has one or two R atoms. B It is replaced by each R B R is independently selected from the group consisting of fluoro and -OH. In some embodiments, R 2B These are oxetan-3-yl or oxolan-3-yl, which are either unsubstituted or substituted with one fluoropolymer, respectively.

[0194] In some embodiments, R 2BThese include 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,4-dioxepan-6-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazol-5-yl, azetidine-3-yl, bicyclo[1.1.1]pentan-1-yl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, oxazole-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydro These are furan-3-yl), phenyl, piperidine-4-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, pyrrolidine-1-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, or thiazole-4-yl; each is either unsubstituted or substituted with one or more groups independently selected from the group consisting of -CH2CN, -CN, difluoromethyl, ethyl, fluoro, methyl, methylsulfonyl, methylsulfonyloxy, -OH, oxo, phenyl, and trifluoromethyl.

[0195] In some embodiments, R 2BThese include 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-oxadiazole-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanopiperidine-4-yl, 1-fluorocyclobutyl, 1-fluorocyclopropyl, 1H-imidazole-2-yl, 1H-tetrazole-5-yl, 1-hydroxycyclobutyl, 1-methylazetidine-3-yl, 2-ethylcyclopropyl, 2-fluorocyclopentyl, 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-yl, 3,3-difluorocyclopentyl, 3,3-difluoropyrrolidine-1-yl, and 3-fluorobicyclo[1.1.1]pentane -1-yl, 3-fluorooxetane-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-cyanopyridine-2-yl, 5-methyl-1,3-oxazole-2-yl, 6-cyanopyridine-2 -yl, 6-fluoro-1,4-dioxepant-6-yl, cyclobutyl, cyclopropyl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, oxazole-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), phenyl, pyridine-3-yl, pyrimidine-2-yl, 3-cyanophenyl, or 2,2-difluorocyclopropyl.

[0196] In some embodiments, R 2B is 1-((methylsulfonyl)oxy)cyclopropyl. In some embodiments, R 2B R is 1-(cyanomethyl)cyclopropyl. In some embodiments, R 2BR is 1-(difluoromethyl)cyclopropyl. In some embodiments, R 2B R is 1-(methylsulfonyl)cyclopropyl. In some embodiments, R 2B R is 1-(trifluoromethyl)cyclopentyl. In some embodiments, R 2B is 1,1-dioxidetetrahydro-2H-thiopyran-4-yl. In some embodiments, R 2B is 1,2,4-oxadiazole-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-cyanopiperidine-4-yl. In some embodiments, R 2B R is 1-fluorocyclobutyl. In some embodiments, R 2B R is 1-fluorocyclopropyl. In some embodiments, R 2B is 1H-imidazole-2-yl. In some embodiments, R 2B is 1H-tetrazole-5-yl. In some embodiments, R 2B R is 1-hydroxycyclobutyl. In some embodiments, R 2B is 1-methylazetidine-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-methylthiazole-4-yl. In some embodiments, R 2B R is 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl. In some embodiments, R 2B is 3,3-difluorocyclopentyl. In some embodiments, R 2B is 3,3-difluoropyrrolidine-1-yl. In some embodiments, R 2B is 3-fluorobicyclo[1.1.1]pentan-1-yl. In some embodiments, R 2BR is 3-fluorooxetane-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 R is 4-((difluoromethyl)sulfonyl)phenyl. In some embodiments, R 2B R is 4-(trifluoromethyl)phenyl. In some embodiments, R 2B is 4,4-difluoro-1-hydroxycyclohexyl. In some embodiments, R 2B R is 4-fluorophenyl. In some embodiments, R 2B is 5-cyanofuran-2-yl. In some embodiments, R 2B is 5-cyanopyridine-2-yl. In some embodiments, R 2B is 5-methyl-1,3-oxazol-2-yl. In some embodiments, R 2B is 6-cyanopyridine-2-yl. In some embodiments, R 2B is 6-fluoro-1,4-dioxepane-6-yl. In some embodiments, R 2B is cyclobutyl. In some embodiments, R 2B is cyclopropyl. In some embodiments, R 2B is imidazole-1-yl. In some embodiments, R 2B isoxazole-3-yl. In some embodiments, R 2B is isoxazole-4-yl. In some embodiments, R 2B is isoxazole-5-yl. In some embodiments, R 2B R is oxazole-4-yl. In some embodiments, R 2B R is oxetane-2-yl. In some embodiments, R 2B R is oxetane-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 pyridine-3-yl. In some embodiments, R 2B is pyrimidine-2-yl. In some embodiments, R 2B R is 3-cyanophenyl. In some embodiments, R 2B It is 2,2-difluorocyclopropyl.

[0197] In some embodiments, R 1 ha-(CH2) n -OR 2C That is the case.

[0198] In some embodiments, the compound is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, where n and R 2C Each has the same definition as described herein and can be independently selected from any of the embodiments described above and below herein.

[0199] In some embodiments, the compound is selected from formula (Va), formula (Vc), formula (Ve), or formula (Vg): [ka] [ka] or a pharmaceutically acceptable salt thereof, where n and R 2C Each has the same definition as described herein and can be independently selected from any of the embodiments described above and below herein.

[0200] In some embodiments, the compound of formula (I) is the compound of formula (Va). In some embodiments, the compound of formula (I) is the compound of formula (Vc). In some embodiments, the compound of formula (I) is the compound of formula (Ve). In some embodiments, the compound of formula (I) is the 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 Each of these is either unsubstituted or one or more R C It is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocycline that is substituted with R. C If R exists, it is understood that they may be the same or different. In some embodiments, there are more than one R C If present, they are the same. In some embodiments, there are more than one R C If they exist, they are different.

[0207] In some embodiments, R 2C Each of these is either unsubstituted or has one, two, three, or four Rs. C These are C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocyclyl molecules substituted with R. In some embodiments, R 2C Each is either unsubstituted or one R CThese are C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocyclyl molecules substituted with R. In some embodiments, R 2C These are either unsubstituted or two R's C These are C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocyclyl molecules substituted with R. In some embodiments, R 2C Each is either unsubstituted or one of the three R C These are C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocyclyl molecules substituted with R. In some embodiments, R 2C Each is either unsubstituted or one of the four R C These are C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or 4-7 member heterocyclyl molecules that are substituted with a different compound.

[0208] In some embodiments, R 2C is either unsubstituted or one or more R C These are C1-C4 alkyl groups that are substituted with R, where R C This is as described above and below in this specification. In some embodiments, R 2C Each of these is either unsubstituted or one or more R C It is substituted with ethyl, isopropyl, or methyl.

[0209] In some implementations, each R C These are independently -CN or C3-C6 cycloalkyl. In some embodiments, each R C The compound is independently selected from the group consisting of cyclopropyl and -CN.

[0210] In some embodiments, R 2C Each of these is either unsubstituted or one or more R compounds independently selected from the group consisting of cyclopropyl and -CN. C It is substituted with ethyl, isopropyl, or methyl. In some embodiments, R2C These are methyl, cyano(cyclopropyl)methyl, 2-cyanopropan-2-yl, cyanomethyl, or 1-cyanoethyl.

[0211] In some embodiments, R 2C is either unsubstituted or one or more R C It is a C3-C8 cycloalkyl substituted with, where R C This is as described above and below in this specification.

[0212] In some embodiments, R 2C is either unsubstituted or one or more R C It is cyclobutyl substituted with [a specific compound].

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

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

[0215] In some embodiments, R 2C is either unsubstituted or one or more R C It is a 4-7 member heterocyclyl substituted with, where R C This is as described above and below in this specification.

[0216] In some embodiments, R 2C Each of these is either unsubstituted or one or more R C It is oxycetan-3-yl or tetrahydro-2H-pyran-4-yl, which is substituted with R. In some embodiments, C is -CN.

[0217] In some embodiments, R 2CThese are oxetan-3-yl or tetrahydro-2H-pyran-4-yl, which are either unsubstituted or substituted with one or more -CNs. In some embodiments, R 2C These are oxetan-3-yl or 4-cyanotetrahydro-2H-pyran-4-yl.

[0218] In some embodiments, R 2C Each of these has one, two, three, or four R's. C It is a C1-C4 alkyl or C3-C5 cycloalkyl that is substituted with, and each R C Independently, R is either -CN or C3-C6 cycloalkyl. In some embodiments, R 2C Each of these is one or more R C It is a C1-C4 alkyl or C3-C5 cycloalkyl that is substituted with, and each R C Independently, R is either -CN or C3-C6 cycloalkyl. In some embodiments, R 2C is a cyclobutyl substituted with one -CN. In some embodiments, R 2C is a C1-C3 alkyl group substituted with one -CN and one C3-C5 cycloalkyl group. In some embodiments, R 2C is a C1-C2 alkyl group substituted with one -CN and one C3-C4 cycloalkyl group. In some embodiments, R 2C is a C1-C2 alkyl group substituted with one -CN and one cyclopropyl. In some embodiments, R 2C These are C1-C3 alkyl groups substituted with one -CN.

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

[0220] In some embodiments, R2C These are 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-cyanopropane-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 R is oxetane-3-yl. In some embodiments, R 2C It is 4-cyanotetrahydro-2H-pyran-4-yl.

[0222] R 1 base In some embodiments, R 1These include methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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- (Iyl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl, 1-methylazetidine-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-Oxadiazole-5-yl)methyl, (1-Cyanocyclobutyl)methyl, (1-Cyanocyclopropyl)methyl, (1-Cyanopiperidine-4-yl)methyl, (1-Fluorocyclobutyl)methyl, (1-Fluorocyclopropyl)methyl, (1H-Imidazole-2-yl)methyl, (1H-Tetazol-5-yl)methyl, (1-Hydroxycyclobutyl)methyl, (1-Methylazetidine-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-cyanopyridine-2-yl)methyl, (5-methyl-1,3-oxazole-2-yl)methyl, (6-cyanopyridine-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazole-3 -yl)methyl, (isoxazole-5-yl)methyl, (oxazole-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridine-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-(1H-imidazole-1-yl)ethyl, 2-(3,3-difluoropyrrolidine-1-yl)ethyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl , cyclopropylmethyl, pyrimidine-2-ylmethyl, (2-cyanopropane-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-(oxetane-3-yloxy)ethyl, 2-methoxyethyl, 5,5,5-trifluoropentyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, 4,4,It is 4-trifluorobutyl or (2,2-difluorocyclopropyl)methyl.

[0223] In some embodiments, R 1 This includes methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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- These are 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)pyrrolidine-3-yl, 1-methylazetidine-3-yl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl.

[0224] In some embodiments, R 1(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-oxadiazole-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl (Pyropropyl)methyl, (1-cyanopiperidine-4-yl)methyl, (1-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazole-2-yl)methyl, (1H-tetrazole-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylazetidine-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-cyanopyridine-2-yl)methyl, (5-methyl-1,3-oxazole-2-yl)methyl, (6-cyanopyridine-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazole-3-yl)methyl, (isoxazole-5-yl)methyl, (oxazole-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridine-3-yl)methyl, 2-(1 These are (-cyanocyclopropyl)ethyl, 2-(1H-imidazole-1-yl)ethyl, 2-(3,3-difluoropyrrolidine-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), pyrimidine-2-ylmethyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, or (2,2-difluorocyclopropyl)methyl.

[0225] In some embodiments, R 1 These are (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-(oxetane-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 is 2,2-difluoropropyl. In some embodiments, R 1 is 3,3,3-trifluoropropyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 R is 2-fluoroethyl. In some embodiments, 1 is 3-fluoropropyl. In some embodiments, R 1 is propane-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 R is 2-hydroxypropyl. In some embodiments, 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 R is 3-hydroxypropyl. In some embodiments, 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 R 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 R is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R 1 is 2-fluorocyclopentyl. In some embodiments, R 1 is 3,3-difluorocyclopentyl. In some embodiments, R 1 R is oxetane-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)pyrrolidine-3-yl. In some embodiments, R 1 is 1-methylazetidine-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-dioxidetetrahydro-2H-thiopyran-4-yl)methyl. In some embodiments, R 1 is (1,2,4-oxadiazole-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-cyanopiperidine-4-yl)methyl. In some embodiments, R 1 R is (1-fluorocyclobutyl)methyl. In some embodiments, R 1 is (1-fluorocyclopropyl)methyl. In some embodiments, R 1 is (1H-imidazole-2-yl)methyl. In some embodiments, R 1 is (1H-tetrazole-5-yl)methyl. In some embodiments, R 1 is (1-hydroxycyclobutyl)methyl. In some embodiments, R 1 is (1-methylazetidine-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 R 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-cyanopyridine-2-yl)methyl. In some embodiments, R 1 is (5-methyl-1,3-oxazol-2-yl)methyl. In some embodiments, R 1 is (6-cyanopyridine-2-yl)methyl. In some embodiments, R 1 is (6-fluoro-1,4-dioxepand-6-yl)methyl. In some embodiments, R 1 is (isoxazole-3-yl)methyl. In some embodiments, R 1 is (isoxazole-5-yl)methyl. In some embodiments, R 1 is (oxazole-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 (pyridine-3-yl)methyl. In some embodiments, R 1 is 2-(1-cyanocyclopropyl)ethyl. In some embodiments, R 1 is 2-(1H-imidazole-1-yl)ethyl. In some embodiments, R 1 is 2-(3,3-difluoropyrrolidine-1-yl)ethyl. In some embodiments, R 1 is 3-fluorobenzyl. In some embodiments, R 1 R is 4-((difluoromethyl)sulfonyl)benzyl. In some embodiments, R 1 R 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 R is pyrimidine-2-ylmethyl. In some embodiments, R 1 (2-cyanopropan-2-yl)oxy)ethyl is used in some embodiments. 1 is 2-((4-cyanotetrahydro-2H-pyran-4-yl)oxy)ethyl. In some embodiments, R 1 R is 2-(1-cyanocyclobutoxy)ethyl. In some embodiments, R 1 is 2-(1-cyanoethoxy)ethyl. In some embodiments, R 1 R is 2-(cyano(cyclopropyl)methoxy)ethyl. In some embodiments, R 1 is 2-(cyanomethoxy)ethyl. In some embodiments, R 1 R is 2-(oxetane-3-yloxy)ethyl. In some embodiments, R 1 R is 2-methoxyethyl. In some embodiments, R 1 is 5,5,5-trifluoropentyl. In some embodiments, R 1 is 3-cyanobenzyl. In some embodiments, R 1 is 4-fluorophenethyl. In some embodiments, R 1 R is cyclobutylmethyl. In some embodiments, R 1 is 4,4,4-trifluorobutyl. In some embodiments, R 1 It is (2,2-difluorocyclopropyl)methyl. 1 If the group has a chiral carbon, it is understood that this chiral carbon may be (R) or (S). In some embodiments, R 1 If the group has a chiral carbon, this chiral carbon is (R). In some embodiments, R 1If the group has a chiral carbon, this chiral carbon is (S). Furthermore, R 1 When a group has two chiral carbons, it is understood that these chiral carbons may independently be (R) or (S). In some embodiments, R 1 If the group has two chiral carbons, both chiral carbons are (R). In some embodiments, R 1 If the group has two chiral carbons, both chiral carbons are (S). In some embodiments, R 1 If a group has two chiral carbon atoms, one chiral carbon atom is (R) and the other chiral carbon atom is (S).

[0227] In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CD3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CD2CD3. In some embodiments, R 1 These are -CH2CH2OCH3, -CH2CH(OH)CH3, -CH2CH(OH)CF3, -CH2CF3, -CH2CF2H, -CH2CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, or -CH(CH3)(CF3). In some embodiments, R 1 These are -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] That is the case.

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

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

[0231] Some embodiments include all combinations of one or more compounds selected from the following groups shown in Table A and their pharmaceutically acceptable salts. [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 compound, method, composition, or use of formula (I) described herein may also include, as necessary, the limitation that the compound of formula (I) is not one or more compounds selected from the group consisting of compounds 4-33, 4-34, 4-35, 4-37, 4-95, 4-96, 4-97, 4-100, 4-101, 4-102, 4-103, 4-104, 4-105, 4-106, 4-107, 4-108, 4-109, 4-110, 4-111, 4-112, 4-113, and 5-4.

[0233] Some embodiments provide compounds from Table 10A and / or Table 10B, or pharmaceutically acceptable salts thereof. Some embodiments provide structures: [ka] [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0234] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0235] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0236] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0237] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0238] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0239] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0240] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0241] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0242] Some embodiments have the following structure: [ka] The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0243] A useful intermediate in the preparation of the compound of formula (I). Certain intermediates described above and below in this specification are novel and useful in the preparation of compounds of formula (I).

[0244] In some embodiments, the compounds are 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-one (compound 1-B) and 9-(benzyloxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C). It is selected from the group consisting of 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]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-2-one (compound 1-B(3R,11bR)), or a salt thereof. In some embodiments, the compound is [ka] That is the case.

[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]isoquinoline-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]isoquinoline-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] That is the case.

[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)), ( It is selected from the group consisting of (2S,3R,11bR)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D(2S,3R,11bR)) and (2R,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(2R,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. In some embodiments, the compound is [ka] That is the case.

[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]isoquinoline-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]isoquinoline-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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3R,11bR)), or a salt thereof. In some embodiments, the compound is [ka] That is the case.

[0249] For clarity, certain features described in the context of separate embodiments can also be provided in combination within a single embodiment. Conversely, various features described in the context of a single embodiment can also be provided separately or in any preferred subcombination.

[0250] Pharmaceutical compositions, formulations, and dosage forms This disclosure further provides pharmaceutical products such as pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0251] This disclosure further provides pharmaceutical compositions comprising one of the compounds described herein (e.g., compounds of formula (I), including specific compounds described herein) that are VMAT2 inhibitors, for use in the methods described herein, such as for treating hyperactivity disorder, and at least one pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic and inert material or raw material that does not interfere with the activity of the active pharmaceutical ingredient, and the excipient may also be called a carrier. The formulation methods and excipients described herein are illustrative and not limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical field, for example, 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 This is described in Ed. Mack Pub. Co., Easton, PA (2005).

[0252] The composition may be formulated as pills, capsules, granules, or tablets containing, in addition to the VMAT2 inhibitor, a diluent, a dispersant and surfactant, a binder, and a lubricant. Those skilled in the art will know how to appropriately formulate such a composition as disclosed in Remington above. VMAT2 inhibitors can be further formulated according to established practices.

[0253] Methods of administration include systemic administration of the VMAT2 inhibitor described herein, preferably in the form of the pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions.

[0254] Pharmaceutical preparations for oral administration can be obtained by any preferred method, typically by uniformly mixing a compound(s) in the required proportion with a liquid or pulverized solid carrier or both; then, if necessary, processing the mixture after adding a suitable adjuvant; and, if desired, forming the resulting mixture into a desired shape to obtain tablets or sugar-coated tablet cores.

[0255] Conventional additives such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants, and disintegrants can be used in orally administered tablets and capsules. Orally administered liquid preparations may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral preparations may be in the form of a dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Parenteral dosage forms may be prepared by dissolving the compound in a suitable liquid vehicle and filtering the solution before lyophilization, or simply by filling and sealing it in a suitable vial or ampoule.

[0256] Some embodiments provide a method for preparing a pharmaceutical composition, comprising the step of mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

[0257] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays, each containing, in addition to the active pharmaceutical ingredient, a carrier known to be suitable in the art.

[0258] When preparing a pharmaceutical composition, the active pharmaceutical ingredient (API) is typically mixed with an additive, diluted by the additive, or encapsulated in a carrier such as a capsule, sachet, paper, or other container. When the additive acts as a diluent, it can be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the API. Thus, the composition can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

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

[0260] To prepare the suppositories, a mixture of fatty acid glycerides or a low-melting-point wax such as cocoa butter is first melted, and the active ingredient is homogeneously dispersed in it by stirring or other means. Then, the molten homogeneous mixture is poured into a mold of a suitable size and cooled, thereby solidifying.

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

[0262] The pharmaceutical composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain compounding agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the pharmaceutical composition may be in powder form for composition with a suitable vehicle before use, such as sterile pyrogen-free water, obtained by sterile isolation of a sterile solid or by lyophilization from a solution.

[0263] Pharmaceutical compositions may be formulated as aqueous solutions, aqueous alcohol solutions, solid suspensions, emulsions, liposome suspensions, or freeze-dried powders for reconstitution. Such pharmaceutical compositions may be administered directly or as admixtures for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and infusion.

[0264] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners as desired.

[0265] Aqueous suspensions suitable for oral use can be prepared by dispersing a finely powdered active pharmaceutical ingredient in water containing a viscous material.

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

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

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

[0269] Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, or a mixed powder of compounds in a suitable powder base such as lactose, starch, or a starch derivative. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example, in capsules or cartridges of gelatin, or in blister packs in which the powder can be administered using an inhaler.

[0270] Compounds of formula (I), or pharmaceutically acceptable salts thereof, may also be administered via a rapidly dissolving or slowly releasing composition, wherein the composition comprises a biodegradable rapidly dissolving carrier or a slowly releasing carrier.

[0271] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate amount of the active pharmaceutical ingredient. The unit dosage form may be a packaged preparation, and the packaging may contain discrete quantities of the preparation, such as individually packaged tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or any of these in an 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 formulation for intravenous administration.

[0272] The composition may be formulated in unit dosage forms, each dose containing the active pharmaceutical ingredient or an equivalent mass of the active pharmaceutical ingredient. The term “unit dosage form” refers to a physically discontinuous unit of a formulation suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active ingredient, calculated to produce the desired therapeutic effect, together with suitable excipients as described herein.

[0273] Liquid forms containing the active pharmaceutical ingredient, which may be incorporated for oral or injectable administration, include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with added edible oil.

[0274] The pharmaceutical compositions described herein may be sterilized by conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for ready use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier before administration.

[0275] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable additives as described herein. In some embodiments, compositions are administered orally or via nasal respiratory routes for local or systemic effects. Compositions may be sprayed using an inert gas. Sprayed solutions may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive airway pressure (PAP) respirator. Solutions, suspensions, 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 that may contain one or more unit dosage forms containing the active pharmaceutical ingredient, if desired. The pack may include metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for use for administration. The pack or dispenser may also be accompanied by a cautionary note associated with the container in a form determined by the government agency that regulates the manufacture, use or sale of the drug, and such cautionary note reflects agency approval of the drug in human or veterinary administration form. Such cautionary notes may be, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an approved product insert. Compositions that may contain the compounds described herein, formulated in a suitable pharmaceutical carrier, may be prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

[0277] To prepare solid compositions such as tablets, the active pharmaceutical ingredient (API) can be mixed with additives to form a solid pre-formulation composition containing a homogeneous mixture of components. When these pre-formulation compositions are referred to as homogeneous, the API is typically evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets and capsules.

[0278] Kits are provided that contain a unit dose of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, typically in oral or injectable doses. Such kits may include a container containing the unit dose, an informational leaflet describing the use of the drug and its associated benefits in treating the condition of interest, and, if necessary, an instrument or device for delivering the composition.

[0279] The compounds described herein, or pharmaceutically acceptable salts thereof, may be effective over a wide range of dosages and are generally administered in therapeutically effective doses. However, it should be understood that the actual amount of compound administered will usually be determined by a physician in accordance with relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual subject, and the severity of the subject's symptoms.

[0280] The amount of compound or composition administered to a subject will vary depending on what is being administered, the purpose of administration (e.g., protection or therapy), the subject's condition, and the method of administration. For therapeutic purposes, a composition may be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially halt the symptoms and / or pathology of the disease and its complications. The effective therapeutic dose will be determined by the attending physician's judgment, taking into account the medical condition being treated, as well as factors such as the severity of the disease, the subject's age, weight, and overall health.

[0281] The desired dose may, conveniently, be presented as a single dose or as divided doses administered at appropriate intervals, such as two, three, four or more subdose doses per day. The subdose itself may be further divided into, for example, several discrete, loosely spaced doses. The daily dose may be divided into several doses, such as two, three, or four, especially when a relatively large dose is administered as appropriate. Where appropriate, it may be necessary to deviate from the prescribed daily dose, depending on the individual's behavior.

[0282] It will be apparent to those skilled in the art that the dosage forms described herein may include the compounds described herein or pharmaceutically acceptable salts thereof.

[0283] preparation As used herein, “Preparation” is the product of a process used to produce or isolate the compound as disclosed and described herein, wherein 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, “chemical entity” as defined in the context of “preparation” refers to the compound as disclosed and described herein, and at least one other component in addition to the compound. For example, the chemical entity may be a cocrystal or salt of the compound as disclosed and described herein.

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

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

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

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

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

[0290] How to use The compounds of formula (I) as disclosed and described herein are inhibitors of VMAT2. Accordingly, this disclosure includes methods for inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing the expression of VMAT2) by contacting VMAT2 with the compounds as disclosed and described herein or pharmaceutically acceptable salts thereof. In some embodiments, contact may occur in vitro, such as when VMAT2 is located in cells outside of a purified preparation or living organism (e.g., in a tissue sample or cell preparation). In some embodiments, contact may occur in vivo, such as when VMAT2 is located in a living organism.

[0291] The VMAT2 inhibitors described herein can reduce monoamine levels in the central nervous system. Accordingly, this disclosure includes a method for reducing monoamine levels in the central nervous system of a subject, comprising the step of administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to reduce the monoamine level compared to a pre-administration level.

[0292] VMAT2 inhibitors as disclosed and described herein are considered to have utility across a wide range of therapeutic applications and may be used to treat or prevent a variety of disorders caused by or related to inhibition of human vesicular monoamine transporter isoform 2. These disorders include neurological and psychiatric disorders, such as hyperactivity disorder, schizophrenia, and mood disorders. Compounds of formula (I), or pharmaceutically acceptable salts thereof, may be used in any of the therapeutic methods disclosed and described herein. Furthermore, (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 5-A(3R,11bR)) or a pharmaceutically acceptable salt thereof, or (3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 5-A(3S,11bS)) or a pharmaceutically acceptable salt thereof, or isotopic variants of compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may be used in any of the therapeutic methods disclosed and described herein. In some embodiments, isotopic variants of compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may have deutherium at three or more positions in a proportional isotopic distribution that differs from that typically found in nature. In some embodiments, compound 5-A(3R,11bR) or compound 5-A(3S,11bS) may have deutherium incorporation at three or more positions with at least 95%, 97%, 99%, 99.5%, or 99.9%, or at three or more positions within the range defined by any of the aforementioned figures.

[0293] Accordingly, various embodiments as disclosed herein provide a method for treating or preventing a neurological and / or psychiatric disorder or condition in a subject requiring such treatment, comprising administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof. The neurological and / or psychiatric disorder or condition may be, for example, hyperactivity 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 (e.g., restricted and repetitive behaviors associated with autism spectrum disorder (ASD)), Rett syndrome, or acanthocyte chorea.

[0294] In various other embodiments disclosed herein, methods are provided for treating or preventing vesicular monoamine transporter-2 (VMAT2) disease or disorder in subjects requiring such treatment, comprising administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof. VMAT2 disease or disorder may be, for example, ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jawbone disorders; dyskinesia; dystonia; endocrine, nutritional or metabolic disorders; epilepsy; habitual or impulsivity 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 motor disorders; neurological or psychiatric disorders or disorders; nervous system or motor dysfunction; Parkinson's disease / parkinsonism; childhood-onset behavioral and affective disorders; pervasive developmental disorders; and substance abuse or addiction disorders.

[0295] Accordingly, various embodiments as disclosed herein provide a method for treating or preventing hyperactive movement disorders in subjects requiring such treatment, comprising administering to subjects requiring such treatment a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the hyperactive movement disorder is tardive dyskinesia, Tourette syndrome, Huntington's disease, chorea associated with Huntington's disease, or tics. In other embodiments, the hyperactive movement disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless legs syndrome, or tremor.

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

[0297] In some embodiments as disclosed herein, a method is provided for treating or preventing schizophrenia or schizoaffective disorder in a subject requiring such treatment, comprising administering to the subject requiring such treatment a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the neurological or psychiatric disorder or disorder is hyperactivity disorder.

[0299] In some embodiments, hyperactivity disorder is tardive dyskinesia.

[0300] In some embodiments, hyperactivity disorder is Tourette's syndrome.

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

[0302] In some embodiments, hyperactivity disorder manifests as tics.

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

[0304] In some embodiments, hyperactive movement disorders include ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless legs syndrome, or tremor.

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

[0306] In some embodiments, the neurological or psychiatric disorder or disorder is obsessive-compulsive and impulsive-compulsive disorder in partially and non-responsive (or completely resistant) individuals with obsessive-compulsive disorder (OCD). In some embodiments, the neurological or psychiatric disorder or disorder is obsessive-compulsive and impulsive-compulsive disorder in partially and non-responsive (or completely resistant) individuals 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 in conjunction with primary therapy, which is treatment with antidepressants.

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

[0308] In some embodiments, a VMAT2 inhibitor of formula (I), or a pharmaceutically 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 bulbar spinal muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disorders, and hereditary spastic paraplegia; Chorea, for example, benign hereditary chorea, chorea, chorea associated with mitochondrial disease / cause, chorea associated with Wilson's disease, chorea during pregnancy, acanthocyaninous chorea, drug-induced chorea, unilateral ballism, rheumatic / sydenham chorea, and thyroid-toxic / hyperthyroid chorea; Congenital malformations, deformities, or abnormalities, such as Angelman syndrome, congenital neurological disorders, Aicardi syndrome, neurofibromatosis, congenital facial nerve dysplasia, Moebius syndrome II, Cockayne syndrome, Sjögren-Larsson syndrome, Laurence Moon-Burdett-Beadle syndrome, Fragile X syndrome, and Prader-Willi syndrome; Dementia, including 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 jawbone, including glossodynia / burning mouth syndrome and temporomandibular joint disorders; Dyskinesia, for example, pharyngeal dyskinesia, dyskinesia, neonatal dyskinesia, esophageal dyskinesia, levodopa-induced dyskinesia, paroxysmal exercise-induced dyskinesia, paroxysmal non-exercise-induced dyskinesia, and respiratory dyskinesia; Dystonia, for example, blepharospasm, buccoglossal syndrome, drug-induced acute dystonia, dystonia, early-onset primary dystonia, hereditary torsional dystonia, hand dystonia / writer's cramp, idiopathic nonfamilial dystonia, idiopathic orofacial dystonia / Meige's disease, laryngeal dystonia, mangooral 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 seizures, epilepsy, congenital epilepsy, laforamyoclonic epilepsy, severe myoclonic epilepsy of infants, and seizures; Habitual and impulsivity disorders, such as binge eating disorder, kleptomania, impulse control disorder, trichotillomania, intermittent explosive disorder, pathological gambling, and pyromania; Huntington's disease or related disorders, e.g., Huntington's disease, Huntington's disease-like syndromes 1-3, Huntington's chorea, and X-linked McLeod neuroacanthoplasty syndrome; Mood or psychotic disorders, such as schizophrenia, psychosis, mania, bipolar disorder, depression, and mood disorders; Other diseases or disorders, such as fumbling, motor impairment, motor impairment (neonatal), motor disorders, rabbit syndrome, spasticity, vertical movement, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders, and rheumatoid arthritis; Neurotic, stress-related, and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and psychogenic movement disorders; other degenerative diseases of the basal ganglia, such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglia degeneration, and neuroferritinosis; Other extrapyramidal and motor disorders, such as unilateral ballism, extrapyramidal disorders, essential tremor, geniospasm, hyperarousal, sitting incapacitation, ballism / unilateral ballism, myoclonus, and restless legs syndrome / Willis-Ekbom syndrome; Other nervous system or motor function disorders, such as sleep-related bruxism, abnormal involuntary movement disorders, alien rim syndrome, Alzheimer's disease (excitement), claustrophobia, clonic hemifacial spasm, olfactory nerve aplasia, congenital cranial nerve palsy, 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 in children, motor developmental delay, cerebral palsy, athetoid cerebral palsy, posturing, pseudoparalysis, and cerebral palsy. Hyperkinesia, bradykinesia, synkinesis, akinesia, Riley-Day syndrome, and athetosis; Parkinson's disease / parkinsonism, for example, parkinsonism, drug-induced parkinsonism, micrographia, and Parkinson's disease; Childhood-onset behavioral and emotional disorders, such as attention deficit hyperactivity disorder, attention deficit disorder, hyperkinetic disorder, neonatal hyperkinetic disorder, oppositional defiant disorder, provisional tic disorder, persistent (chronic) motor or vocal tic disorder, stereotypic movement disorder, stereotypic syndrome, and Tourette syndrome; Pervasive developmental disorders, for example, autism spectrum disorder, Rett syndrome, Asperger's syndrome, pervasive developmental disorder NOS, and dyslexia; and Substance abuse or addiction, including, for example, addiction disorders, alcoholism, cocaine addiction, illegal drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine-like substance abuse, nicotine addiction, polypharmacy, and prescription drug abuse.

[0309] In some embodiments, the patient being treated is determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to developing mental disorders due to 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 mental disorders due to having COMT haploinsufficiency.

[0310] In another embodiment, the VMAT2 inhibitors described herein may be hydrolyzed in the mammalian body to become compounds that can inhibit human vesicular monoamine transporter isoform 2. Therefore, these VMAT2 inhibitors may have additional utility in modifying the in vivo properties of the mammalian metabolite, 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 a spontaneous motor activity (LMA) assay. Another in vivo animal model involves conditioned avoidance response (CAR) testing, 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 this disclosure, or pharmaceutically acceptable salts thereof, may be used as monotherapy or in combination with one or more other pharmaceutically active substances. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered together (simultaneously or sequentially) with one or more pharmaceutically active substances selected from antidepressants, antipsychotics (typical or atypical), antiepileptics, antimicrobial agents, antiarrhythmics, mood stabilizers, and gastrointestinal agents. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in adjunctive therapy, which refers to a treatment used in conjunction with primary treatment, the purpose of which is to support primary treatment. Adjunctive therapy is typically co-administration therapy. As an example of adjunctive therapy, when obsessive-compulsive disorder is being treated, primary treatment may be, for example, an antidepressant, and co-administration of the compounds described herein would be considered adjunctive therapy.

[0313] compound synthesis Detailed methods for synthesizing the compounds are described in the examples herein. Generally, the starting components are commercially available chemicals, which may be obtained from commercial sources, or may be prepared by starting from commercially available chemicals and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art.

[0314] In general, the compounds used in the reactions described herein can be prepared starting from commercially available chemicals and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art. Methods known to those skilled in the art can be identified through various reference books and databases. Suitable reference books and specialized publications that provide references to papers detailing the synthesis of reactants useful in the preparation of the compounds of this disclosure, or describing the preparations, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd Ed., WA 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 American Chemical Society's chemical information retrieval service, which are available in most public and university libraries, and through online databases (for further details, contact the American Chemical Society, Washington, DC). Chemicals that are publicly known but not commercially available in catalogs may be prepared by contract chemical synthesis houses according to known methods, and many standard chemical supply houses (e.g., those listed above) offer contract synthesis services.

[0316] The term "reducing agent" refers to a compound that converts a ketone-containing reactant compound into an alcohol-producing compound, or an ester-containing reactant compound into an alcohol-producing compound, by imparting a hydride to the electrophilic position of a reactant compound, such as an unsaturated carbon (e.g., the carbon in the carbonyl portion). A reducing agent can be a hydride reducing agent. Examples of hydride reducing agents include diborane, borane (e.g., boranetetrahydrofuran complex), 9-borabicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminum hydride, diisobutyl-tert-butoxyaluminum lithium hydride, tri-tert-butoxyaluminum lithium hydride, tris[(3-ethyl-3-pentyl)oxy]aluminolithium hydride, sodium bis(2-methoxyethoxy)aluminum dihydride, sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, and water. This includes, but is not limited to, tetramethylammonium boron hydride, bis(triphenylphosphine)copper(I) boron hydride, 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, etc.

[0317] The term "halogenating agent" refers to a compound that imparts a halogen atom to a reactant compound, such as by converting an alcohol reactant compound into an alkyl halide 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.

[0318] The term "base" refers to a compound that acts as 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 (e.g., an amine base) that contains at least one CH bond. In some embodiments, the amine base may be a primary, secondary, or tertiary amine.

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

[0322] The term "acid" refers to a compound that acts as 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 carbon bonds. Inorganic acids can be strong acids or weak acids.

[0325] The term "organic acid" refers to an acid that contains at least one CH bond, CF bond, or CC bond.

[0326] A certain abbreviation This specification contains numerous abbreviations, the definitions of which are listed in the table below. [Table 18] [Examples]

[0327] The following embodiments are included to demonstrate embodiments of the present disclosure. However, those skilled in the art will see that many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the present disclosure, and similar or equivalent results can still be obtained.

[0328] Analytical HPLC analysis was performed using an LC-MS system employing a UV detector (Dionex® UVD 170u UV / VIS detector), Corona array detectors (Thermo® Veo® RS), and a mass spectrometer (Dionex MSQ Plus®). Reverse-phase preparative HPLC purification was performed using a Phenomenex C18 Kinetics 5μ 100A liquid chromatography-mass spectrometry (LCMS) system, running at 1.1 mL / min and 50°C with an ACN / water gradient containing 0.05% TFA. The procedure was performed using a 150 × 21.2 mm column. Supercritical fluid chromatography (SFC) purification was performed using a UV detector (Waters® 2998 Photodiode Array). Detector(TM)) and mass spectrometer (Waters(TM) Acquity The analysis was performed using a Waters® Prep 100q® system equipped with a QDa Detector®. A Waters® Viridis® BEH 2-ethylpyridine 130Å 5μm, 30mm × 100mm column was used with a 0.3% NH4OH gradient in CO2 and MeOH, and the analysis was performed at 100 mL / min, 40°C, and with a 105 bar back pressure regulator. All final compounds were analyzed by analytical HPLC-MS, and peaks were monitored for purity at UV220, 212, 270, and 254 nm by mass spectrometer and via a charged aerosol detector. 1H was recorded using a Z gradient with a Bruker 400 MHz spectrometer equipped with a broadband NMR probe or a Bruker 500 MHz spectrometer equipped with a 5 mm QNP probe in a suitable NMR solvent such as dimethyl sulfoxide-d6 (DMSO-d6). 1 The H chemical signal is expressed in parts per million (ppm), and the residual solvent signal is used as a reference. Chemical shifts are expressed in ppm (δ), and coupling constants (J) are reported in Hertz (Hz). Reactions were carried out under a dry nitrogen atmosphere unless otherwise specified.

[0329] I. A general synthesis scheme for the preparation of the compound of formula (I) is shown in Figure 6, where X is a halo (e.g., I, Cl or Br), OS(O)2OR 1 Or OS(O)2R z And here, R z The compound is a C1-C6 alkyl, halo-C1-C6 alkyl, or phenyl, wherein the phenyl is unsubstituted or substituted with one or more halo, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy. As an alternative, commercially available HO-R 1 By reacting it with a halogenating agent, R 1 -X [wherein X is I, Cl, or Br] can be prepared.

[0330] As shown in Figure 6, the compound of general formula (I) as described herein can be synthesized in several steps from compound 1-A. In one example, the sequence for the formation of the compound of general formula (I) involves the condensation of compound 1-A with 3-[(dimethylamino)methyl]-5,5-dimethylhexane-2-one in a solvent or a solvent mixture such as i-PrOH / water, in the presence of additives such as acid and NaI as needed, to obtain compound 1-B. Sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, tetramethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, 9-borabicyclo[3.3.1]nonanelithium triacetoxyborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, tri-sec-butyl Compound 1-C is obtained by reducing compound 1-B in a solvent or a solvent mixture such as methanol or MTBE, and optionally in the presence of additives such as acetic acid, in the presence of a reducing agent such as sodium boro, potassium tricyamylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidineborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, or sodium borohydride. Compound 1-D can be prepared by hydrolysis or solvolysis, for example, by treating compound 1-C with an acid in a solvent such as methanol. Finally, compound 1-D is reduced to R 1 Compounds of general formula (I) can be obtained by treating them with -X [wherein X is a leaving group such as I, Br, Cl, or triflate] or an epoxide in the presence of a base in a solvent such as DMF or acetone.

[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 Figure 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]isoquinoline-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 equivalents) in water (63 mL) was prepared and cooled to 0°C. Then, aqueous HCl (6.7 mL, 12.1 N, 1.05 equivalents) was added, followed by sodium iodide (5.83 g, 38.9 mmol, 0.5 equivalents), and the resulting mixture was warmed to room temperature. Finally, a solution of 3-[(dimethylamino)methyl]-5,5-dimethylhexane-2-one (14.4 g, 77.9 mmol, 1.0 equivalent) in i-PrOH (22 mL) was added, and the reaction mixture was vigorously stirred at 45°C for 3 days. The resulting suspension was cooled, the precipitate was collected, and the filtrate was extracted into DCM. The collected precipitate was dissolved in DCM and added to the combined organic layers, dried over MgSO4, filtered to remove the solid, and concentrated under vacuum. The compounds were loaded onto silica gel columns (220g x 2, 120g x 1) using DCM and run on hexane with a gradually increasing gradient of siRNA (0-40% over 20 minutes) to obtain 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 1-B, 22.6g, 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]isoquinoline-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]isoquinoline-2-one (compound 1-B, 22.6 g, 55.5 mmol, 1.0 equivalent) in MTBE:MeOH (4:1, 113 mL) and acetic acid (3.2 mL, 55.5 mmol, 1.0 equivalent), solid sodium borohydride (2.3 g, 61.0 mmol, 1.1 equivalent) was carefully added in small amounts. The reaction progress was monitored every hour by LC / MS. Subsequently, 4:1 MTBE:MeOH (56 mL), 0.5 equivalents of acetic acid, and an additional 2.0 equivalents of sodium borohydride were added to the stirred mixture. After stirring overnight at room temperature, 180 mL of 1N NaOH was added, and the resulting mixture was heated to 50°C for 3 hours. The mixture was cooled to room temperature and allowed to stand for 1 hour. The resulting precipitate was collected by vacuum filtration, rinsed with excess water (approximately 600 mL) until pH < 10, and finally washed with MTBE. The filtration cake was dried to obtain 9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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]isoquinoline-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]isoquinoline-2-ol (compound 1-C, 18.7 g, 42.1 mmol, 1.0 equivalent) in MeOH (150 mL), (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanediic acid (DPTTA, 17.9 g, 46.3 mmol, 1.1 equivalent) was added in fractional amounts. Additional MeOH (100 mL) and heat (65 °C) were required to dissolve the solid. The resulting solution was cooled to 60 °C, and seed crystals of compound 1-C(2R,3R,11bR)·(DPTTA) (138 mg, see, e.g., Example 1B) prepared earlier were added and the mixture was stirred at 60 °C for 30 minutes. The mixture was then cooled to room temperature at a rate of 4°C / hour and stirred overnight at room temperature. 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®). Chiral Technologies Inc. (trademark) ChiralPak (trademark) 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 a 1500 psi back pressure regulator. The 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 basicized with saturated NH4OH aqueous solution until the pH was approximately 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO4, filtered, and concentrated under vacuum to obtain (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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]isoquinoline-2-ol (compound 1-C(2R,3R,11bR), 6.9 g, 16.8 mmol, 1.0 equivalent) in MeOH (68 mL) cooled to 0°C, 34 mL of 37% aqueous HCl was added dropwise over 30 minutes. The resulting mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 30 minutes, and finally stirred overnight at 80°C. The mixture was transferred to a 2 L flask, diluted with water (60 mL) and DCM (100 mL), and cooled to 0°C. Next, saturated aqueous NaHCO3 was added dropwise until the pH reached approximately 8, 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 the solid, and concentrated under vacuum. The resulting solid was combined with the filtration cake to obtain (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 near 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]isoquinoline-2-ol and (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanediic acid salts (compound 1-C(2R,3R,11bR)(DPTTA)), see Figure 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]isoquinoline-2-ol (compound 1-C, 506 mg, 1.24 mmol, 1.0 equivalent) in MeOH (7 mL), (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanediic acid (DPTTA, 494 mg, 1.24 mmol, 1.0 equivalent) was added in fractional amounts. The resulting mixture was heated under reflux with stirring to obtain a clear solution. The mixture was cooled to room temperature without stirring and allowed to stand at room temperature for 16 hours. The resulting precipitate was collected by vacuum filtration, rinsed with methanol (1 mL), and dried to obtain compound 1-C·(2R,3R,11bR)(DPTTA) (365 mg, 37%) as a white solid. The 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®). Chiral Technologies Inc. (trademark) ChiralPak (trademark) 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 a 1500 psi back pressure regulator. The extracted wavelength of 285 nm was used for %ee quantification and analysis. 20 mg of the solid sample was set aside for further recrystallization, and the mother liquor and the remaining white solid were combined again and concentrated under vacuum. This mixture was suspended in MeOH (5 mL) and heated to reflux to obtain a clear solution. Stirring was stopped, the mixture was cooled to 60°C, and 2 mg of the previously mentioned 90% ee compound 1-C·(2R,3R,11bR)(DPTTA) solid seed crystal was added. The mixture was allowed to stand at 60°C for 1 hour, then the temperature was reduced by 5°C per hour until it reached room temperature, and then it was allowed to stand for 16 hours.The resulting precipitate was collected by vacuum filtration, rinsed with methanol (1 mL), and dried to obtain compound 1-C·(2R,3R,11bR)(DPTTA) (200 mg, 20%). The optical purity of the single diastereomer at 100% ee was 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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3S,11bS)), see Figure 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]isoquinoline-2-one (compound 2-B).

[0345] To a solution of 7-methoxy-3,4-dihydroisoquinoline-6-ol (compound 2-A, 7.2 g, 40.7 mmol, 1.2 equivalents) in EtOH (66 mL), [2-(2,2-dimethylpropyl)-3-oxobutyl]trimethylazanium iodide (11.1 g, 33.9 mmol, 1.0 equivalent) was added, and the resulting mixture was stirred and refluxed for 3 days. The mixture was cooled, diluted with aqueous NaHCO3 solution, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was dry-loaded onto Celite and chromatographed using a silica gel column (220 g) with a gradually increasing siRNA gradient in hexane (0-60% over 20 minutes). Due to co-eluted impurities, the material was dry-loaded onto Celite and chromatographed again using a silica gel column (80g) with a shallower gradient of siRNA than hexane (0-45% over 20 minutes) to obtain 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, 4.2g, 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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3S,11bS)).

[0347] The separation of the enantiomer of 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) was achieved by preparing a solution in a minimum volume of MeOH 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 a 100 bar back pressure 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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3S,11bS)) (100%ee) were isolated.

[0348] Suitable crystals were generated by the slow evaporation of a solution of compound 2-B(3S,11bS) in acetone. Absolute stereochemistry was confirmed by obtaining the crystal structure of small molecules 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]isoquinoline-2-one (compound 2-B(3S,11bS)) was determined. When the configuration assignment is accurate, the absolute configuration parameter (flac parameter) is near zero, and when the configuration is incorrect, it is near +1. For this dataset, the flac parameter for the assignment shown in Figure 1A is 0.06(3). Crystallographic information is shown in Table 1. [Table 1]

[0351] (Example 3) Alternative preparations 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 Figure 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]isoquinoline-2-one (compound 2-B(3R,11bR), 733 mg, 2.31 mmol, 1.0 equivalent) in MeOH (5 mL), sodium borohydride (131 mg, 3.46 mmol, 1.5 equivalents) was added. The resulting mixture was stirred at room temperature for 16 hours, at which point additional sodium borohydride (44 mg, 1.16 mmol, 0.5 equivalents) was added. The mixture was stirred at room temperature for an additional 3 hours. 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 under vacuum. The resulting solid was suspended in MTBE (5.9 mL) and MeOH (1.5 mL), and the resulting mixture was heated at 50°C for 1 hour with stirring. The suspension was cooled to room temperature, and the solid was collected by filtration. The filtration cake was rinsed with MTBE (2.2 mL), and the solid was collected to obtain (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 several slow thermal cycles from 5°C to 80°C. Multiple vials were used. After thermal cycling, large needle-shaped crystals formed on the sides of the vials. The solvent was decanted, and the crystals were analyzed. Crystals suitable for single-crystal X-ray structure determination were selected. Similar preparations using ACN also provided crystals, but the crystals grown from DMF provided better crystals that were more suitable for further analysis.

[0356] The crystal structure of compound 1-D(2R,3R,11bR) was analyzed. The structure was determined to be anhydrous and nonsolvated, and all three chiral centers at C2, C3, and C11b were determined to have the R configuration. See Figure 1B for the asymmetric units of the crystal structure. Table 2 shows the crystal data, unit system, and space group for compound 1-D(2R,3R,11bR). Table 3 shows the data collection and refinement parameters for compound 1-D(2R,3R,11bR). [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 using a similar method to that used to prepare compound 1-D(2R,3R,11bR), with (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)) 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 Figure 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]isoquinoline-2-one (compound 2-B(3R,11bR), 48 mg, 0.15 mmol, 1.0 equivalent) in THF (0.75 mL) was cooled to 0°C. Then, a solution of tri-sec-butylborolithium hydride (1 M THF, 0.30 mL, 0.30 mmol, 2.0 equivalents) was added dropwise. The resulting mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 3 hours. The mixture was concentrated under vacuum, diluted with water, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. The compounds were loaded onto a silica gel column (4 g) using DCM and run on an increasing gradient ELISA in hexane (0-60% over 30 minutes). The fractions were split between the pure product (compound 1-D(2S,3R,11bR), 16 mg) and the product with the secondary diastereomer (28 mg, with a diastereomer ratio of 10:1 between compound 1-D(2S,3R,11bR) and 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 using a similar method to that used to prepare compound 1-D(2S,3R,11bR), with (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)) 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]isoquinoline-2-ol (compound 4-1), see Figure 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 equivalent) in acetone (6.3 mL), cesium carbonate (0.61 g, 1.9 mmol, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.19 g, 0.82 mmol, 1.3 equivalents) was added, and the mixture was stirred overnight at room temperature. 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 under vacuum. A silica gel column (40 g) was loaded using DCM and run on hexane with a gradually increasing gradient of siRNA (0-50% over 25 minutes) to obtain (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]isoquinoline-2-ol (compound 4-1, 0.19 g, 0.47 mmol, 75%) as a white solid. 1 1H 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]isoquinoline-2-ol (compound 4-27). [ka]

[0367] 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 equivalent) was added to DMF (40 mL) with cesium carbonate (2.44 g, 7.50 mmol, 3.0 equivalent) at 50°C. A solution of cyclopropyltrifluoromethanesulfonate (0.60 g, 3.13 mmol, 1.25 equivalent) in DMF (3 mL) was added via syringe pump over 6 hours. The resulting mixture was stirred for an additional 10 hours at 50°C. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. Loaded onto a silica gel column (24 g) using DCM, and run on an increasing gradient of siRNA in hexane (0-100% over 25 minutes) to obtain impure (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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 equivalent) was dissolved in anhydrous THF (14 mL) under a nitrogen atmosphere at 0°C with stirring. A 2M solution of lithium aluminum hydride (2.3 mL, 4.62 mmol, 2.0 equivalents) was added dropwise to THF over 10 minutes. The temperature was raised to 60°C and the mixture was stirred for 16 hours. The mixture was cooled to 0°C, and then sodium sulfate dodecahydrate (0.65 g, 2.02 mmol, 0.9 equivalents) was added over 10 minutes, followed by stirring for 20 minutes. The mixture was filtered through Celite, and the filter cake was rinsed with acetone, MeOH, and DCM. The filtrate was concentrated under vacuum, then redissolved in 1:1 DCM / siRNA, and washed three times with 1M NaOH aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum.Crude material was subjected to three chromatographic separations: a silica gel column (12 g) loaded with DCM and run with siRNA (0–75%) in hexane with an increasing gradient (0–75%) over 25 minutes; a basic alumina column (24 g) run with siRNA (0–75%) in hexane with an increasing gradient (0–75%) over 25 minutes; and a reversed-phase C18 column (30 g) loaded with DMSO and run with MeCN (10–70%) in water with an increasing gradient (10–70%) over 20 minutes to obtain (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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-(oxetane-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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 equivalent) in DMF (6 mL), cesium carbonate (0.61 g, 1.88 mmol, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, 3-bromooxetane (0.12 mL, 1.56 mmol, 2.5 equivalents) was added, and the mixture was stirred at 60°C for 6 hours. The mixture was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude material was subjected to two chromatographic separations: a silica gel column (4 g) loaded with DCM and run with siRNA in hexane with an increasing gradient (0-100%) over 30 minutes, and a reversed-phase C18 column (16 g) loaded with DMSO and run with MeCN in water with an increasing gradient (10-100%) over 25 minutes, to obtain (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetane-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30, 0.15 g, 0.41 mmol, 65%) as a white solid. 1 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]isoquinoline-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 equivalent) in DMF (6 mL), cesium carbonate (0.61 g, 1.88 mmol, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, (2S)-2-(trifluoromethyl)oxirane (72 μL, 0.94 mmol, 1.5 equivalents) was added, and the mixture was stirred at room temperature for 6 hours. The additional (2S)-2-(trifluoromethyl)oxirane (24 μL, 0.31 mmol, 0.5 equivalents) was added, and the mixture was stirred at room temperature for an additional 1 hour. The mixture was diluted with water and extracted three times with RINKAN. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude material was subjected to two chromatographic separations: a silica gel column (12 g) loaded with DCM and run with a gradually increasing gradient of siRNA in hexane (0–65% over 20 minutes), and a reversed-phase C18 column (16 g) loaded with DMSO and run with a gradually increasing gradient of MeCN in water (10–40% over 25 minutes, then 40–90% over 15 minutes) to obtain (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]isoquinoline-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)-oxolane-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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 equivalent) in DMF (3 mL), cesium carbonate (0.92 g, 2.82 mmol, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, (3S)-3-iodooxolane (0.15 mL, 1.41 mmol, 1.5 equivalents) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted three times with ELISA. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. Crude material was separated by four chromatographic methods: a dry-loaded (Celite) basic alumina column (24g) run with a gradually increasing gradient of MeOH in DCM (0-5% over 10 minutes, then 100% over 10 minutes), a dry-loaded (Celite) silica column (4g) run with a gradually increasing gradient of SiO2 in hexane (0-100% over 20 minutes), and a reverse-phase C18 column (30g) loaded with DMSO and run with a gradually increasing gradient of MeCN in water (10-50% over 20 minutes). The compounds were then submitted to a dry-loaded (Celite) silica column (4 g) run with a gradually increasing gradient of siRNA in hexane (0-100% over 20 minutes) to obtain (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxolane-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-53, 0.14 g, 0.35 mmol, 38%) as a white solid. 1 H 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]isoquinoline-2-ol (compound 4-55), see Figure 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 equivalent) in DMF (28 mL), cesium carbonate (3.06 g, 9.39 mmol, 3.0 equivalent) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, (R)-2-methyloxirane (0.31 mL, 6.26 mmol, 2 equivalents) was added, and the mixture was stirred at 80°C for 16 hours. An additional (R)-2-methyloxirane (0.16 mL, 3.13 mmol, 1 equivalent) was added, and the mixture was stirred at 80°C for an additional 4 hours. A third additional (R)-2-methyloxirane (39 μL, 0.78 mmol, 0.25 equivalents) was added, and the mixture was stirred at 80°C for an additional 3 hours. 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 under vacuum. Loaded onto a silica gel column (24 g) using DCM, and run on an increasing gradient of siRNA in hexane (0-100% over 20 minutes) to obtain the 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]isoquinoline-2-ol (compound 4-55, 0.95 g) as an off-white solid. The crude white solid was recrystallized from 1:1 hexane / siRNA to obtain crude product 4-55 (0.70 g) as an off-white solid. This was loaded onto a reversed-phase C18 column (100 g) using DMSO and run on MeCN with a gradually increasing gradient in water (10-70% over 25 minutes) to obtain (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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] Typical reagents used to synthesize the compounds in Tables 10A and 10B (i.e., R 1 -X) includes those shown in Table 8. [Table 8]

[0377] Typical 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 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 prepared in a manner similar to the procedures described in the above examples. In many cases, dialkyl sulfates, alkyl bromides, alkyl chlorides, or alkyl iodides shown in Table 8 were used instead of triflates. In other cases, epoxides shown in Table 9 were used instead of triflates. Also frequently, the final compounds were subjected 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] Tables 11 and 12 provide an overview of the typical physical properties of compound 4-1 prepared according to the method disclosed herein, and Tables 13 and 14 provide an overview of the typical physical properties of compound 4-15 prepared according to the method disclosed herein.

[0381] (Example 6) Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) 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]isoquinoline-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]isoquinoline-2-ol (compound 4-15). [ka]

[0382] Powder X-ray diffraction (PXRD) Powder X-ray diffraction (PXRD) analysis was performed using a Rigaku Miniflex 600 powder X-ray diffractometer, 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 sheet of weighing paper, and the sample holder was placed in the sample changer. Operating parameters: Miniflex counter detector, Kb filter (×2), scan axis theta / 2-theta, continuous mode, start (°) 2.0, stop (°) 45.0, step (°) 0.020, speed (° / min) 10.0, spin-on, voltage (kV) 40, current (mA) 15. The reported 2θ value may vary by plus or minus 0.2° (i.e., ±0.2°).

[0383] It is understood that peak intensities can vary for the same crystalline morphology depending on the diffraction pattern, based on any number of factors known to those skilled in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, equipment used, and sample purity. Those skilled in the art will understand that, despite the differences in peak intensities, a particular crystalline morphology can be identified by its characteristic peak(s).

[0384] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): DSC and TGA analyses were performed using 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 pressed with tweezers. The pan was transferred to the DSC autosampler for analysis. The method for analysis was a gradient up to 275°C at 10°C / min. A reference pan was prepared using the same procedure, but without the material.

[0385] In TGA analysis, a standard aluminum sample pan was placed in a platinum TGA pan, and the tare weight of the blank was measured using an instrument. Approximately 1–5 mg of the material was added to the standard aluminum pan and analyzed at a maximum of approximately 400°C at 10°C / min. For TGA and DSC, the temperature characteristics reported herein may vary by plus or minus 3°C (i.e., ±3°C).

[0386] Table 11 provides selected powder X-ray diffraction (PXRD) diffraction pattern peak positions at 2θ, DSC, and TGA data for the free base crystalline form I 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]isoquinoline-2-ol (compound 4-1). [Table 11]

[0387] Table 12 provides the peak positions of the powder X-ray diffraction (PXRD) diffraction pattern at 2θ for free base crystalline form I 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]isoquinoline-2-ol (compound 4-1). [Table 12-1] [Table 12-2]

[0388] Table 13 provides selected powder X-ray diffraction (PXRD) diffraction pattern peak positions at 2θ, DSC, and TGA data for the free base crystalline form I 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]isoquinoline-2-ol (compound 4-15). [Table 13]

[0389] Table 14 shows the peak positions of the powder X-ray diffraction (PXRD) diffraction pattern at 2θ for free base crystalline form I 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]isoquinoline-2-ol (compound 4-15). [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]isoquinoline-2-ol (compound 5-1), see Figure 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]isoquinoline-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]isoquinoline-2-one (compound 2-B(3R,11bR), 95 mg, 0.30 mmol, 1.0 equivalent) in acetone (1.5 mL), cesium carbonate (0.19 g, 0.60 mmol, 2.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 10 minutes. Then, dimethyl sulfate (17 μL, 0.18 mmol, 0.6 equivalents) was added, and the resulting mixture was stirred at room temperature for 1 hour. An additional 0.1 equivalent of dimethyl sulfate was added, and the mixture was stirred for an additional 30 minutes. The resulting suspension was filtered to remove the solid, and concentrated under vacuum. The crude material was redissolved in DCM, quenched with 1M NaOH aqueous solution, and extracted with DCM. The combined organic layer was dried over MgSO4, filtered to remove the solid, and concentrated under vacuum. A silica gel column (12 g) was loaded using DCM and run with phenylethylamine (0-40%) over a gradually increasing gradient in hexane (25 minutes) to obtain (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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]isoquinoline-2-ol (compound 5-1).

[0394] A solution of (3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 5-A(3R,11bR), 33 mg, 0.10 mmol, 1.0 equivalent) was added to EtOH (0.6 mL) cooled to 0°C, to which sodium borohydride (7.4 mg, 0.20 mmol, 2.0 equivalents) was added. The resulting mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 1 hour. The mixture was diluted with DCM, washed twice with saturated K2CO3 aqueous solution, and the aqueous layer was further extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. A silica gel column (12 g) was loaded using DCM and run on an increasing gradient siRNA (0-60%) in hexane for 15 minutes to obtain (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 5-1, 20 mg, 0.06 mmol, 60%) as a white solid. 10 mg was dissolved in MeOH (1 mL) and subjected to further purification by preparative HPLC. 1 H 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]isoquinoline-2-ol (compound 5-3), see Figure 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]isoquinoline-2-one (compound 5-A(3S,11bS)).

[0397] Compound 5-A(3S,11bS) was prepared using the same procedure as used to prepare compound 5-A(3R,11bR) (see Example 7, Step 1), but with compound 2-B(3S,11bS) instead of compound 2-B(3R,11bR). See Figure 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]isoquinoline-2-ol (compound 5-3).

[0399] Compound 5-3 was prepared using the same procedure as that used to prepare Compound 5-1 (see Example 7, Step 2), but with 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]isoquinoline-2-ol (compound 5-2), see Figure 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]isoquinoline-2-one (compound 5-A(3R,11bR), 27 mg, 0.08 mmol, 1.0 equivalent) in THF (0.6 mL) was prepared and cooled to 0°C. Then, tri-sec-butylborolithium hydride (1 M THF, 0.16 mL, 0.16 mmol, 2.0 equivalents) 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 the solid, and concentrated under vacuum. A silica gel column (4 g) was loaded using DCM and run on siRNA with an increasing gradient in hexane to obtain (2S,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-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). Compound 5-2 The observed (Obs) ion m / z ratio 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]isoquinoline-2-ol (compound 5-4), see Figure 14. [ka]

[0403] (2R,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 5-4) was prepared using the same procedure as for preparing compound 5-2 (see Example 9), but with 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) A method for determining the VMAT2 inhibitory activity of a compound.

[0405] Examples of techniques for determining the ability of compounds to inhibit VMAT2 are provided below. Procedures were adapted from those previously described (see, e.g., Near, (1986), Mol. Pharmacol. 30: 252-57; Teng, et al., J. Neurochem. 71, 258-65, 1998). Homogenates from human platelets were prepared by homogenization and then washed by centrifugation as previously described (see, e.g., Hoare et al., (2003) Peptides 24:1881-97).

[0406] The 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 by hand from powder stock or from DMSO stock using serial dilution with Vantage (Hamilton) or direct dilution with Echo655 (Beckman). Twelve concentrations of the test compounds were added to a total volume of 0.145 to 0.150 mL in a low-binding 96-well plate (Corning 3605) using human platelet homogenate (30 μg of membrane protein per well) in a VMAT2 binding buffer (Dulbeccio phosphate-buffered saline, 1 mM EDTA, pH 7.4) at 10 nM 3 H-dihydrotetrabenazine ( 3 H-dihydrotetrabenezine)(American Radiolabeled) The samples were compared against chemicals. After incubation at 25°C for 90 minutes, the bound radioligands were collected by rapid filtration using either a Unifilter-96 harvester (PerkinElmer) or a Microlabostar (Hamilton) onto either a GF / B or GF / C glass fiber filter pre-treated with 0.1% polyethyleneimine. After harvesting, the filter plates were washed with 0.8 mL of VMAT2-bound buffer, and the bound radioligands were quantified by scintillation counting using TopCount NXT or a Microplate Counter Microbeta (PerkinElmer). Data from 12-point concentration-response curves were analyzed and IC was calculated using a 4-parameter logistic regression algorithm. 50 The following was calculated, where the apex was constrained to 100 and the base to 0. The Ki value for each compound was calculated using the Chen-Prusov formula, depending on the batch of platelets and radiolabeling used in each experiment. 3 The calculations for H-dihydrotetrabenazine were performed using 2.5 nM or 4.06 nM Kd.

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

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

[0409] Figures 15 to 21 show VMAT2 K for representative compounds and comparative compounds of formula (I). i Provides (nM) values. VMAT2 K i The values ​​were determined according to Example 11. The comparative compounds were prepared as described in International Publication No. WO2018 / 195121A1, which is incorporated herein by reference in its entirety. A representative compound of formula (I) is VMAT2 K i In terms of potency, it is more potent than the comparison compound (e.g., 4.1 times to 20.9 times stronger).

[0410] (Example 12) VMAT2 inhibitors for reduced open-field spontaneous motor activity (hypololocomotor activity) Reduced inducibility.

[0411] The effect of VMAT2 inhibitors on dopamine depletion was measured using a spontaneous motility activity (LMA) assay. After 60 or 120 minutes of pretreatment, male Sprague-Dolly rats (200–250 g) were placed in transparent cages (San Diego Instruments) surrounded by a photoelectric detector. Spontaneous motility activity in rats was detected by blocking the photocell beam, and activity was defined as the number of beam blockages over 30 minutes. Data were analyzed for significance using one-way analysis of variance (ANOVA; Sigmast version 3.0.1, SPSS, Chicago, IL), followed by a post-hoc test by Student-Newman-Coirs. ED 50This was calculated for compound 4-1 (0.24 mg / kg, see Figure 22), compound 4-15 (0.18 mg / kg, see Figure 22), compound 4-27 (0.14 mg / kg, see Figure 23), compound 4-31 (0.31 mg / kg, see Figure 24), compound 4-50 (0.21 mg / kg, see Figure 23), and compound 4-55 (0.29 mg / kg, see Figure 23).

[0412] (Example 13A) Conditioned avoidance response assay for antipsychotic activity.

[0413] The conditioned avoidance response (CAR) test has been shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds. In the CAR paradigm, rats are trained to respond to a conditioned stimulus (auditory) with negative reinforcement in a two-chamber shuttle box. If the animal is unable to move to the other chamber when the auditory stimulus is presented, a mild foot shock is administered to the side where the rat is located. The rat learns to avoid the mild foot shock by moving to the other chamber at the start of the auditory signal, a behavior known as the conditioned avoidance response. Crossing to the other chamber during the execution of the shock is called the escape response. If the rat is unable to move to the other chamber even during the execution of the foot shock, the rat is considered to have failed to escape. Numerous studies have shown that typical and atypical antipsychotics selectively inhibit 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 were trained daily for 3 to 4 weeks. During training sessions, rats were placed in a CAR bidirectional shuttle box, and a training period of 20 trials followed. Each trial consisted of a 10-second presentation of 80 dB white noise, followed by an encrypted 0.6 mA foot shock lasting up to 20 seconds. The interval between trials ranged from 20 to 60 seconds. When the conditioned stimulus was presented, the rats learned to avoid the shock by moving from one compartment to another (conditioned avoidance response). A rat was considered sufficiently trained if it avoided the shock when the conditioned stimulus was presented in at least 19 of the 20 trials. Rats that did not meet these criteria were not used.

[0415] On the day of the experiment, trained animals are acclimatized to the test room for 30 minutes prior to the experiment. The animals are then administered the compound and placed in a CAR bidirectional shuttle box. The experiment consists of 20 trials for each rat. In each trial, a conditioned stimulus (10-second presentation of 80 dB white noise) is applied, followed by a foot shock (encrypted 0.6 mA foot shock lasting up to 20 seconds). If an animal moves to another room upon presentation of the conditioned stimulus, it is scored as a conditioned avoidance response. If an animal moves upon presentation of the foot shock, it is scored as escape. If an animal is unable to move upon presentation of the foot shock, it is scored as escape failure. Antipsychotic efficacy is evident by an increase in the number of escapes. Data are analyzed by arranged analysis of variance (ANOVA), followed, where appropriate, by post-hoc comparisons using the Bonferroni test. An effect is considered significant if p < 0.05. Outliers, defined as a standard deviation of 2 above or below the mean, are detected and removed from all analyses.

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

[0417] Animals: Mature male Wistar rats from Envigo (Indianapolis, IN) were used in this study. The rats were received at approximately 150g, assigned unique identification numbers, and housed in groups of 2-3 rats per cage in ventilated cages. Before the start of the study, all rats were examined, touched, and weighed to ensure they were in good health and fit. A 12 / 12 light / dark cycle was maintained throughout the study. Room temperature was maintained between 20°C and 23°C, and relative humidity around 50%. Chow food and water were freely provided throughout the study period. All tests were 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 at a dose volume of 3 mL / kg 120 minutes prior to the test.

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

[0420] Behavioral testing - conditioned avoidance response Conditioned avoidance response (CAR) trials have been shown to be a highly reliable animal model for screening antipsychotic drugs (Wadenberg & Hicks, Neuroscience and See Biobehavioral Reviews, (1999) 23:851-862). In the CAR paradigm, The object is trained to respond to conditioned stimuli (auditory and visual) through negative reinforcement (foot shock). Numerous studies have shown that typical and atypical antipsychotics selectively suppress CARs, 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 in a CAR bidirectional shuttle box, followed by a training period of 20 trials. Each trial consisted of a 10-second presentation of 80 dB white noise, followed by an encrypted 0.6 mA foot shock lasting up to 20 seconds. The intervals between trials ranged from 20 to 60 seconds. When a cue was presented, the rats learned to avoid the shock by moving from one compartment to another. If they were unable to do so, the rats received a foot shock, most likely during which they crossed compartments to escape the shock. Finally, if they were unable to leave a compartment, the rats endured the full 20 seconds of foot shock. The following measurements were captured from the assay:

[0422] Avoidance response: When rats move from one compartment to another during cue stimulus (CS) presentation. A decrease in the avoidance response is a typical sign of an effective dose of antipsychotic medication.

[0423] Escape failure: If the rat is unable to move to another compartment during a 20-second foot shock.

[0424] Data Analysis Avoidance response data was expressed as the number of avoidance responses and as a percentage of avoidance responses based on three baseline responses prior to the drug trial. Avoidance failure was expressed as the total number of failures during the trial session.

[0425] Weight and avoidance data were analyzed by arranged analysis of variance (ANOVA), followed, where appropriate, by Dunnett's post-hoc comparisons. Escape failure was analyzed by the Kruskal-Wallis nonparametric analysis, followed, where appropriate, by Dunnett's post-hoc comparisons. Results are reported as mean ± SEM. An effect was considered statistically significant if p < 0.05.

[0426] Regarding compound 4-1 (0.55 mg / kg) ED 50 The calculation was performed. The same was done for compound 4-15 (0.44 mg / kg) using ED. 50The (mg / kg) dose was calculated. In addition, rats treated with either compound 4-1 or compound 4-15 were observed to show a reduction in avoidance at 0.3 mg / kg without a significant increase in escape failure.

[0427] (Example 14) A method for determining the stability of compounds in human liver microsomes.

[0428] The test compound (0.5 μM) was incubated with pooled mixed male and female human liver microsomes (total protein 0.5 mg / mL) at 37°C in the presence of a NADPH-producing system containing 50 mM, pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 unit / mL glucose-6-phosphate dehydrogenase. All concentrations were relative to a final incubation volume of 125 μL. Incubation was performed in a water bath at 37°C for 0, 5, 10, 20, 40, and 60 minutes, terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing an internal standard. Prior to LC-MS / MS analysis, precipitated proteins were removed by centrifugation. Aliquots of the resulting supernatant fraction were analyzed for depletion of the parent compound by LC-MS / MS monitoring. Using XLfit scientific curve fitting software (IDBS Ltd., Surrey, UK), the resulting peak area ratio versus time data was fitted to a nonlinear regression, and the emission half-life (t) was calculated from the slope. 1 / 2 The pharmacokinetic parameters were calculated (in minutes). 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 efflux half-life data and then scaled to represent the expected clearance across the entire animal population (see Table 16 (Human)). Additional values ​​calculated included predicted extraction rates and predicted maximum bioavailability.

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

[0430] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or included in the application data sheets are incorporated herein by reference in their entirety. The aspects of the embodiments may be modified, if necessary, to provide further embodiments using concepts from various patents, applications, and publications.

[0431] In light of the detailed description above, these and other modifications may be made to the embodiments. In general, the terms used in the following claims should not be interpreted as limiting the claims to the specific embodiments disclosed herein and in the claims, but rather as encompassing all conceivable embodiments, along with the entire scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure. In a particular embodiment, for example, the following items are provided: (Item 1) Compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 R 2A ,-(CH2) m -R 2B or -(CH2) n -OR 2C And, R 2A Each of these is either unsubstituted or one or more R A A C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4-7 member heterocyclyl that is substituted with Each R A These are 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, halo-C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C2-C4 dialkylamino, 4-7 membered heterocyclyl, -CN, -OH, and oxo. R 2B Each of these is either unsubstituted or one or more R B These are substituted with aryl, C3-C8 cycloalkyl, 5-10 member heteroaryl, or 4-7 member heterocyclyl compounds. Each R B These are independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halo-C1-C4 alkyl, halo-C1-C4 alkylsulfonyl, oxo, and -OH. R 2C Each of these is either unsubstituted or one or more R C A C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 member heterocycline that is substituted with Each R C These are independently -CN or C3-C6 cycloalkyl groups. m is 0, 1, 2, 3, or 4. n is 1, 2, or 3. (Item 2) The aforementioned compound is of formula (Ia): [ka] A compound described in item 1, or a pharmaceutically acceptable salt thereof, having the same properties. (Item 3) The compound has formula (Ic): [ka] A compound described in item 1, or a pharmaceutically acceptable salt thereof, having the same properties. (Item 4) The aforementioned compound is of formula (Ie): [ka] A compound described in item 1, or a pharmaceutically acceptable salt thereof, having the same properties. (Item 5) The compound has formula (Ig): [ka] A compound described in item 1, or a pharmaceutically acceptable salt thereof, having the same properties. (Item 6) R 1 R 2A The compound described in any one of items 1 through 5, or a pharmaceutically acceptable salt thereof. In some embodiments, R 2A Each of these is either unsubstituted or one or more R A These are C2-C4 alkenyls, C1-C6 alkyls, C3-C8 cycloalkyls, or 4-7 member heterocyclines that are substituted with a specific compound. (Item 7) R 2A However, it is either non-substituted or one or more R A Compounds listed in item 6, or pharmaceutically acceptable salts thereof, which are C2-C4 alkenyls substituted with . (Item 8) R 2A However, it is either non-substituted or one or more R A The compounds listed in item 7, or pharmaceutically acceptable salts thereof, which are methyl allyl substituted with . (Item 9) R A Compounds listed in item 7 or 8, or pharmaceutically acceptable salts thereof, wherein the halogen is present. (Item 10) R A A compound described in any one of items 7 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro. (Item 11) R 2A The compounds listed in item 6, or pharmaceutically acceptable salts thereof, which are propa-2-en-1-yl, either unsubstituted or substituted with one or more methyl groups. (Item 12) R 2A The compounds listed in item 6, or pharmaceutically acceptable salts thereof, wherein the compound is methyl allyl. (Item 13) R 2A However, it is either non-substituted or one or more R A A compound listed in item 6, or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl substituted with . (Item 14) R 2A However, each is either non-substitutable or one or more R A Compounds listed in item 13, or pharmaceutically acceptable salts thereof, which are substituted with n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl, or n-pentyl. (Item 15) Each R AThe compounds described in item 13 or 14, independently selected from the group consisting of C1-C4 alkoxys, C1-C4 alkylaminos, C1-C4 alkylsulfonyls, C2-C4 dialkylaminos, C2-C4 dialkylsulfamoyls, halogens, halo-C1-C4 alkoxys, halo-C2-C4 dialkylaminos, 4-7 member heterocyclyls, -CN, -OH, and oxo, or pharmaceutically acceptable salts thereof. (Item 16) Each R A The compounds described in either item 13 or 15, which are 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, or pharmaceutically acceptable salts thereof. (Item 17) R 2A However, each R is either unsubstituted or independently selected from the group consisting of C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylsulfamoyl, halogen, halo-C1-C4 alkoxy, halo-C2-C4 dialkylamino, 4-7 member heterocyclyl, -CN, -OH, and oxo. A The compounds listed in item 6, or pharmaceutically acceptable salts thereof, which are substituted with n-butyl, ethyl, 2-ethylbutyl, n-propyl, propan-2-yl, 2-methylpropyl, methyl, or n-pentyl. (Item 18) R 2AHowever, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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-(dimethyl The compounds listed in item 6, which are methylamino)-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, or pharmaceutically acceptable salts thereof. (Item 19) R 2A However, it is either non-substituted or one or more R A A compound listed in item 6, or a pharmaceutically acceptable salt thereof, which is a C3-C8 cycloalkyl substituted with . (Item 20) R 2A However, each is either non-substitutable or one or more R A The compounds listed in item 19, or pharmaceutically acceptable salts thereof, which are substituted with cyclobutyl, cyclopropyl, cyclopentyl, or cyclohexyl. (Item 21) Each R AHowever, the compounds described in item 19 or 20, independently selected from the group consisting of halogens and halo C1-C4 alkyls, or pharmaceutically acceptable salts thereof. (Item 22) Each R A However, a compound described in any one of items 19 to 21, independently selected from the group consisting of fluoromethyl and trifluoromethyl compounds, or a pharmaceutically acceptable salt thereof. (Item 23) R 2A However, each of the following R compounds is independently selected from the group consisting of unsubstituted or fluoro and trifluoromethyl compounds. A The compounds listed in item 6, or pharmaceutically acceptable salts thereof, which are substituted with cyclobutyl, cyclopropyl, cyclopentyl, or cyclohexyl. (Item 24) R 2A The compounds listed in item 6, which are cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, or 3,3-difluorocyclopentyl, or pharmaceutically acceptable salts thereof. (Item 25) R 2A However, it is either non-substituted or one or more R A A compound described in item 6, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocycline substituted with . (Item 26) R 2A However, each is either non-substitutable or one or more R A The compounds listed in item 25, or pharmaceutically acceptable salts thereof, which are substituted with azetidine-3-yl, oxetan-3-yl, or pyrrolidine-3-yl. (Item 27) Each R A However, the compounds described in item 25 or 26, or pharmaceutically acceptable salts thereof, are independently selected from the group consisting of C1-C6 alkyl, halo-C1-C4 alkyl, and oxo. (Item 28) R AHowever, a compound described in any one of items 25 to 27, independently selected from the group consisting of methyl, 2,2,2-trifluoroethyl, and oxo, or a pharmaceutically acceptable salt thereof. (Item 29) R 2A However, each is either unsubstituted or one or more R compounds independently selected from the group consisting of methyl, 2,2,2-trifluoroethyl, and oxo. A The compounds listed in item 6, or pharmaceutically acceptable salts thereof, which are substituted with azetidine-3-yl, oxetan-3-yl, or pyrrolidine-3-yl. (Item 30) R 2A The compounds listed in item 6, which are oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl or 1-methylazetidine-3-yl, or pharmaceutically acceptable salts thereof. (Item 31) R 2A The R is methylallyl, n-butyl, ethyl, 2-ethylbutyl, n-propyl, propane-2-yl, 2-methylpropyl(isobutyl), methyl, n-pentyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidine-3-yl, oxetane-3-yl, or pyrrolidine-3-yl; each is either unsubstituted or one or more R 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 The compounds listed in item 6, or pharmaceutically acceptable salts thereof, substituted with [the compound]. (Item 32) R 2AHowever, methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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 The compounds listed in item 6, which are -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)pyrrolidine-3-yl, 1-methylazetidine-3-yl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl, or pharmaceutically acceptable salts thereof. (Item 33) R 1 ga-(CH2) m -R 2B The compound described in any one of items 1 through 5, or a pharmaceutically acceptable salt thereof. (Item 34) A compound listed in item 33, or a pharmaceutically acceptable salt thereof, where m is 0. (Item 35) A compound listed in item 33, or a pharmaceutically acceptable salt thereof, where m is 1. (Item 36) A compound listed in item 33, or a pharmaceutically acceptable salt thereof, where m is 2. (Item 37) A compound listed in item 33, or a pharmaceutically acceptable salt thereof, where m is 3. (Item 38) A compound listed in item 33, or a pharmaceutically acceptable salt thereof, where m is 4. (Item 39) R 2B However, it is either non-substituted or one or more R B A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is an aryl substituted with. (Item 40) R 2B However, it is either non-substituted or one or more R B A compound listed in item 39, which is a phenyl compound substituted with [a specific compound]. (Item 41) Each R B However, the compounds described in item 39 or 40, independently selected from the group consisting of halogens, halo C1-C4 alkyls, halo C1-C4 alkylsulfonyls, and -CN, or pharmaceutically acceptable salts thereof. (Item 42) Each R B However, a compound described in any one of items 39 to 41, independently selected from the group consisting of fluoromethyl, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN, or a pharmaceutically acceptable salt thereof. (Item 43) R 2B However, one or more R compounds are either unsubstituted or independently selected from the group consisting of fluoromethyl, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN. B A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is a phenyl substituted with . (Item 44) R2B The compounds described in any one of items 33 to 38, which are phenyl, 4-fluorophenyl, 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-((difluoromethyl)sulfonyl)phenyl, or 3-cyanophenyl, or pharmaceutically acceptable salts thereof. (Item 45) R 2B However, it is either non-substituted or one or more R B A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is a C3-C8 cycloalkyl substituted with . (Item 46) R 2B However, each is either non-substitutable or one or more R B The compounds described in item 45, which are substituted with cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, or bicyclo[1.1.1]pentan-1-yl. (Item 47) Each R B However, the compounds described in item 45 or 46, which are independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halo-C1-C4 alkyl and -OH, or pharmaceutically acceptable salts thereof. (Item 48) Each R B The compounds described in any one of items 45 to 47, which are independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CH2CN, fluoro, difluoromethyl, trifluoromethyl, and -OH, or pharmaceutically acceptable salts thereof. (Item 49) R 2B However, each R is either unsubstituted or one or more Rs independently selected from the group consisting of ethyl, methylsulfonyl, methylsulfonyloxy, -CN, -CH2CN, fluoro, difluoromethyl, trifluoromethyl, and -OH. BCompounds described in items 33 to 38, or pharmaceutically acceptable salts thereof, which are substituted with cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, or bicyclo[1.1.1]pentan-1-yl. (Item 50) R 2B The compounds listed in items 33 to 38, which are 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, or pharmaceutically acceptable salts thereof. (Item 51) R 2B However, it is either non-substituted or one or more R B A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is a 5- to 10-membered heteroaryl substituted with . (Item 52) R 2B However, each is either non-substitutable or one or more R B The compounds listed in item 51, or pharmaceutically acceptable salts thereof, which are substituted with 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,3-oxazole-4-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazole-5-yl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, or thiazole-4-yl. (Item 53) Each R B However, the compounds described in item 51 or 52, or pharmaceutically acceptable salts thereof, are independently selected from the group consisting of C1-C4 alkyl and -CN. (Item 54) Each R B However, a compound described in any one of items 51 to 53, independently selected from the group consisting of methyl and -CN, or a pharmaceutically acceptable salt thereof. (Item 55) R 2B However, each R is either unsubstituted or one or more Rs independently selected from the group consisting of methyl and -CN. B Compounds listed in items 33 to 38, or pharmaceutically acceptable salts thereof, which are substituted with 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,3-oxazole-4-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazole-5-yl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, or thiazole-4-yl. (Item 56) R 2B The compounds listed in items 33 to 38, which are imidazole-1-yl, 5-methyl-1,3-oxazole-2-yl, 5-cyanofuran-2-yl, isoxazole-3-yl, oxazole-4-yl, 6-cyanopyridine-2-yl, 5-cyanopyridine-2-yl, 1,2,4-oxadiazole-5-yl, pyridine-3-yl, pyrimidine-2-yl, isoxazole-5-yl, 1H-imidazole-2-yl or 1H-tetrazole-5-yl, or pharmaceutically acceptable salts thereof. (Item 57) R 2B However, it is either non-substituted or one or more R B A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocycline substituted with . (Item 58) R 2B However, it is either non-substituted or one or more R B Compounds listed in item 57, or pharmaceutically acceptable salts thereof, which are substituted with oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidine-1-yl, piperidine-4-yl, tetrahydro-2H-pyran-4-yl, azetidine-3-yl, 1,4-dioxepan-6-yl or tetrahydro-2H-thiopyran-4-yl. (Item 59) Each R B However, the compounds described in item 57 or 58, or pharmaceutically acceptable salts thereof, are independently selected from the group consisting of C1-C4 alkyl, halogen, oxo, and -CN. (Item 60) Each R B However, a compound described in any one of items 57 to 59, independently selected from the group consisting of methyl, fluoro, oxo, and -CN, or a pharmaceutically acceptable salt thereof. (Item 61) R 2B However, each R is either unsubstituted or one or more Rs independently selected from the group consisting of methyl, fluoro, oxo, and -CN. B Compounds listed in items 33 to 38, or pharmaceutically acceptable salts thereof, which are substituted with oxetan-3-yl, oxetan-2-yl, oxolan-3-yl (tetrahydrofuran-3-yl), pyrrolidine-1-yl, piperidine-4-yl, tetrahydro-2H-pyran-4-yl, azetidine-3-yl, 1,4-dioxepan-6-yl or tetrahydro-2H-thiopyran-4-yl. (Item 62) R 2BThe compounds listed in items 33 to 38, which are 3-fluorooxetan-3-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 3,3-difluoropyrrolidine-1-yl, 1-cyanopiperidine-4-yl, 1-methylazetidine-3-yl, 6-fluoro-1,4-dioxepan-6-yl or 1,1-dioxidetetrahydro-2H-thiopyran-4-yl, or pharmaceutically acceptable salts thereof. (Item 63) R 2B However, 1,2,4-oxadiazole-5-yl, 1,3-oxazole-2-yl, 1,4-dioxepane-6-yl, 1H-imidazole-2-yl, 1H-pyrazole-5-yl, 1H-tetrazol-5-yl, azetidine-3-yl, bicyclo[1.1.1]pentan-1-yl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, furan-2-yl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, oxazole-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), phenyl, piperidine -4-yl, pyrazine-2-yl, pyridine-2-yl, pyridine-3-yl, pyrimidine-2-yl, pyrrolidine-1-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, or thiazole-4-yl; each compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, is either unsubstituted or substituted with one or more groups independently selected from the group consisting of -CH2CN, -CN, difluoromethyl, ethyl, fluoro, methyl, methylsulfonyl, methylsulfonyloxy, -OH, oxo, phenyl, and trifluoromethyl. (Item 64) R 2BHowever, 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-oxadiazole-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanopiperidine-4-yl, 1-fluorocyclopropyl Tyl, 1-fluorocyclopropyl, 1H-imidazole-2-yl, 1H-tetrazole-5-yl, 1-hydroxycyclobutyl, 1-methylazetidine-3-yl, 2-ethylcyclopropyl, 2-fluorocyclopentyl, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl, 3,3-difluorocyclopentyl, 3,3-difluoropyrrolidine-1-yl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 3-fluoro Rooxetan-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-cyanopyridine-2-yl, 5-methyl-1,3-oxazole-2-yl, 6-cyanopyridine-2-yl, 6-fluoro-1,4-di A compound described in any one of items 33 to 38, or a pharmaceutically acceptable salt thereof, which is oxepan-6-yl, cyclobutyl, cyclopropyl, imidazole-1-yl, isoxazole-3-yl, isoxazole-5-yl, oxazole-4-yl, oxetan-2-yl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), phenyl, pyridine-3-yl, pyrimidine-2-yl, or 3-cyanophenyl. (Item 65) R 1 ga-(CH2) n -OR 2C The compound described in any one of items 1 through 5, or a pharmaceutically acceptable salt thereof. (Item 66) A compound listed in item 65, where n is 1. (Item 67) The compound listed in item 65, where n is 2. (Item 68) The compound listed in item 65, where n is 3. In some embodiments, R 2C Each of these is either unsubstituted or one or more R C These are C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 member heterocyclines that are substituted with a different compound. (Item 69) R 2C However, it is either non-substituted or one or more R C A compound described in any one of items 65 to 68, or a pharmaceutically acceptable salt thereof, which is a C1-C4 alkyl substituted with . (Item 70) R 2C However, each is either non-substitutable or one or more R C The compounds listed in item 69, or pharmaceutically acceptable salts thereof, which are substituted with ethyl, isopropyl, or methyl. (Item 71) Each R C However, independently, the compounds described in item 69 or 70, which are C3-C6 cycloalkyl or cyclic C3-C6 cycloalkyl, or pharmaceutically acceptable salts thereof. (Item 72) Each R C However, a compound described in any one of items 69 to 71, independently selected from the group consisting of cyclopropyl and -CN, or a pharmaceutically acceptable salt thereof. (Item 73) R 2C However, each of them is either unsubstituted or one or more R compounds independently selected from the group consisting of cyclopropyl and -CN. C A compound described in any one of items 65 to 68, or a pharmaceutically acceptable salt thereof, which is substituted with ethyl, isopropyl, or methyl. (Item 74) R 2CThe compound is methyl, cyano(cyclopropyl)methyl, 2-cyanopropan-2-yl, cyanomethyl, or 1-cyanoethyl, as described in any one of items 65 to 68, or a pharmaceutically acceptable salt thereof. (Item 75) R 2C However, it is either non-substituted or one or more R C A compound described in any one of items 65 to 68, or a pharmaceutically acceptable salt thereof, which is a C3-C8 cycloalkyl substituted with . (Item 76) R 2C However, it is either non-substituted or one or more R C The compounds listed in item 75, or pharmaceutically acceptable salts thereof, which are cyclobutyl substituted with cyclobutyl. (Item 77) Each R C A compound as described in item 75 or 76, wherein is -CN. (Item 78) R 2C The compounds described in any one of items 65 to 68, or pharmaceutically acceptable salts thereof, which are cyclobutyl that is unsubstituted or substituted with one or more -CNs. (Item 79) R 2C A compound according to any one of items 65 to 68, wherein is 1-cyanocyclobutyl. (Item 80) R 2C However, each is either non-substitutable or one or more R C A compound described in any one of items 65 to 68, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocycline substituted with . (Item 81) R 2C However, each is either non-substitutable or one or more R C The compounds listed in item 80, or pharmaceutically acceptable salts thereof, which are substituted with oxetan-3-yl or tetrahydro-2H-pyran-4-yl. (Item 82) R CA compound listed in item 80 or 81, or a pharmaceutically acceptable salt thereof, wherein the compound is -CN. (Item 83) R 2C The compounds described in any one of items 65 to 68, or pharmaceutically acceptable salts thereof, which are oxetan-3-yl or tetrahydro-2H-pyran-4-yl, each being unsubstituted or substituted with one or more -CN groups. (Item 84) R 2C The compound described in any one of items 65 to 68, which is oxetan-3-yl or 4-cyanotetrahydro-2H-pyran-4-yl, or a pharmaceutically acceptable salt thereof. (Item 85) R 2C The compounds described in any one of items 65 to 68, or pharmaceutically acceptable salts thereof, are ethyl, isopropyl, methyl, cyclobutyl, oxetan-3-yl, or tetrahydro-2H-pyran-4-yl, each being either unsubstituted or substituted with one or more groups independently selected from the group consisting of cyclopropyl and -CN. (Item 86) R 2C The compound described in any one of items 65 to 68, which is methyl, cyano(cyclopropyl)methyl, 2-cyanopropan-2-yl, cyanomethyl, 1-cyanoethyl, 1-cyanocyclobutyl, oxetane-3-yl, or 4-cyanotetrahydro-2H-pyran-4-yl, or a pharmaceutically acceptable salt thereof. (Item 87) R 1However, methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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- (Iyl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl, 1-methylazetidine-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-Oxadiazole-5-yl)methyl, (1-Cyanocyclobutyl)methyl, (1-Cyanocyclopropyl)methyl, (1-Cyanopiperidine-4-yl)methyl, (1-Fluorocyclobutyl)methyl, (1-Fluorocyclopropyl)methyl, (1H-Imidazole-2-yl)methyl, (1H-Tetazol-5-yl)methyl, (1-Hydroxycyclobutyl)methyl, (1-Methylazetidine-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-cyanopyridine-2-yl)methyl, (5-methyl-1,3-oxazole-2-yl)methyl, (6-cyanopyridine-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazole-3 -yl)methyl, (isoxazole-5-yl)methyl, (oxazole-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridine-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-(1H-imidazole-1-yl)ethyl, 2-(3,3-difluoropyrrolidine-1-yl)ethyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl , cyclopropylmethyl, pyrimidine-2-ylmethyl, (2-cyanopropane-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-(oxetane-3-yloxy)ethyl, 2-methoxyethyl, 5,5,5-trifluoropentyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, 4,4,4-trifluorobutyl, or (2,2-difluorocyclopropyl)methyl, any of the compounds described in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof. (Item 88) R 1 However, methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propane-2-yl, 1,1,1-trifluoropropane-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 C-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)cyclo A compound described in any one of items 1 to 5, which is hexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxetan-3-yl, oxolan-3-yl (tetrahydrofuran-3-yl), 2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl, 1-methylazetidine-3-yl, 5,5,5-trifluoropentyl, or 4,4,4-trifluorobutyl, or a pharmaceutically acceptable salt thereof. (Item 89) R 1However, (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-oxadiazole-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl (Pyropropyl)methyl, (1-cyanopiperidine-4-yl)methyl, (1-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazole-2-yl)methyl, (1H-tetrazole-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylazetidine-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-cyanopyridine-2-yl)methyl, (5-methyl-1,3-oxazole-2-yl)methyl, (6-cyanopyridine-2-yl)methyl, (6-fluoro-1,4-dioxepan-6-yl)methyl, (isoxazole-3-yl)methyl, (isoxazole-5-yl)methyl, (oxazole-4-yl)methyl, (oxetan-2-yl)methyl, (oxetan-3-yl)methyl, (pyridine-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-( A compound listed in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, which is 1H-imidazole-1-yl)ethyl, 2-(3,3-difluoropyrrolidine-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), pyrimidine-2-ylmethyl, 3-cyanobenzyl, 4-fluorophenethyl, cyclobutylmethyl, or (2,2-difluorocyclopropyl)methyl, or a pharmaceutically acceptable salt thereof. (Item 90). R 1 The compounds listed in any one of items 1 to 5, which are (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-(oxetane-3-yloxy)ethyl, or 2-methoxyethyl, or pharmaceutically acceptable salts thereof. (Item 91) The following compounds: (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]isoquinoline-2-ol (compound 4-1); (2R,3S,11bS)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-2); (2R,3S,11bS)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-3); (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-4); (2R,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compounds 4-5); (2S,3S,11bS)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-6); (2S,3S,11bS)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-7); (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-8); (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-9); (2S,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-10); (2S,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-11); (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-12); (2R,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-13); (2R,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-14); (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]isoquinoline-2-ol (compound 4-15); (2S,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-16); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-ethoxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-17); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-fluoroethoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-18); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(3-fluorooxetan-3-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-19); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[2-(oxetane-3-yloxy)ethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-20); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-oxetane-2-ylmethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-21); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetan-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-22); 1-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)cyclobutan-1-carbonitrile (compound 4-23); 2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}acetonitrile (compound 4-24); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-hydroxycyclobutyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-25); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2-methoxyethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-26); (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-27); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(3-fluoropropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-28); 1-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)cyclopropane-1-carbonitrile (compound 4-29); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetane-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-31); (2R,3R,11bR)-9-cyclobutoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-32); 2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}-N,N-dimethylacetamide (compound 4-33); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-(1H-imidazole-1-yl)ethoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-34); 2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}-N-methylacetamide (compound 4-35); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(5-methyl-1,3-oxazol-2-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-36); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylazetidine-3-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-37); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(propan-2-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-38); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1,1,1-trifluoropropan-2-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-39); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(ethoxy-d5)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-40); 4-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)oxane-4-carbonitrile (compound 4-41); 1-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)cyclobutan-1-carbonitrile (compound 4-42); 2-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)-2-cyclopropylacetonitrile (compound 4-43); 2-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)-2-methylpropanenitrile (compound 4-44); 1-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethyl)cyclopropane-1-carbonitrile (compound 4-45); 2-[1-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)cyclopropyl]acetonitrile (compound 4-46); (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]isoquinoline-2-ol (compound 4-47); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxy-3-methoxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-48); (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]isoquinoline-2-ol (compound 4-49); (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]isoquinoline-2-ol (compound 4-50); (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]isoquinoline-2-ol (compound 4-51); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(methoxy-d3)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-52); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxolane-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-53); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3S)-oxolane-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-54); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-55); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2-methylpropane-2-en-1-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-56); (2R,3R,11bR)-9-{[1-(difluoromethyl)cyclopropyl]methoxy}-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-57); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxybutoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-58); 5-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)furan-2-carbonitrile (compound 4-59); (2R,3R,11bR)-9-(benzyloxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-60); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclobutyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-61); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(4,4,4-trifluoro-2-hydroxybutoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-62); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(4-fluorophenyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-63); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(3-fluorophenyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-64); (2R,3R,11bR)-9-(2-chloro-2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-65); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-66); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-67); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxybutoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-68); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-oxazole-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-69); 2-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)acetonitrile (compound 4-70); (2R,3R,11bR)-9-[2-(3,3-difluoropyrrolidine-1-yl)ethoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-71); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(6-fluoro-1,4-dioxepand-6-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-72); 4-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)piperidine-1-carbonitrile (compound 4-73); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-74); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,3-oxazole-4-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-75); (2R,3R,11bR)-9-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-76); 6-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)pyridine-2-carbonitrile (compound 4-77); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-{[3-hydroxy-3-(trifluoromethyl)cyclobutyl]methoxy}-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-78); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-79); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[1-(trifluoromethyl)cyclopentyl]methoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-80); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[4-(trifluoromethyl)phenyl]methoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-81); 6-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)pyridine-3-carbonitrile (compound 4-82); (2R)-3-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}propane-1,2-diol (compound 4-83); 2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound 4-84); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(3-methanesulfonylpropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-85); 1-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}-N,N-dimethylmethanesulfonamide (compound 4-86); 3-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}-1-(2,2,2-trifluoroethyl)pyrrolidine-2-one (compound 4-87); (2R,3R,11bR)-9-(cyclopropylmethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-88); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(3-hydroxypropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-89); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-{[(1R,2R)-2-ethylcyclopropyl]methoxy}10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-90); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2R)-2-methoxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-91); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-2-methoxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-92); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-ethyl-2-hydroxybutoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-93); 1-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}methyl)cyclopropylmethanesulfonate (compound 4-94); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2,4-oxadiazole-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-95); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-methanesulfonylcyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-96); 4-({[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxymethyl)-1λ 6 -thian-1,1-dione (compound 4-97); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-hydroxyethoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-98); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[4-(trifluoromethyl)cyclohexyl]oxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-99); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2-fluorocyclopentyl)oxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-100); (2R,3R,11bR)-9-[(3,3-difluorocyclopentyl)oxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-101); (2R,3R,11bR)-9-[(4-difluoromethanesulfonylphenyl)methoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-102); (2R,3R,11bR)-9-(3-chloro-3,3-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-103); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylazetidine-3-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-104); 2-(2-{[(2R,3R,11bR)-3-(2,2-dimethylpropyl)-2-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-9-yl]oxy}ethoxy)propanenitrile (compound 4-105); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-({3-fluorobicyclo[1.1.1]pentan-1-yl}methoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-106); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyridine-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-107); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyrimidine-2-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-108); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-oxazole-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-109); (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(1H-imidaz...

Claims

[Claim 1] The invention described herein.

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