Vmat2 inhibitors and methods of use

Abstract

This invention relates generally to VMAT2 inhibitor compounds, compositions, and related methods.

Description

[Technical Field]

[0001] This invention generally relates to VMAT2 inhibitor compounds, compositions, and related methods. [Previous Technology]

[0002] Dysfunction of the dopamine system is an essential condition for several central nervous system (CNS) disorders, including neurological and psychiatric illnesses and conditions. These neurological and psychiatric illnesses and conditions include hyperactivity disorders and symptoms such as schizophrenia and mood disorders. Vesicular monoamine transporter-2 (VMAT2) plays an important role in presynaptic dopamine release and regulates the uptake of monoamines from the cytoplasm to synaptic vesicles for storage and release.

[0003] For decades, (±)-tetrabenazine ((±)-TBZ) has been used as a drug. (±)-TBZ has been reported as a potent and reversible inhibitor of catecholamine uptake via VMAT2 (IC50 = 3.2 nM) (see, for example, Scherman et al., Proc. Natl. Acad. Sci. USA, (1983) 80:584-8), and is currently used to treat various hyperactivity disorders. Inhibition of VMAT2 by (±)-TBZ causes in vivo depletion of brain monoamines (see, for example, Pettibone et al., Eur. J. Pharmacol. (1984) 102:431-6). (±)-TBZ also inhibits presynaptic and postsynaptic dopamine receptors in the rat brain (see, for example, Login et al., (1982) Ann. Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521). After oral administration to humans, (±)-TBZ exhibits extensive first-pass metabolism, with little or no (±)-TBZ observed in systemic circulation. Therefore, the pharmacological activity of (±)-TBZ is considered to be primarily mediated by its active metabolite. (±)-TBZ possesses two antipallic centers and is a racemic mixture of two stereoisomers. Four metabolic stereoisomers of (±)-TBZ have been identified in vivo by carbonyl reductase rapidly and adequately metabolized to 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 inhibitory constants of these four metabolites of VMAT2 have been reported in examples such as WO2008 / 058261, Example 7. As shown, only two of the four DHTBZ isomers ([+]-α-DHTBZ and [+]-β-DHTBZ) exhibit significant efficacy as VMAT2 inhibitors. (±)-TBZ metabolites pKi Ki [+]-α-DHTBZ (2R,3R,11bR) 8.7 ± 0.2 (n=6) 1.9 nM [+]-β-DHTBZ (2S,3R,11bR) 7.9 ± 0.1 (n=5) 13 nM [-]-α-DHTBZ (2S,3S,11bS) 6.7 ± 0.1 (n=3) 202 nM [-]-β-DHTBZ (2R,3S,11bS) 6.1 ± 0.1 (n=4) 714 nM

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

[0005] (±)-TBZ has a narrow therapeutic window and its clinical use requires careful dose titration. Side effects associated with (±)-TBZ and / or its metabolites include sedative-malignant syndrome, somnolence, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia, and Parkinson's disease. Generally, the probability of observing side effects is a function of the plasma concentration achieved by the established dosing regimen. Given equivalent dosing intervals, compounds with longer half-lives (t1 / 2) and lower clearance will exhibit lower peak-to-trough fluctuations in plasma exposure. These longer-half-lived compounds can exhibit improved tolerability by maintaining drug concentrations at levels necessary for efficacy but below levels that may cause side effects.

[0006] A fundamental and effective strategy for improving drug half-life is to reduce clearance. Clearance, as a term, describes the process by which a drug is eliminated from the body or from a single organ, and is defined as the fluid volume of drug cleared from the body per unit time. Clearance is a fundamental pharmacokinetic parameter and is frequently measured in drug research and development because it affects drug properties, such as half-life, and ultimately, dosing regimens. When compound and dose selection is optimized, the benefits of smaller plasma concentration fluctuations seen in compounds with low clearance include the potential for reduced steady-state peak concentrations, increased trough concentrations, and the possibility of improved drug adherence due to a potentially improved risk-benefit profile.

[0007] Despite advancements in this technology, modified VMAT2 inhibitors, including related compounds, compositions, and methods, are still needed. Identifying small VMAT2 molecules with long half-lives / low clearance is beneficial for drug development, especially for long-term administration. In certain disease populations where patient compliance and pill load pose ongoing challenges, reducing dosing frequency is highly desirable and provides increased patient benefits.

[0008] The present invention satisfies such, such as improved in vitro VMAT2 efficacy or improved pharmacokinetics or both, and other needs, as will be apparent from the following disclosure. [Summary of the Invention]

[0009] Some embodiments provide compounds of formula (I): , or pharmaceutically acceptable salts thereof, wherein: R1 is R2A, -(CH2)m-R2B or -(CH2)n-OR2C; R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4 to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RAs; each RA 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 dialkylaminosulfonyl, halogen, halogroup C1-C4 alkoxy, halogroup C1-C4 alkyl, halogroup C2-C4 dialkylamino, 4 to 7-membered heterocyclic group, -CN, -OH and side oxygen groups; R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RBs; each RB is independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halogroup C1-C4 alkyl, halogroup C1-C4 alkylsulfonyl, lateral oxygen, and -OH; R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RCs; each RC is independently -CN or C3-C6 cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0010] This article also provides a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] This article also provides a pharmaceutical product selected from: pharmaceutical compositions, formulations, unit dosage forms and kits; each containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] This article also provides a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] This article also provides a pharmaceutical product 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.

[0014] This article also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0015] This document also provides a compound of formula (I) or a medically acceptable salt thereof for the treatment of neurological or psychiatric diseases or conditions in individuals in need.

[0016] This article also provides a method for inhibiting VMAT2, which includes contacting the VMAT2 with a compound of formula (I).

[0017] This article also provides a method for reducing the monoamine content in the central nervous system of an individual, which includes administering to the individual a certain amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such amount being sufficient to reduce the monoamine content in the central nervous system relative to the content before administration.

[0018] This article also provides a method for treating vesicle monoamine transporter-2 (VMAT2) disease or condition in an individual in need, comprising administering to the individual: 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.

[0019] This article also provides a method for treating a neurological or mental illness or condition in an individual in need, comprising administering to the individual: 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.

[0020] This article also provides a method for treating an individual’s neurological or mental illness or condition, which includes administering to the individual a compound of formula (I) or a medically acceptable salt thereof.

[0021] This article also provides a method for treating a neurological or mental illness or condition in an individual in need, comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof, and other pharmaceutical agents selected from: antidepressants, antipsychotics (typical or atypical), antiepileptics, antimicrobial agents, antiarrhythmics, mood stabilizers, and gastrointestinal drugs.

[0022] This article also provides a method for improving one or more symptoms of a neurological or psychiatric illness or condition, comprising administering to an individual in need an effective amount of at least one compound of formula (I) or a medically acceptable salt thereof; wherein the neurological or psychiatric illness or condition is selected from the group consisting of: hyperactivity disorder, schizophrenia, affective schizophrenia, mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, X-chromosome fragility syndrome or X-chromosome fragility-associated tremor-dyskinesia syndrome, autism spectrum disorder, Rett syndrome, and chorea-like acanthosis.

[0023] This document also provides the use of 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, and a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating vesicular monoamine transporter-2 (VMAT2) disease or condition.

[0024] This document also provides the use of 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, and a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neurological or mental illnesses or conditions.

[0025] This document also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neurological or mental illnesses or conditions.

[0026] This document also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of neurological or psychiatric disorders or conditions, wherein the neurological or psychiatric disorders or conditions are selected from the group consisting of: hyperactivity disorder, schizophrenia, affective schizophrenia, mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Leni syndrome, agitation associated with Alzheimer's disease, X-chromosome fragility syndrome or X-chromosome fragility-associated tremor-dysregulation syndrome, pan-autism disorder, Rett syndrome and chorea-like acanthosis.

[0027] This document also provides 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, and a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, used in a method of treating a human or animal body by means of a therapy.

[0028] Also provided herein are a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used in a method of treating a human or animal body by resorting to therapy.

[0029] Also provided herein are a compound of formula (I) or a pharmaceutically acceptable salt thereof, a medical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used in a method of treating a vesicular monoamine transporter protein-2 (VMAT2) disease or condition.

[0030] Also provided herein are a compound of formula (I) or a medically acceptable salt thereof, a medical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used in a method of treating a neurological or psychiatric disorder or condition.

[0031] A compound of formula (I) or a medically acceptable salt thereof is also provided herein for the treatment of a neurological or psychiatric disorder or condition.

[0032] In some embodiments, the neurological or psychiatric disorder or condition is selected from the group consisting of: hyperkinetic movement disorder, schizophrenia, affective schizophrenia, mood disorder, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lenny syndrome, irritability associated with Alzheimer's disease, X chromosome fragility syndrome or X chromosome fragility-associated tremor-ataxia syndrome, pan-autistic chorea-acant syndrome, Rett-like syndrome.

[0033] In some embodiments, the vesicular monoamine transport protein-2 (VMAT2) disease or condition is selected from the group consisting of: arrhythmia or spinal muscular dystrophy; chorea; congenital malformations, deformities, or abnormalities; dementia; diseases of the oral cavity, salivary glands, or palate; movement difficulties; muscle dystonia; endocrine, nutritional, or metabolic diseases; epilepsy; habitual or impulsive disorder; disease); [Implementation Method]

[0035] For clarity and consistency, the following definition will be used throughout this patent document.

[0036] As used herein, “about” means ±20% of the stated value, and more specifically includes ±10%, ±5%, ±2% and ±1% of the stated value.

[0037] As used herein, “administer” means to deliver to an individual the compound or other therapy described herein in a therapeutically useful form and in a therapeutically useful amount, including but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions and the like; injectable dosage forms, such as IV, IM, IP and the like; transdermal dosage forms, including creams, gels, powders and patches; buccal dosage forms; inhaled powders, sprays, suspensions and the like; and rectal suppositories.

[0038] Healthcare providers may directly provide individuals with the compounds described herein in sample form or indirectly by providing oral or written prescriptions for the compounds. Alternatively, for example, individuals may obtain the compounds independently without the involvement of a healthcare provider. When a compound is administered to an individual, the body is transformed to some extent by the compound. When the compounds described herein are provided in combination with one or more other pharmaceutical agents, it should be understood that "administration" includes the simultaneous or separate administration of the compound and other pharmaceutical agents. When a combination of agents is administered simultaneously, it may be administered as a single composition or separately. Preferred administration methods may vary depending on various factors, such as the composition of the pharmaceutical preparation, the location of the disease, and the severity of the disease.

[0039] The term "composition" means a compound or its crystalline form in combination with at least one other component, including but not limited to salts, solvates and hydrates of the compounds described herein, such as compositions obtained / prepared during synthesis, pre-formulation, process testing (e.g., TLC, HPLC, NMR samples) and the like.

[0040] As used herein, the term "compound" means to include all stereoisomers, geometric isomers, tautomers, and isotopic variants of the described structure. The term also means the compound described herein prepared in any manner, such as synthetically, via biological processes (e.g., metabolism or enzymatic conversion), or a combination thereof. All compounds and their pharmaceutically acceptable salts may be present with or be separable from other substances such as water and solvents (e.g., hydrates and solvates). When in the solid state, the compounds and their salts described herein may exist in various forms, and may be, for example, in the form of eutectic or solvates (including hydrates). Compounds may be in any solid form, such as polymorphs or solvates, and therefore, unless otherwise clearly indicated, references to compounds and their salts in the specification should be understood to cover any solid form of the compound. In some embodiments, the compounds or their salts described herein are substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, compositions rich in the compounds described herein. The separation may substantially include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound or its salt described herein.

[0041] As used herein, the term "solvent" refers to the solid form of the compound described herein or its pharmaceutically acceptable salt, including stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0042] As used herein, the term "hydrate" means the compound or salt thereof described herein that further includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0043] The terms "requiring treatment" and "needing" when referring to treatment are used interchangeably, meaning a judgment made by a caregiver (e.g., a physician, nurse, or registered nurse in the case of humans; or a veterinarian in the case of animals including non-human mammals) that an individual or animal needs treatment or will benefit from treatment. This judgment is based on a variety of factors within the caregiver's area of ​​expertise, in addition to knowledge that the individual or animal is sick or will become sick due to a disease, symptom, or condition that can be treated by the compounds described herein. Therefore, the compounds described herein may be used in a protective or preventative manner; or the compounds described herein may be used to alleviate, suppress, or improve a disease, symptom, or condition.

[0044] The term "individual" means 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, screening, or activity studies, an individual may be a healthy volunteer or participant without potential VMAT2-mediated conditions or symptoms, or a volunteer or participant who has been diagnosed with a condition or symptom requiring medical treatment as determined by a healthcare professional. Outside of clinical trials, individuals diagnosed with a condition or symptom under the care of a healthcare professional are typically described as patients.

[0045] The term "pediatric individual" refers to an individual who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further subdivided into various subgroups including: newborns (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (up to but not including the twenty-second birthday)), see, for example, Berhman et al., Textbook of Pediatrics, 15th edition Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994.

[0046] The phrase “medically acceptable” means a compound (and its salts), composition and / or dosage form that is suitable for contact with human and animal tissues within the scope of reasonable medical judgment and without excessive toxicity, irritation, allergic reaction or other problems or complications, and whose benefits / risks are commensurate with reasonable risk.

[0047] The term "pharmaceutical composition" means a particular composition comprising at least one active ingredient, including but not limited to salts, solvates, and hydrates of compounds described herein, which enables the study of a specified efficacy outcome of the composition in mammals (e.g., but not limited to humans). Those skilled in the art will understand and appreciate the techniques suitable for determining, on the basis of the needs of a technician, whether an active ingredient has the desired efficacy outcome.

[0048] The term "prevent / preventing / prevention" refers to eliminating or reducing the occurrence or onset of one or more symptoms associated with a specific condition. For example, the term "prevention" may refer to administering therapy to an individual who may eventually develop at least one symptom of the condition but has not yet done so, on a preventative or preventative basis. Such individuals may be identified based on known risk factors associated with the subsequent occurrence of the disease, such as the presence of biomarkers. Alternatively, preventative therapy may be administered as a preventative measure without prior identification of risk factors. Delaying at least one onset of the condition and / or the onset of symptoms may also be considered prevention or preventative. In some embodiments, the individual may be a pediatric individual.

[0049] The term "treatment" refers to the medical management of an individual's (i.e., a patient's) disease, condition, or symptom (see, for example, Stedman's Medical Dictionary). Generally, appropriate doses and treatment regimens provide an amount of VMAT2 inhibitor sufficient to provide therapeutic benefit. The therapeutic benefits to individuals given the VMAT2 inhibitor compounds described herein include, for example, improved clinical outcomes, where the goal is to prevent or slow or delay (reduce) unwanted physiological changes associated with the disease or to prevent or slow or delay (reduce) the progression or severity of such disease. The effects of one or more VMAT2 inhibitors may include beneficial or desired clinical outcomes, including, but not limited to, reduction, alleviation, or relief of symptoms caused by or related to the disease being treated; reduction of symptom incidence; improvement of quality of life; prolongation of disease-free status (i.e., reducing the likelihood or predisposition of an individual to present with symptoms based on a disease diagnosis); reduction of disease severity; stabilization of the disease state (i.e., preventing its deterioration); delay or slowing of disease progression; improvement or mitigation of the disease state; and remission (whether partial or complete), whether detectable or undetectable; and / or overall survival. In some embodiments, the individual may be a pediatric individual.

[0050] The term “therapeutic effective amount” means the amount of the compound described herein or a pharmaceutically acceptable salt thereof, or the amount of a pharmaceutical composition containing the compound described herein or a pharmaceutically acceptable salt thereof, which elicits a biological or pharmaceutical response in an individual, researcher, veterinarian, physician or other clinician or caregiver, in a tissue, system, animal or human, which may include one or more of the following: (1) prevention of disease, such as prevention of disease, symptom or condition in an individual who may be susceptible to disease, symptom or condition but has not yet experienced or shown the relevant pathology or symptoms; (2) inhibition of disease, such as inhibition of disease, symptom or condition in an individual who is experiencing or showing the relevant pathology or symptoms (i.e., curbing the further development of the pathology and / or symptoms); and (3) improvement of disease, such as improvement of disease, symptom or condition in an individual who is experiencing or showing the relevant pathology or symptoms (i.e., reversing the pathology and / or symptoms).

[0051] As used herein, the term "contact" means bringing the indicated portion into an in vitro or in vivo system. For example, "contacting" the VMAT2 protein with the compounds provided herein includes administering the compounds provided herein (or their pharmaceutically acceptable salts) to an individual (such as a human) possessing the VMAT2 protein, and, for example, introducing the compounds provided herein into a sample containing cells or a purified formulation (containing the VMAT2 protein).

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, applications, publications and other publications are incorporated herein by reference in their entirety. Unless otherwise stated, where multiple definitions exist for a term herein, the definition in this section shall prevail.

[0053] The term "n-membered" where n is an integer typically describes the number of cyclic atoms in a portion, where the number of cyclic atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclic ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0054] For compounds of formula (I) and their pharmaceutically acceptable salts, where the variable appears more than once, each variable may be an independently selected different part of the group defining the variable. For example, in the case where the structure is described to have, for example, two R groups present simultaneously on the same compound, the two R groups may represent independently selected different parts of the group defined for R, or the two R groups may be the same.

[0055] Whenever a group is described as "substituted", the group may be substituted by one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituent may be one or more of the indicated substituents. It should be understood that substitution at a given atom is subject to valence number restrictions.

[0056] As used herein, “Ca-Cb”, where “a” and “b” are integers, refers to, for example, the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, or aryl ring. That is, such groups may contain “a” to “b” carbon atoms (including the endpoints). Thus, for example, “C1-C4 alkyl” refers to all alkyl groups having 1 to 4 carbons, namely, methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), secondary butyl (CH3CH2CH(CH3)-), and tertiary butyl ((CH3)3C-). Unless "a" and "b" are specified with respect to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl, the broadest range described in these definitions shall apply.

[0057] Except as stated above, unless otherwise indicated, the following terms shall have the meanings indicated as used in this specification and the appended claims:

[0058] The term "alkenyl" refers to an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. Examples of alkenyl groups include alladienyl, vinylmethyl, and vinyl. Examples of alkenyl groups include: vinyl (CH2=CH-), propen-1-en-2-yl (CH2=C(Me)-), propen-1-en-1-yl (MeCH=CH-), allyl (CH2=CHCH2-), buten-2-en-2-yl (CH3CH=C(Me)-), buten-1-en-1-yl (MeCH2CH=CH-), buten-1-en-2-yl (CH2=C(Et)-), 2-methylpropen-1-en-1-yl (Me2C=CH-), buten-3-en-2-yl (CH2=CHCH(Me)-), 2-methylallyl (CH2=C(Me)CH2-), buten-2-en-1-yl (MeCH=CHCH2-), buten-3-en-1-yl (CH2=CHCH2CH2-), and buten-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 names.

[0059] The term "alkoxy" refers to the formula -OR, where R is an alkyl group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy, and tertiary butoxy. Alkoxy groups may be "C1-C6 alkoxy," "C1-C4 alkoxy," or similar names. In some embodiments, the alkoxy group may be substituted or unsubstituted.

[0060] The term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon group. An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 20" refer to integers within a defined range; for example, "1 to 20 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some embodiments, an alkyl group may have 1 to 6 carbons (i.e., "C1-C6 alkyl"). Some embodiments have 1 to 5 carbons (i.e., C1-C5 alkyl), some embodiments have 1 to 4 carbons (i.e., C1-C4 alkyl), some embodiments have 1 to 3 carbons (i.e., C1-C3 alkyl), and some embodiments have 1 or 2 carbons. By way of example only, "C1-C4 alkyl" The specification indicates that one to four carbon atoms are present in the alkyl chain, meaning the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl. Examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, pentyl, isopentyl, tertiary pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and similar groups. When one or more substituents are present on the alkyl group, the substituents can be bonded at any available carbon atom. In some embodiments, the alkyl group may be substituted or unsubstituted.

[0061] The term "alkylamine" refers to an amino group (-NH2) in which a nitrogen atom is substituted by an alkyl group. The term "alkyl" has the same definition as described herein. An "alkylamine" may have 1 to 4 carbon atoms (i.e., C1-C4 alkylamine). Examples of alkylamine groups include -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3) and similar groups.

[0062] The term "alkynyl" refers to an alkyl group containing one or more linkages in a straight-chain or branched hydrocarbon chain. Examples of alkynyl groups 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 2 to 6 carbon atoms. The alkenyl group of the compound may be designated as "C2-C6 alkynyl" or a similar name.

[0063] The term "alkylsulfonyl" refers to a group consisting of an alkyl group bonded to a sulfur atom of an alkyl group of the formula: -S(=O)2-, wherein the alkyl group has the same definition as described herein. An "alkylsulfonyl" may have 1 to 4 carbon atoms (i.e., C1-C4 alkylsulfonyl). Examples include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, secondary butanesulfonyl, isobutanesulfonyl, tertiary butanesulfonyl, and similar groups.

[0064] The term "alkylsulfonyloxy" refers to a group consisting of an alkyl group bonded to a sulfur atom of a sulfonyloxy group of the formula: -S(=O)2O-, wherein the alkyl group has the same definition as described herein. An "alkylsulfonyloxy" may have 1 to 4 carbon atoms (i.e., C1-C4 alkylsulfonyloxy). Examples include methylsulfonyloxy (CH3S(=O)2O-), ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, secondary butylsulfonyloxy, isobutylsulfonyloxy, tertiary butylsulfonyloxy, and similar groups.

[0065] The term "amine group" refers to the group -NH2.

[0066] The term "aryl" refers to an aromatic ring system containing 6, 10, or 14 carbon atoms, which may contain a monocyclic, two-fused, or three-fused rings, such as phenyl, naphthyl, and phenanthrene. In some embodiments, the aryl group may have 6 or 10 carbon atoms (i.e., C6 or C10 aryl). In some embodiments, the aryl group is phenyl. When one or more substituents are present on the "aryl" ring, the substituents may be bonded to any available ring carbon. In some embodiments, the aryl group may be substituted or unsubstituted.

[0067] "C-amino group" refers to "-C(=O)N(RARB)" which is attached to the rest of the molecule via a carbon atom, and wherein RA and RB can be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C10 aryl, heteroaryl or heterocyclic group.

[0068] The term "carbonyl" refers to the group -C(=O)-.

[0069] The term "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond exists, the double bond cannot extend to all rings to form a completely nonlocalized π-electronic system (i.e., an aromatic system), otherwise the group will be "aryl" as defined herein. When composed of two or more rings, the rings can be fused, bridged, or spirocoupled together. The cycloalkenyl group may contain 3 to 12 atoms or 3 to 8 atoms in the ring. 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"). An example is cyclohexenyl.

[0070] The term "cycloalkyl" refers to all fully saturated monocyclic or polycyclic systems of carbon atoms. 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"). Some embodiments contain 3 to 6 carbons (i.e., "C3-C6 cycloalkyl"). Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, bicyclic [1.1.1]pentane, and cyclohexyl. When one or more substituents are present on a cycloalkyl group, the substituents may be bonded to any available carbon atom. In some embodiments, the cycloalkyl group may be substituted or unsubstituted.

[0071] The term "dialkylamino" refers to an amino group (-NH2) in which nitrogen is substituted by two alkyl groups. The two alkyl groups may be the same or different. The term "alkyl" has the same definition as described herein. "Dialkylamino" may have 1 to 4 carbon atoms (i.e., C2-C4 dialkylamino), limited by the condition that the two alkyl groups do not exceed a total of 4 carbon atoms between the two groups. Examples include -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CH2CH2CH3) and similar groups.

[0072] The term "dialkylamine sulfonyl" refers to a sulfonamide group (-S(=O)2NH2) in which nitrogen is substituted by two alkyl groups, which may be the same or different. The term "alkyl" has the same definition as described herein. "Dialkylamine sulfonyl" may have 1 to 4 carbon atoms (i.e., C2-C4 dialkylamine sulfonyl), limited by the condition that the two alkyl groups do not exceed a total of 4 carbon atoms between the two alkyl groups. Examples include -SO2N(CH3)2, -SO2N(CH3)(CH2CH3), -SO2N(CH3)(CH2CH2CH3), -SO2N(CH2CH3)2, -SO2N(CH2CH3)(CH2CH2CH3) and similar groups.

[0073] 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 1 to 6 carbon atoms. The haloalkoxy group of a compound may be designated as "haloC1-C6 alkoxy," "haloC1-C4 alkoxy," or similar names.

[0074] As defined herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by halogen atoms (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). In some embodiments, the haloalkyl group may have 1 to 6 carbon atoms (i.e., "haloC1-C6 alkyl"). The haloC1-C6 alkyl group may be fully substituted, in which case it may be represented by the formula CnL2n+1, where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. When more than one halogen is present, it may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl group contains 1 to 5 carbon atoms (i.e., haloC1-C5 alkyl). In some embodiments, the haloalkyl group contains 1 to 4 carbon atoms (i.e., haloC1-C4 alkyl). In some embodiments, the haloalkyl group contains 1 to 3 carbon atoms (i.e., haloC1-C3 alkyl). In some embodiments, the haloalkyl group contains 1 or 2 carbon atoms. Examples of alkyl halides include fluoromethyl, difluoromethyl, trifluoromethyl, dichlorofluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl and the like.

[0075] The term "haloalkylsulfonyl" refers to a group consisting of a haloalkyl group bonded to a sulfur group of the formula: -S(=O)2-, wherein the haloalkyl group has the same definition as described herein. "Haloalkylsulfonyl" may have 1 to 4 carbon atoms (i.e., halogroup C1-C4 alkylsulfonyl). Examples include fluoromethanesulfonyl, difluoromethanesulfonyl, trifluoromethanesulfonyl, chlorodifluoromethanesulfonyl, 1-fluoroethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, pentafluoroethanesulfonyl, 4,4,4-trifluorobutyryl and similar groups.

[0076] The term "halodialkylamine" refers to an amino group (-NH2) in which nitrogen is substituted by one alkyl group and one or two haloalkyl groups. When nitrogen is substituted by two haloalkyl groups, these groups may be the same or different. The terms "alkyl" and "haloalkyl" have the same definitions as described herein. "Halodialkylamine" may have 1 to 4 carbon atoms (i.e., halogroup C2-C4 dialkylamine), limited by the condition that the two groups do not exceed a total of 4 carbon atoms between the two groups. Examples include -N(CH3)(CF3), -N(CH3)(CF3), -N(CF3)2, -N(CH3)(CH2CF3), -N(CH2CF3)2 and similar groups.

[0077] The terms "halogen" or "halogen group" refer to a fluorine group, a chlorine group, a bromine group, or an iodine group. In some embodiments, the halogen or halogen group is fluorine, chlorine, or bromine. In some embodiments, the halogen or halogen group is fluorine or chlorine. In some embodiments, the halogen or halogen group is fluorine.

[0078] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system having at least one heteroatom in the ring system, that is, an element other than carbon, including but not limited to nitrogen, oxygen and sulfur. Some embodiments are "5- to 6-membered heteroaryl", which refers to an aromatic ring containing 5 to 6 ring atoms in a single ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridinyl, pyridyl, pyridyl, trifuryl, furanyl, quinolinyl, isoquinolinyl, thiophenyl, imidazolyl, thiazolyl, indole, isoindole, acezolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, isoacezolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazoleyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenazinyl, benzimidazolyl, pyrroleyl, quinolinyl, isoquinolinyl, benzoisoacezolyl imidazo[1,2-b]thiazolyl, and the like. Heteroaryl groups 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 "5 to 7-membered heteroaryl," "5 to 10-membered heteroaryl," or similar names. In some embodiments, the heteroaryl group may be a C1-C13 monocyclic, bicyclic, or tricyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, whether substituted or unsubstituted. In some embodiments, the heteroaryl group may be a C1-C5 monocyclic ring comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, whether substituted or unsubstituted. In some embodiments, the heteroaryl group may be a C5-C98-membered, 9-membered, or 10-membered bicyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, whether substituted or unsubstituted. In some embodiments, the heteroaryl group is a C5-C98-membered, 9-membered, or 10-membered heteroaryl group, whether substituted or unsubstituted. In some embodiments, the C5-C98, 9, or 10-member bicyclic heteroaryl group is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoisoazolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinolinyl, pyrido[3,4-b]pyridyl, or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryl group is a substituted or unsubstituted C8-C1313 or 14-member tricyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group may be an azole group, such as imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, acezolyl, or isoacezolyl, each of which may be substituted or unsubstituted. In some embodiments, the heteroaryl group is a C1-C45 heteroaryl group.In some embodiments, the C1-C45 heteroaryl group is furanyl, thiophene, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isozolyl, acezolyl, pyrroleyl, triazolyl, or tetrazolyl. In some embodiments, the heteroaryl group is C3-C56 heteroaryl. In some embodiments, the C3-C56 heteroaryl group is pyridinyl, pyrimidinyl, pyridyl, pyridyl, or triazolyl. In some embodiments, "5 to 10 heteroaryl groups" refers to: furanyl, thiopheneyl, pyrrolyl, imidazolyl, acezolyl, thiazolyl, isoacezolyl, pyrazolyl, isothiazolyl, acediazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, quinolinyl, triazolyl, benzofuranyl, 1H-indolyl, benzo[b]thiopheneyl, and similar groups. In some embodiments, "5 to 10 heteroaryl groups" refers to: pyridyl, pyridyl, pyridyl, pyrimidinyl, 1H-indolyl, quinolinyl, thiadiazolyl, and similar groups. In some embodiments, "5 to 10 heteroaryl groups" refers to: pyridyl, pyridyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinolinyl, thiadiazolyl, imidazo[4,5-c]pyridinyl, and similar groups. In some embodiments, the heteroaryl groups may be substituted or unsubstituted.

[0079] The term "heterocyclic group" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, or up to 18-membered monocyclic, bicyclic, and tricyclic ring systems, wherein a carbon atom, together with 1 to 5 heteroatoms, constitutes the ring system and, where appropriate, contains one or more unsaturated bonds, however, such unsaturated bonds are positioned such that a completely delocalized π-electron system (aromatic system) does not appear in the monocyclic or at least one ring of 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 by fusion, bridging, or spirocoupling, wherein heteroatoms may be present in non-aromatic or aromatic rings of the ring system. In some embodiments, "4- to 7-membered heterocyclic group" refers to a saturated non-aromatic ring system containing 4 to 7 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "3- to 6-membered heterocyclic group" refers to a saturated non-aromatic cyclic group containing 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclic group" refers to a saturated non-aromatic cyclic group containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, one or two heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, the heterocyclic group may include a carbonyl group (C=O) adjacent to the heteroatom, i.e., substituted with a side oxygen group on the carbon adjacent to the heteroatom, wherein the substituted ring system is an lactone, lactone, cycloalimine, cyclic thioalimine, or cyclic carbamate.Examples of "heterocyclic groups" that are unsubstituted or substituted with a side oxygen group include, but are not limited to, aziridinyl, acrylyl, tetrahydrofuranyl, 1,3-dioxacyclohexenyl, 1,3-dioxacyclohexyl, 1,4-dioxacyclohexyl, 1,2-dioxopentyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-oxothiocyclohexyl, and 1,4-thiazolyl. α-yl, 1,3-oxothiacyclopentyl, 1,3-dithiacyclopentenyl, 1,3-dithiacyclopentyl, 1,4-oxothiacyclohexyl, tetrahydro-1,4-thiazolinyl, 2H-1,2-α-yl, cis-butenylideneimino, succinylimino, dioxypiperyl, lactouryl, imidazolinyl, imidazodinyl, iso-α-azolinyl, iso-α-azolinyl, iso-α-azolinyl, iso-α-azolinyl Indololinyl, indololinyl, acezolinyl, acezolinyl, acezolinone, thiazolinyl, thiazolinyl, cyclolinyl, ethylene oxide, piperidinyl N-oxide, piperidinyl, piperidinyl, pyrrolidyl, pyrrolidone, pyrrolididinedione, 4-piperidinone, pyrzolinyl, pyrrolidyl, 2-side-oxypyrrolidyl, tetrahydropiperanyl, 4H-piperanyl, tetrahydrothiaranyl The heterocyclic group may be designated as "3 to 10-membered heterocyclic group" or similar designations. In some embodiments, the heterocyclic group may be a C2-C12 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or up to 13-membered monocyclic, bicyclic, or tricyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group may be a C2-C6 3-member, 4-member, 5-member, 6-member, or 7-member monocyclic ring comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted. In some embodiments, the heterocyclic group may be a C2-C10 4-member, 5-member, 6-member, 7-member, 8-member, 9-member, 10-member, or 11-member bicyclic system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted. In some embodiments, the heterocyclic group may be a C7-C12 12-member, or 13-member tricyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted. In some embodiments, the heteroatoms of a six-membered monocyclic heterocyclic group are selected from one to three O (oxygen), N (nitrogen), or S (sulfur), and the heteroatoms of a five-membered monocyclic heterocyclic group are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur).In some embodiments, the heterocyclic group may be aziridinyl, acrylyl, tetrahydrofuranyl, 1,3-dioxacyclohexenyl, 1,3-dioxacyclohexyl, 1,4-dioxacyclohexyl, 1,2-dioxopentyl, 1,3-dioxopentyl, 1,3-oxothionyl, 1,4-oxothionyl, 1,3-oxothionylpentyl, 1,3-dithionylpentenyl, 1,3-dithionyl... Cyclopentyl, 1,4-oxothiacyclohexyl, tetrahydro-1,4-thiazolinyl, imidazolinyl, imidazodinyl, isoazolinyl, isoazolinyl, isoindololinyl, indololinyl, azolinyl, azolinyl, thiazolinyl, thiazodinyl, cyclohexyl, ethylene oxide, piperidinyl, piperidyl, pyrrolidinyl, pyrazolinyl, pyrazolidyl, tetrahydropiperanyl, tetrahydrothiaranyl, 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, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2,6-dipyridyl, 1,2,3,4-tetrahydro-2,7-dipyridyl, 1,2,3,4-tetrahydro-1,7-dipyridyl, 1,2,3,4 -Tetrahydro-1,6-pyridinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, [1,3]dioxacyclopenta[4,5-c]pyridinyl, [1,3]dioxacyclopenta[4,5-b]pyridinyl, [1,3]dioxacyclopenta[4,5-d]pyrimidinyl or 3,4-methylenedioxyphenyl. In some embodiments, the unsubstituted or substituted heterocyclic group may be selected from aziridinyl, acrylyl, piperidinyl, oxadiazine, piperidine, pyrrolidinyl, thio-oxadiazine, 2-piperidinone, 1,1-dioxo-iono-thio-oxadiazine, oxadiazine (tetrahydrofuranyl), and oxadiazine (tetrahydropiperanyl). When one or more substituents are present in the heterocyclic group, the substituents may be bonded at any available carbon atom and / or heteroatom. In some embodiments, the heterocyclic group may be substituted or unsubstituted.

[0080] The term "side oxygen group" refers to the =O substituent.

[0081] The term "nitro" refers to the -NO2 group.

[0082] The term "aminesulfonyl" refers to the group -S(=O)2NH2.

[0083] As used herein, "excipient" means a substance added to a composition to provide, but not limited to, volume, consistency, stability, binding capacity, lubricity, disintegration capacity, etc. "Diluent" is a type of excipient and refers to a component in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or required. For example, a diluent may be used to increase the volume of an effective drug that is too small for manufacture and / or administration. It may also be a liquid to dissolve a drug to be administered by injection, ingestion, or inhalation. Pharmaceutically acceptable excipients are physiologically and pharmaceutically suitable non-toxic active materials or components that do not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are those well-known in pharmaceutical technology and described, for example, in Rowe et al., *Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety*, 5th edition, 2006, and *Remington: The Science and Practice of Pharmacy* (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, and the like may be provided in pharmaceutical compositions. Those skilled in this art can further formulate compounds as disclosed and described herein in an appropriate manner and according to accepted standards (such as those disclosed in Remington above).

[0084] As used herein, "dose / dosage" refers to the measured amount of a pharmaceutical substance taken by an individual in a single dose. In some embodiments where the pharmaceutical substance is not a free base or free acid, the amount is a molar concentration equivalent to the corresponding amount of a free base or free acid.

[0085] As used herein, "medically acceptable salt" means a salt of a compound having an acidic or basic moiety, which is suitable for use in medicine, either biologically or otherwise. In many cases, the compounds disclosed herein can form acidic and / or basic salts by virtue of the presence of an acidic or basic moiety (e.g., an amino group and / or a carboxyl group or similar groups). Medically acceptable acid addition salts can be formed by combining a compound having a basic moiety with inorganic or organic acids. Medically acceptable base addition salts can be formed by combining a compound having an acidic moiety with inorganic or organic bases.

[0086] The compounds described herein may have one or more stereocenters. Unless otherwise indicated, this refers to all stereoisomers, such as mirror-image isomers and non-mirror-image isomers. It should be understood that in any compound described herein having one or more pisiform centers, unless the absolute stereochemistry is explicitly indicated, each center may independently be (R)-configured or (S)-configured or a mixture thereof. Therefore, the compounds provided herein may be mirror-image isomerically pure, mirror-image isomerically enriched, racemic mixtures, non-mirror-image isomerically pure, non-mirror-image isomerically enriched, or mixtures of stereoisomers. Mirror-image isomerically pure or mirror-image isomerically enriched forms can be prepared by resolution of racemic mixtures or by using mirror-image isomerically pure or enriched starting materials or by stereoselective or stereospecific synthesis. Stereochemical definitions are available in EL Eliel, SH Wilen & LN Mander, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference in its entirety. In some embodiments, where the compounds described herein are pisiform or include one or more stereocenters, compounds having an excess of either mirror-image or non-mirror-image isomers can be prepared as follows: 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%.

[0087] The resolution of racemic mixtures of non-compound compounds can be performed by any of the many methods known in this art. Example methods include stepwise recrystallization using an antichondral resolving organic acid and a racemic compound containing a base. Other antichondral resolving agents suitable for stepwise crystallization methods include methylbenzylamine (e.g., in S and R forms or non-mirror image isomeric pure forms), 2-phenylglycine alcohol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and stereoisomeric pure forms of the like. Similarly, stepwise recrystallization using an antichondral resolving base can be used with a racemic compound containing a base.

[0088] The analysis of racemic mixtures can also be performed by dissociation on a palmar column. Suitable dissociation solvent compositions can be determined by those skilled in this technique.

[0089] In some embodiments, compounds described herein may be prepared having an 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% of an excess of an image-isomer or within the range defined by any of the foregoing figures. In some embodiments, compounds described herein may be prepared having an 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% of an excess of an image-isomer or within the range defined by any of the foregoing figures.

[0090] In some embodiments, compounds described herein may be prepared having an 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% of a non-mirror image isomer, or an excess of a non-mirror image isomer within the range defined by any of the foregoing figures. In some embodiments, compounds described herein may be prepared having an 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% of a non-mirror image isomer, or an excess of a non-mirror image isomer within the range defined by any of the foregoing figures.

[0091] Furthermore, it should be understood that when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, and the like) or other centers with geometric asymmetry, and unless otherwise specified, the compounds include both E and Z geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds described herein can be separated into mixtures of isomers or into separate isomeric forms.

[0092] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers in isoprotonated states having the same empirical formula and total charge. Examples of proton transfer tautomers include keto-enol pairs, amide-imino pairs, amide-amide-imino pairs, enamine-imino pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0093] The compounds described herein and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents, for example, in hydrate or solvate form. When in a solid state, the compounds described herein and their salts may exist in various forms, and may be, for example, in solvate (including hydrate) form. The compounds may be in any solid form, such as crystalline, amorphous, solvated, etc., and unless otherwise clearly indicated, references to compounds and their salts in this specification shall be understood to indicate any solid form of the compounds.

[0094] The compounds described herein may be used in neutral form, such as free acid or free base. Alternatively, the compounds may be used in the form of pharmaceutically acceptable salts (such as pharmaceutically acceptable acid addition salts or base addition salts).

[0095] 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 isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions rich in the compounds described herein. Substantial isolation may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds or salts thereof described herein.

[0096] Isotopes Unless the context clearly specifies otherwise, the compounds disclosed and described herein allow and cover atoms at each position in the compounds to independently have: 1) an isotopic distribution of the chemical element in proportions normally found in nature, or 2) an isotopic distribution in proportions different from those normally found in nature. The number of atoms of a particular chemical element is defined by the number of protons in the nucleus. The number of atoms identifies a particular element, not an isotope; atoms of a given element may have a wide range of neutron numbers. The number of protons and neutrons in the nucleus is the mass number of the atom, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have isotopic distributions in proportions different from those normally found in nature are generally referred to as isotopically labeled. The chemical elements represented in the compound structure may include any isotopic distribution of that element. For example, in the compound structure, hydrogen atoms may be explicitly disclosed or understood to be present in the compound. At any position in a compound in which hydrogen atoms may be present, the hydrogen atoms may be of an isotopic distribution of hydrogen, including but not limited to proportions of those normally found in nature and proportions of protium (¹H) and deuterium (²H) different from those normally found in nature. Therefore, unless the context clearly specifies otherwise, references to compounds herein encompass all potential isotopic distributions for each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. Those skilled in the art will understand that any of the compounds disclosed and described herein may include radioactive isotopes. Therefore, the use of compounds disclosed and described herein in which one or more atoms have isotopic distributions different from those normally found in nature, such as having a larger proportion of ²H or ³H, or a larger proportion of ¹¹C, ¹³C, or ¹⁴C than those found in nature, is also contemplated. Using general examples, but not limited to these, isotopes of hydrogen include protium (¹H), deuterium (²H), and tritium (³H). Isotopes of carbon include carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), and carbon-14 (¹⁴C). Isotopes of nitrogen include nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), and nitrogen-15 (¹⁵N). Isotopes of oxygen include oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), and oxygen-18 (¹⁸O). Isotopes of fluorine include fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), and fluorine-19 (¹⁹F). Phosphorus isotopes include phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), phosphorus-34 (34P), phosphorus-35 (35P) and phosphorus-36 (36P).Sulfur isotopes include sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), and sulfur-38 (38S). Chlorine isotopes include chlorine-35 (35Cl), chlorine-36 (36Cl), and chlorine-37 (37Cl). Bromine isotopes include bromine-75 (75Br), bromine-76 (76Br), bromine-77 (77Br), bromine-79 (79Br), bromine-81 (81Br), and bromine-82 (82Br). Iodine isotopes include iodine-123 (123I), iodine-124 (124I), iodine-125 (125I), iodine-131 (131I), and iodine-135 (135I). In some embodiments, atoms at each position of the compound have an isotopic distribution of each chemical element in proportions normally found in nature. In some embodiments, atoms at one position of the compound have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution in proportions normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution in proportions normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution in proportions normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution in proportions normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in proportions normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have an isotopic distribution of the chemical element in proportions different from those normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in proportions normally found in nature).

[0097] Certain compounds, such as those incorporating radioactive isotopes like 3H and 14C, are also suitable for drug or tissue distribution analysis. Tritium (3H) and carbon-14 (14C) isotopes are particularly preferred due to their ease of preparation and detectability. Compounds having a higher proportion of naturally occurring isotopes (such as deuterium (2H)) may offer certain therapeutic advantages due to greater metabolic stability (such as extended in vivo half-life or reduced dose requirements). Isotopically labeled compounds can generally be prepared using procedures routinely performed in this chemical technique. Such isotopic perturbations or enrichments can be measured using readily available methods, such as mass spectrometry, and for radioactive isotopes, other methods can be used, such as radiodetectors used in conjunction with HPLC or GC.

[0098] As used herein, "isotope variant" means a compound that contains an isotope in a non-natural proportion at one or more of the atoms constituting the compound. In some embodiments, the "isotopic variants" of the compound contain one or more isotopes in non-natural proportions, including but not limited to protium (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), and sulfur-36. (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In some embodiments, the "isotope variants" of the compound are in a stable form, i.e., non-radioactive. In some embodiments, the "isotope variants" of the compound contain one or more isotopes in non-natural proportions, including but not limited to hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), and oxygen-18 (18O). In some embodiments, the "isotope variants" of the compounds are in an unstable form, i.e., radioactive. In some embodiments, the "isotope variants" of the compounds described herein contain one or more isotopes in non-natural proportions, including but not limited to tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), and oxygen-15 (15O). It should be understood that in the compounds provided herein, any hydrogen may include, for example, 2H as the predominant isotope, or any carbon may include, for example, 13C as the predominant isotope, or any nitrogen may include, for example, 15N as the predominant isotope, and any oxygen may include, for example, 18O as the predominant isotope. In some embodiments, the "isotope variants" of the compounds contain deuterium (2H) in non-natural proportions.

[0099] Regarding the compounds provided herein, when a particular atomic position is specified as having deuterium or "D" or "d", it should be understood that the abundance of deuterium at that position is substantially higher than the natural abundance of deuterium (which is about 0.015%). Sites designated as having deuterium typically have the minimum isotopic enrichment factor, in some embodiments, 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). Similarly, with respect to the compounds provided herein, when any atomic site is designated as a particular isotope, it should be understood that the abundance of that particular isotope at that site is substantially higher than the native abundance of that isotope. In some embodiments, a location designated as having a particular isotope typically has a minimum isotopic enrichment factor of at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 99.5% isotopic inclusion at each designated location.

[0100] Synthetic methods that incorporate radioactive isotopes into organic compounds are applicable to the compounds described herein and are well known in the art. Such synthetic methods (e.g., incorporating an active amount of tritium into the target molecule) are as follows:

[0101] A. Catalytic reduction by tritium: This process usually produces products with high radioactivity and requires halogenated or unsaturated precursors.

[0102] B. Reduction with sodium borohydride [3H]: This procedure is relatively inexpensive and requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters and the like.

[0103] C. Reduction with lithium aluminum hydride [3H]: This procedure provides a product at near-theoretical radioactivity. It also requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, and the like.

[0104] D. Tritium Exposure Marking: This procedure involves exposing a precursor containing exchangeable protons to tritium in the presence of a suitable catalyst.

[0105] E. N-methylation using iodomethane [3H]: This procedure is commonly used to prepare O-methyl or N-methyl (3H) products by treating a suitable precursor with iodomethane (3H) at a high radioactivity level. This method generally allows for higher radioactivity levels, such as about 70-90 Ci / mmol.

[0106] The synthetic method of incorporating the active 125I into the target molecule includes:

[0107] A. Sandmeyer and similar reactions: This procedure converts arylamines or heteroarylamines into diazonium salts, such as diazonium tetrafluoroborate, and then into 125I-labeled compounds using Na125I. A representative procedure was reported by Zhu, GD. and colleagues in J. Org. Chem., 2002, 67, 943-948.

[0108] B. Ortho-125 iodination of phenol: This procedure allows for the incorporation of 125I at the ortho position of phenol, as reported by Collier, TL and colleagues in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.

[0109] C. Exchange of aryl and heteroaryl bromides with 125I: This method is generally a two-step process. The first step involves converting the aryl or heteroaryl bromide into the corresponding trialkyltin intermediate in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3] using, for example, a Pd-catalyzed reaction [i.e., Pd(Ph3P)4] or via aryl or heteroaryl lithium. A representative procedure was reported by Le Bas, M.-D. and colleagues in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

[0110] The radiolabeled forms of the compounds described herein can be used in screening analyses to identify / evaluate compounds. Generally, the ability of newly synthesized or identified compounds (i.e., test compounds) to bind to VMAT2 is evaluated by reducing the ability of the radiolabeled forms of the compounds disclosed herein to bind. The ability of the test compounds to compete with the radiolabeled forms of the compounds described herein for binding to VMAT2 is related to their binding affinity.

[0111] Some examples of compounds provide compounds of formula (I): , or a pharmaceutically acceptable salt thereof, wherein: R1 is R2A, -(CH2)m-R2B or -(CH2)n-OR2C; R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl or 4 to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RAs; each RA 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 dialkylaminosulfonyl, halogen, halogroup C1-C4 alkoxy, halogroup C1-C4 alkyl, halogroup C2-C4 dialkylamino, 4 to 7-membered heterocyclic group, -CN, -OH and side oxygen groups; R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RBs; each RB is independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halogroup C1-C4 alkyl, halogroup C1-C4 alkylsulfonyl, lateral oxygen, and -OH; R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by one or more RCs; each RC is independently -CN or C3-C6 cycloalkyl; m is 0, 1, 2, 3, or 4; and n is 1, 2, or 3.

[0112] Some embodiments provide a compound of formula (I): , or a pharmaceutically acceptable salt thereof, wherein: R1 is R2A, -(CH2)m-R2B or -(CH2)n-OR2C; R2A is an unsubstituted or substituted C1-C4 alkyl group; each RA is independently selected from the group consisting of fluorine and -OH; R2B is a C3-C8 cycloalkyl or a 4- to 6-membered heterocyclic group, each unsubstituted or substituted by one or more RBs; each RB is independently selected from the group consisting of fluorine, -CN, -CH2CN and -OH; R2C is a C1-C4 alkyl or a C3-C8 cycloalkyl, each unsubstituted or substituted by one or more RCs; each RC is independently -CN or a C3-C6 cycloalkyl; m is 0, 1, 2 or 3; and n is 1, 2 or 3.

[0113] In some embodiments, the compound of formula (I) is the compound of formula (Ia), or a pharmaceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ia) is 2R,3R,11bR.

[0114] In some embodiments, the compound of formula (I) is the compound of formula (Ic), or a pharmaceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ic) is 2S,3R,11bR.

[0115] In some embodiments, the compound of formula (I) is the compound of formula (Ie), or a pharmaceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ie) is 2R,3S,11bS.

[0116] In some embodiments, the compound of formula (I) is the compound of formula (Ig), or a pharmaceutically acceptable salt thereof. The stereochemistry of the compound of formula (Ig) is 2S, 3S, 11bS.

[0117] In some embodiments, R1 is R2A.

[0118] In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one or more RAs, wherein the RAs are as described above and below herein. In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one or more RAs, each RA being independently selected from the group consisting of: C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylaminosulfonyl, halogen, halogenated C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C2-C4 dialkylamino, 4- to 7-membered heterocyclic group, -CN, -OH, and side oxygen groups. It should be understood that when there is more than one RA, they may be the same or different. In some embodiments, when there is more than one RA, they are the same. In some embodiments, when there is more than one RA, they are different.

[0119] In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one, two, three, or four RAs. In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one RA. In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with two RAs. In some embodiments, R2A is a C2-C4 alkenyl, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with three RAs.

[0120] In some embodiments, R2A is an unsubstituted or substituted C2-C4 alkenyl group, wherein the RA is as described above and below herein.

[0121] In some embodiments, R2A is an unsubstituted or substituted methylallyl group with one or more RAs.

[0122] In some embodiments, R2A is an unsubstituted or substituted prop-2-en-1-yl group. In some embodiments, R2A is a methylallyl group.

[0123] In some embodiments, R2A is an unsubstituted or substituted C1-C6 alkyl group, wherein the RA is as described above and below herein.

[0124] In some embodiments, R2A is an unsubstituted or substituted C1-C6 alkyl group.

[0125] In some embodiments, R2A is n-butyl, ethyl, 2-ethylbutyl, n-propyl, prop-2-yl, 2-methylpropyl, methyl or n-pentyl, each unsubstituted or substituted by one or more RAs.

[0126] In some embodiments, each RA system is independently selected from the group consisting of: C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylaminesulfonyl, halogen, halogenated C1-C4 alkoxy, halogenated C2-C4 dialkylamino, 4 to 7-membered heterocyclic groups, -CN, -OH, and side oxygen groups. In some embodiments, each RA system is independently selected from the group consisting of: methoxy, methylamino, methanesulfonyl, dimethylamino, N,N-dimethylaminesulfonyl, chlorine, fluorine, trifluoromethoxy, methyl(2,2,2-trifluoroethyl)amino, methyl(trifluoromethyl)amino, (N-hydroxyl), -CN, -OH, and side oxygen groups.

[0127] In some embodiments, R2A is n-butyl, ethyl, 2-ethylbutyl, n-propyl, prop-2-yl, 2-methylpropyl, methyl, or n-pentyl, each unsubstituted or substituted by one or more independently selected RA groups from the group consisting of: C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkylsulfonyl, C2-C4 dialkylamino, C2-C4 dialkylaminosulfonyl, halogen, halogenated C1-C4 alkoxy, halogenated C2-C4 dialkylamino, 4 to 7-membered heterocyclic groups, -CN, -OH, and side oxygen groups.

[0128] In some embodiments, R2A is 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, propyl-2-yl, 1,1,1-trifluoropropyl-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, cyano. Methyl, 2-(dimethylamino)-2-sideoxyethyl, 2-(methylamino)-2-sideoxyethyl, 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-sideoxyethyl, 3-(methylsulfonylurea)propyl, (N,N-dimethylaminosulfonylurea)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-(N-hydroxylinyl)propyl, 5,5,5-trifluoropentyl or 4,4,4-trifluorobutyl.

[0129] In some embodiments, R2A is an unsubstituted or substituted C1-C4 alkyl group with one, two, three, or four RA groups; and each RA group is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2A is an unsubstituted or substituted C1-C4 alkyl group with one, two, or three RA groups; and each RA group is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2A is a C2-C4 alkyl group. In some embodiments, R2A is -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R2A is a C1-C4 alkyl group substituted with one, two, or three fluorine groups. In some embodiments, R2A is a C1-C4 alkyl group substituted with one, two, or three fluorine groups. In some embodiments, R2A is -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CHF2, or -CH2CH2CF3. In some embodiments, R2A is -CH2CH2CHF2 or -CH2CH2CF3.

[0130] In some embodiments, R2A is an unsubstituted or substituted C3-C8 cycloalkyl group, wherein the RAs are as described above and below herein.

[0131] In some embodiments, R2A is an unsubstituted or substituted C3-C8 cycloalkyl group.

[0132] In some embodiments, R2A is cyclobutyl, cyclopropyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or substituted by one or more RAs.

[0133] In some embodiments, each RA system is independently selected from the group consisting of halogens and halogenated C1-C4 alkyl groups. In some embodiments, each RA system is independently selected from the group consisting of fluorine and trifluoromethyl groups.

[0134] In some embodiments, R2A is cyclobutyl, cyclopropyl, cyclopentyl, or cyclohexyl, each unsubstituted or substituted by one or more independently selected RAs from the group consisting of fluorine and trifluoromethyl. In some embodiments, R2A is cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, or 3,3-difluorocyclopentyl.

[0135] In some embodiments, R2A is a 4 to 7 member heterocyclic group that is unsubstituted or substituted with one or more RAs, wherein the RAs are as described above and below herein.

[0136] In some embodiments, R2A is acryl-3-yl, oxadiazine-3-yl, or pyrrolidone-3-yl, each unsubstituted or substituted by one or more RAs.

[0137] In some embodiments, each RA system is independently selected from the group consisting of: C1-C6 alkyl, halogenated C1-C4 alkyl, and oxy-group. In some embodiments, each RA system is independently selected from the group consisting of: methyl, 2,2,2-trifluoroethyl, and oxy-group.

[0138] In some embodiments, R2A is acryl-3-yl, oxetane-3-yl, or pyrrolidin-3-yl, each unsubstituted or substituted with one or more independently selected RAs from the group consisting of: methyl, 2,2,2-trifluoroethyl, and sero-oxy. In some embodiments, R2A is oxetane-3-yl, oxetane-3-yl (tetrahydrofuran-3-yl), 2-sero-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, or 1-methylacryl-3-yl.

[0139] In some embodiments, R2A is methylallyl, n-butyl, ethyl, 2-ethylbutyl, n-propyl, prop-2-yl, 2-methylpropyl (isobutyl), methyl, n-pentyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, acryl-3-yl, oxacyclobutyl-3-yl, or pyrrolidin-3-yl; each unsubstituted or substituted by one or more independently selected RAs from the group consisting of: methoxy, methylamino, methanesulfonyl, dimethylamino, N,N-dimethylaminosulfonyl, chlorine, fluorine, trifluoromethoxy, methyl(2,2,2-trifluoroethyl)amino, methyl(trifluoromethyl)amino, (N-trifluorolinyl), -CN, -OH, trifluoromethyl, methyl, 2,2,2-trifluoroethyl, and sideoxy.

[0140] In some embodiments, R2A is methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, prop-2-yl, 1,1,1-trifluoropropyl-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-sideoxyethyl, 2-(methylamino)-2-sideoxyethyl, 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-sideoxyethyl, 3-(methylsulfonylurea)propyl, (N,N-dimethylaminesulfonylurea)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3- (N-N-phosphoryl)propyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxacyclobut-3-yl, oxacyclopent-3-yl (tetrahydrofuran-3-yl), 2-sideoxy-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylacetyl-3-yl, 5,5,5-trifluoropentyl or 4,4,4-trifluorobutyl.

[0141] In some embodiments, R2A is methylallyl. In some embodiments, R2A is 2,2,2-trifluoroethyl. In some embodiments, R2A is 2,2-difluoroethyl. In some embodiments, R2A is 2,2-difluoropropyl. In some embodiments, R2A is 3,3,3-trifluoropropyl. In some embodiments, R2A is ethyl. In some embodiments, R2A is 2-fluoroethyl. In some embodiments, R2A is 3-fluoropropyl. In some embodiments, R2A is prop-2-yl. In some embodiments, R2A is 1,1,1-trifluoroprop-2-yl. In some embodiments, R2A is 2-hydroxy-2-methylpropyl. In some embodiments, R2A is 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R2A is 3,3-difluoro-2-hydroxypropyl. In some embodiments, R2A is methyl. In some embodiments, R2A is 2-hydroxypropyl. In some embodiments, R2A is 2-hydroxybutyl. In some embodiments, R2A is 4,4,4-trifluoro-2-hydroxybutyl. In some embodiments, R2A is 3,3,3-trifluoro-2-hydroxy-2-methylpropyl. In some embodiments, R2A is 2,3-dihydroxypropyl. In some embodiments, R2A is 3-hydroxypropyl. In some embodiments, R2A is 2-hydroxyethyl. In some embodiments, R2A is cyanomethyl. In some embodiments, R2A is 2-(dimethylamino)-2-sideoxyethyl. In some embodiments, R2A is 2-(methylamino)-2-sideoxyethyl. In some embodiments, R2A is 2-hydroxy-3-methoxypropyl. In some embodiments, R2A is 2-chloro-2,2-difluoroethyl. In some embodiments, R2A is 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl. In some embodiments, R2A is 2-(methyl(2,2,2-trifluoroethyl)amino)-2-sideoxyethyl. In some embodiments, R2A is 3-(methylsulfonylurea)propyl. In some embodiments, R2A is (N,N-dimethylaminesulfonylurea)methyl. In some embodiments, R2A is 2-methoxypropyl. In some embodiments, R2A is 2-ethyl-2-hydroxybutyl. In some embodiments, R2A is 3-chloro-3,3-difluoropropyl. In some embodiments, R2A is 2-hydroxy-3-(N-hydroxylinyl)propyl. In some embodiments, R2A is cyclopropyl. In some embodiments, R2A is cyclobutyl. In some embodiments, R2A is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R2A is 2-fluorocyclopentyl. In some embodiments, R2A is 3,3-difluorocyclopentyl. In some embodiments, R2A is oxacyclobut-3-yl. In some embodiments, R2A is oxacyclopent-3-yl (tetrahydrofuran-3-yl).In some embodiments, R2A is 2-sideoxy-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl. In some embodiments, R2A is 1-methylacartin-3-yl. In some embodiments, R2A is 5,5,5-trifluoropentyl. In some embodiments, R2A is 4,4,4-trifluorobutyl.

[0142] In some embodiments, R1 is -(CH2)m-R2B.

[0143] In some embodiments, the compound of formula (I) is the compound of formula (III): , or a pharmaceutically acceptable salt thereof, wherein: m and R2B have the same definitions as described herein and may be independently selected from any of the embodiments described above and below herein.

[0144] In some embodiments, the compound of formula (I) is a compound selected from formula (IIIa), formula (IIIc), formula (IIIe) or formula (IIIg), or a pharmaceutically acceptable salt thereof, wherein: m and R2B have the same definitions as described herein and may each be independently selected from any of the embodiments described above and below herein.

[0145] In some embodiments, the compound of formula (I) is a compound of formula (IIIa). In some embodiments, the compound of formula (I) is a compound of formula (IIIc). In some embodiments, the compound of formula (I) is a compound of formula (IIIe). In some embodiments, the compound of formula (I) is a compound of formula (IIIg).

[0146] In some embodiments, m is 0, 1, 2, 3 or 4.

[0147] In some embodiments, m is 0, 1, 2 or 3.

[0148] In some embodiments, m is 0, 1 or 2.

[0149] In some embodiments, m is 0 or 1.

[0150] In some embodiments, m is 0.

[0151] In some embodiments, m is 1.

[0152] In some embodiments, m is 2.

[0153] In some embodiments, m is 3.

[0154] In some embodiments, m is 4.

[0155] In some embodiments, R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one or more RBs. It should be understood that when more than one RB is present, they may be the same or different. In some embodiments, when more than one RB is present, they are the same. In some embodiments, when more than one RB is present, they are different.

[0156] In some embodiments, R2B is aryl, C3-C8 cycloalkyl, 5 to 10-membered heteroaryl or 4 to 7-membered heterocyclic, unsubstituted or substituted by one, two, three or four RBs.

[0157] In some embodiments, R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by one RB. In some embodiments, R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by two RBs. In some embodiments, R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by three RBs. In some embodiments, R2B is an aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic group, each unsubstituted or substituted by four RBs.

[0158] In some embodiments, R2B is an aryl group that is unsubstituted or substituted with one or more RBs, wherein the RBs are as described above and below herein.

[0159] In some embodiments, R2B is an unsubstituted or phenyl group substituted with one or more RBs.

[0160] In some embodiments, each RB system is independently selected from the group consisting of: halogen, halogenated C1-C4 alkyl, halogenated C1-C4 alkylsulfonyl, and -CN. In some embodiments, each RB system is independently selected from the group consisting of: fluorine, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN.

[0161] In some embodiments, R2B is an unsubstituted or RB-substituted phenyl group consisting of one or more independently selected groups of the following: fluoro, trifluoromethyl, (difluoromethyl)sulfonyl, and -CN. In some embodiments, R2B is phenyl, 4-fluorophenyl, 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-((difluoromethyl)sulfonyl)phenyl, or 3-cyanophenyl.

[0162] In some embodiments, R2B is an unsubstituted or substituted C3-C8 cycloalkyl group, wherein the RBs are as described above and below herein.

[0163] In some embodiments, R2B is cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or bicyclo[1.1.1]pent-1-yl, each unsubstituted or substituted by one or more RBs.

[0164] In some embodiments, each RB system is independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonyloxy, -CN, -CH2CN, halogen, halogenated C1-C4 alkyl and -OH.

[0165] In some embodiments, each RB system is independently selected from the group consisting of: ethyl, methanesulfonyl, methylsulfonyloxy, -CN, -CH2CN, fluorine, difluoromethyl, trifluoromethyl and -OH.

[0166] In some embodiments, R2B is cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or bicyclo[1.1.1]pent-1-yl, each unsubstituted or substituted by one or more independently selected RBs from the group consisting of: ethyl, methanesulfonyl, methylsulfonoxy, -CN, -CH2CN, fluorine, difluoromethyl, trifluoromethyl and -OH.

[0167] In some embodiments, R2B is 1-hydroxycyclobutyl, cyclopropyl, 1-cyanocyclopropyl, 1-fluorocyclopropyl, cyclobutyl, 1-cyanocyclobutyl, 1-(cyanomethyl)cyclopropyl, 4,4-difluoro-1-hydroxycyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorobicyclo[1.1.1]pent-1-yl, 1-(difluoromethyl)cyclopropyl, 3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl, 3-hydroxy-3-(trifluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclopentyl, 2-ethylcyclopropyl, 1-((methylsulfony)oxy)cyclopropyl, 1-(methylsulfony)cyclopropyl or 2,2-difluorocyclopropyl.

[0168] In some embodiments, R2B is an unsubstituted or substituted C3-C6 cycloalkyl group with one or two RBs; and each RB is independently selected from the group consisting of fluorine, CN, -CH2CN and -OH. In some embodiments, R2B is cyclopropyl, cyclobutyl or cyclopentyl, each unsubstituted or substituted with one or two fluorines.

[0169] In some embodiments, R2B is a 5 to 10 heteroaryl group that is unsubstituted or substituted with one or more RBs, wherein the RBs are as described above and below herein.

[0170] In some embodiments, R2B is 1,2,4-diazol-5-yl, 1,3-diazol-2-yl, 1,3-diazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazole-5-yl, 1H-tetrazole-5-yl, furan-2-yl, imidazol-1-yl, isodiazol-3-yl, isodiazol-5-yl, pyridine-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or thiazol-4-yl, each unsubstituted or substituted with one or more RBs.

[0171] In some embodiments, each RB system is independently selected from the group consisting of C1-C4 alkyl and -CN. In some embodiments, each RB system is independently selected from the group consisting of methyl and -CN.

[0172] In some embodiments, R2B is 1,2,4-diazol-5-yl, 1,3-diazol-2-yl, 1,3-diazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazole-5-yl, 1H-tetrazole-5-yl, furan-2-yl, imidazol-1-yl, isodiazol-3-yl, isodiazol-5-yl, pyridine-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or thiazol-4-yl, each unsubstituted or substituted with one or more independently selected RBs from the group consisting of methyl and -CN. In some embodiments, R2B is imidazole-1-yl, 5-methyl-1,3-carbazo-2-yl, 5-cyanofuran-2-yl, isocarbazo-3-yl, carbazo-4-yl, 6-cyanopyridin-2-yl, 5-cyanopyridin-2-yl, 1,2,4-carbazo-5-yl, pyridin-3-yl, pyrimidin-2-yl, isocarbazo-5-yl, 1H-imidazole-2-yl, or 1H-tetrazole-5-yl.

[0173] In some embodiments, R2B is a 4 to 7 member heterocyclic group that is unsubstituted or substituted with one or more RBs, wherein the RBs are as described above and below herein.

[0174] In some embodiments, R2B is oxetane-3-yl, oxetane-2-yl, oxetane-3-yl (tetrahydrofuran-3-yl), pyrrolidin-1-yl, piperidin-4-yl, tetrahydro-2H-piperan-4-yl, acryl-3-yl, 1,4-dioxane-6-yl or tetrahydro-2H-thiaran-4-yl, which is unsubstituted or substituted by one or more RBs.

[0175] In some embodiments, each RB system is independently selected from the group consisting of: C1-C4 alkyl, halogen, oxy group and -CN. In some embodiments, each RB system is independently selected from the group consisting of: methyl, fluorine, oxy group and -CN.

[0176] In some embodiments, R2B is oxetane-3-yl, oxetane-2-yl, oxetane-3-yl (tetrahydrofuran-3-yl), pyrrolidin-1-yl, piperidin-4-yl, tetrahydro-2H-piperan-4-yl, acryl-3-yl, 1,4-dioxane-6-yl or tetrahydro-2H-thiaran-4-yl, each unsubstituted or substituted by one or more independent RBs selected from the group consisting of: methyl, fluorine, side-oxygen and -CN. In some embodiments, R2B is 3-fluorooxetrazine-3-yl, oxetrazine-2-yl, oxetrazine-3-yl, oxetrazine-3-yl (tetrahydrofuran-3-yl), 3,3-difluoropyrrolidin-1-yl, 1-cyanopiperidin-4-yl, 1-methylacetate-3-yl, 6-fluoro-1,4-dioxetrazine-6-yl, or 1,1-dioxo-ionized tetrahydro-2H-thiaran-4-yl.

[0177] In some embodiments, R2B is a 4- to 5-membered monocyclic heterocyclic group having a ring-forming heteroatom selected from oxygen and sulfur, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a C3-C44- to 5-membered monocyclic heterocyclic group having a ring-forming oxygen, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a 4- to 5-membered monocyclic heterocyclic group having a ring-forming oxygen, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two fluorines. In some embodiments, R2B is a C3-C44 to 5-membered monocyclic heterocyclic group having a ring-forming heteroatom selected from oxygen and sulfur, wherein the C3-C44 to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a 4- to 5-membered monocyclic heterocyclic group having a ring-forming oxygen, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a C3-C44 to 5-membered monocyclic heterocyclic group having a ring-forming oxygen, wherein the C3-C44 to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a 4- to 5-membered monocyclic heterocyclic group having one ring forming an oxygen atom, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted with one or two fluorine atoms. In some embodiments, R2B is an oxetane-3-yl or oxetane-3-yl, each unsubstituted or substituted with one fluorine atom.

[0178] In some embodiments, R2B is an unsubstituted or substituted heterocyclic group with one or more RBs; and each RB is independently selected from the group consisting of: fluorine, chlorine, bromine, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3 and -OCH2CH3. In some embodiments, R2B is a monocyclic, bicyclic or tricyclic heterocyclic ring system having 1 to 5 ring-forming heteroatoms selected from nitrogen, oxygen and sulfur, consisting of 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered or 13-membered rings, wherein the heterocyclic group is unsubstituted or substituted with one or more RBs; and each RB is independently selected from the group consisting of: fluorine, chlorine, bromine, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3 and -OCH2CH3. In some embodiments, R2B is a monocyclic heterocyclic ring having one to five heteroatoms selected from nitrogen, oxygen, and sulfur rings forming heteroatoms of 3, 4, 5, 6, or 7 members, wherein the heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine, chlorine, bromine, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R2B is a bicyclic heterocyclic ring system having one to five heteroatoms selected from nitrogen, oxygen, and sulfur rings forming heteroatoms of 4, 5, 6, 7, 8, 9, 10, or 11 members, wherein the heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine, chlorine, -CN, -CHF2, -CF3, -OH, and -OCH3. In some embodiments, R2B is a 4- to 5-membered monocyclic heterocyclic group having one ring forming oxygen, wherein the 4- to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a C2-C12 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or up to 13-membered monocyclic, bicyclic, or tricyclic heterocyclic ring system having one to five ring forming heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine, chlorine, bromine, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3.In some embodiments, R2B is a C2-C6 3-member, 4-member, 5-member, 6-member, or 7-member monocyclic heterocyclic ring having one to five heteroatoms selected from nitrogen, oxygen, and sulfur rings, wherein the heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine, chlorine, bromine, -CN, -CH2CN, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, and -OCH2CH3. In some embodiments, R2B is a C2-C10 4-member, 5-member, 6-member, 7-member, 8-member, 9-member, 10-member, or 11-member bicyclic heterocyclic ring having one to five heteroatoms selected from nitrogen, oxygen, and sulfur rings, wherein the heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine, chlorine, -CN, -CHF2, -CF3, -OH, and -OCH3. In some embodiments, R2B is a C3-C44 to 5-membered monocyclic heterocyclic group having a ring-forming heteroatom selected from oxygen and sulfur, wherein the C3-C44 to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or more RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is a C3-C44 to 5-membered monocyclic heterocyclic group having a ring-forming oxygen, wherein the C3-C44 to 5-membered monocyclic heterocyclic group is unsubstituted or substituted by one or two RBs; and each RB is independently selected from the group consisting of fluorine and -OH. In some embodiments, R2B is an oxetane-3-yl or an oxetane-3-yl, each unsubstituted or substituted by one fluorine.

[0179] In some embodiments, R2B is: 1,2,4-diazol-5-yl, 1,3-diazol-2-yl, 1,4-dioxane-6-yl, 1H-imidazol-2-yl, 1H-pyrazole-5-yl, 1H-tetrazole-5-yl, acryl-3-yl, bicyclo[1.1.1]pentyl-1-yl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, furan-2-yl, imidazol-1-yl, isodiazol-3-yl, isodiazol-5-yl, diazol-4-yl, oxacyclobutyl-2-yl, oxacyclobutyl-3-yl, Oxacyclopentan-3-yl (tetrahydrofuran-3-yl), phenyl, piperidin-4-yl, pyridine-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrrolidin-1-yl, tetrahydro-2H-piperan-4-yl, tetrahydro-2H-thiaran-4-yl or thiazolyl; each unsubstituted or substituted with one or more groups independently selected from the group consisting of: -CH2CN, -CN, difluoromethyl, ethyl, fluorine, methyl, methanesulfonyl, methanesulfonoxy, -OH, sideoxy, phenyl and trifluoromethyl.

[0180] In some embodiments, R2B is 1-((methanesulfonyl)oxy)cyclopropyl, 1-(cyanomethyl)cyclopropyl, 1-(difluoromethyl)cyclopropyl, 1-(methanesulfonyl)cyclopropyl, 1-(trifluoromethyl)cyclopentyl, 1,1-dioxo-tetrahydro-2H-thiaran-4-yl, 1,2,4-diazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl , 1-cyanopiperidin-4-yl, 1-fluorocyclobutyl, 1-fluorocyclopropyl, 1H-imidazol-2-yl, 1H-tetrazole-5-yl, 1-hydroxycyclobutyl, 1-methylacetate-3-yl, 2-ethylcyclopropyl, 2-fluorocyclopentyl, 3-(trifluoromethyl)bicyclo[1.1.1]pentyl-1-yl, 3,3-difluorocyclopentyl, 3,3-difluoropyrrolidin-1-yl, 3-fluorobicyclo[1. 1.1] Pentyl-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-cyanopyridin-2-yl, 5-methyl-1,3-azol-2-yl, 6-cyano Pyridin-2-yl, 6-fluoro-1,4-dioxane-6-yl, cyclobutyl, cyclopropyl, imidazol-1-yl, isozol-3-yl, isozol-5-yl, oxazol-4-yl, oxacyclobut-2-yl, oxacyclobut-3-yl, oxacyclopent-3-yl (tetrahydrofuran-3-yl), phenyl, pyridin-3-yl, pyrimidin-2-yl, 3-cyanophenyl, or 2,2-difluorocyclopropyl.

[0181] In some embodiments, R2B is 1-((methanesulfonyl)oxy)cyclopropyl. In some embodiments, R2B is 1-(cyanomethyl)cyclopropyl. In some embodiments, R2B is 1-(difluoromethyl)cyclopropyl. In some embodiments, R2B is 1-(methanesulfonyl)cyclopropyl. In some embodiments, R2B is 1-(trifluoromethyl)cyclopentyl. In some embodiments, R2B is 1,1-dioxo-tetrahydro-2H-thiaran-4-yl. In some embodiments, R2B is 1,2,4-diazol-5-yl. In some embodiments, R2B is 1-cyanocyclobutyl. In some embodiments, R2B is 1-cyanocyclopropyl. In some embodiments, R2B is 1-cyanopiperidin-4-yl. In some embodiments, R2B is 1-fluorocyclobutyl. In some embodiments, R2B is 1-fluorocyclopropyl. In some embodiments, R2B is 1H-imidazol-2-yl. In some embodiments, R2B is 1H-tetrazole-5-yl. In some embodiments, R2B is 1-hydroxycyclobutyl. In some embodiments, R2B is 1-methylacetate-3-yl. In some embodiments, R2B is 2-ethylcyclopropyl. In some embodiments, R2B is 2-fluorocyclopentyl. In some embodiments, R2B is 2-methylthiazolyl-4-yl. In some embodiments, R2B is 3-(trifluoromethyl)bicyclo[1.1.1]pentyl-1-yl. In some embodiments, R2B is 3,3-difluorocyclopentyl. In some embodiments, R2B is 3,3-difluoropyrrolidin-1-yl. In some embodiments, R2B is 3-fluorobicyclo[1.1.1]pentyl-1-yl. In some embodiments, R2B is 3-fluorooxocyclobutyl-3-yl. In some embodiments, R2B is 3-fluorophenyl. In some embodiments, R2B is 3-hydroxy-3-(trifluoromethyl)cyclobutyl. In some embodiments, R2B is 4-((difluoromethyl)sulfonyl)phenyl. In some embodiments, R2B is 4-(trifluoromethyl)phenyl. In some embodiments, R2B is 4,4-difluoro-1-hydroxycyclohexyl. In some embodiments, R2B is 4-fluorophenyl. In some embodiments, R2B is 5-cyanofuran-2-yl. In some embodiments, R2B is 5-cyanopyridin-2-yl. In some embodiments, R2B is 5-methyl-1,3-azol-2-yl. In some embodiments, R2B is 6-cyanopyridin-2-yl. In some embodiments, R2B is 6-fluoro-1,4-dioxane-6-yl. In some embodiments, R2B is cyclobutyl. In some embodiments, R2B is cyclopropyl. In some embodiments, R2B is imidazole-1-yl. In some embodiments, R2B is isozol-3-yl. In some embodiments, R2B is isozol-4-yl. In some embodiments, R2B is isozol-5-yl. In some embodiments, R2B is isozol-4-yl. In some embodiments, R2B is oxacyclobut-2-yl.In some embodiments, R2B is oxacyclobut-3-yl. In some embodiments, R2B is oxacyclopent-3-yl (tetrahydrofuran-3-yl). In some embodiments, R2B is phenyl. In some embodiments, R2B is pyridin-3-yl. In some embodiments, R2B is pyrimidin-2-yl. In some embodiments, R2B is 3-cyanophenyl. In some embodiments, R2B is 2,2-difluorocyclopropyl.

[0182] In some embodiments, R1 is -(CH2)n-OR2C.

[0183] In some embodiments, the compound is a compound of formula (V): , or a pharmaceutically acceptable salt thereof, wherein: n and R2C have the same definitions as described herein, and each may be independently selected from any of the embodiments described above and below herein.

[0184] In some embodiments, the compound is a compound selected from formula (Va), formula (Vc), formula (Ve) or formula (Vg), or a pharmaceutically acceptable salt thereof, wherein: n and R2C have the same definitions as described herein and may each be independently selected from any of the embodiments described above and below herein.

[0185] In some embodiments, the compound of formula (I) is a compound of formula (Va). In some embodiments, the compound of formula (I) is a compound of formula (Vc). In some embodiments, the compound of formula (I) is a compound of formula (Ve). In some embodiments, the compound of formula (I) is a compound of formula (Vg).

[0186] In some embodiments, n is 1, 2 or 3.

[0187] In some embodiments, n is 1 or 2.

[0188] In some embodiments, n is 1.

[0189] In some embodiments, n is 2.

[0190] In some embodiments, n is 3.

[0191] In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one or more RCs. It should be understood that when more than one RC is present, they may be the same or different. In some embodiments, when more than one RC is present, they are the same. In some embodiments, when more than one RC is present, they are different.

[0192] In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one, two, three, or four RC groups. In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with one RC group. In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with two RC groups. In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with three RC groups. In some embodiments, R2C is a C1-C4 alkyl, C3-C8 cycloalkyl, halo-C1-C4 alkyl, or a 4- to 7-membered heterocyclic group, each unsubstituted or substituted with four RC groups.

[0193] In some embodiments, R2C is an unsubstituted or substituted C1-C4 alkyl group, wherein the RC is as described above and below herein. In some embodiments, R2C is ethyl, isopropyl, or methyl, each unsubstituted or substituted with one or more RC groups.

[0194] In some embodiments, each RC is independently -CN or C3-C6 cycloalkyl. In some embodiments, each RC is independently selected from the group consisting of cyclopropyl and -CN.

[0195] In some embodiments, R2C is ethyl, isopropyl, or methyl, each unsubstituted or substituted with one or more independently selected RC groups from the group consisting of cyclopropyl and -CN. In some embodiments, R2C is methyl, cyano(cyclopropyl)methyl, 2-cyanopropyl-2-yl, cyanomethyl, or 1-cyanoethyl.

[0196] In some embodiments, R2C is an unsubstituted or substituted C3-C8 cycloalkyl group, wherein the RC is as described above and below herein.

[0197] In some embodiments, R2C is an unsubstituted or cyclic butyl group substituted with one or more RC groups.

[0198] In some embodiments, each RC is -CN.

[0199] In some embodiments, R2C is an unsubstituted or substituted cyclobutyl group with one or more -CN groups. In some embodiments, R2C is a 1-cyanocyclobutyl group.

[0200] In some embodiments, R2C is a 4 to 7 member heterocyclic group that is unsubstituted or substituted with one or more RCs, wherein the RCs are as described above and below herein.

[0201] In some embodiments, R2C is oxadiazine-3-yl or tetrahydro-2H-piperan-4-yl, each unsubstituted or substituted with one or more RCs. In some embodiments, RC is -CN.

[0202] In some embodiments, R2C is oxetane-3-yl or tetrahydro-2H-piperan-4-yl, each unsubstituted or substituted with one or more -CN groups. In some embodiments, R2C is oxetane-3-yl or 4-cyanotetrahydro-2H-piperan-4-yl.

[0203] In some embodiments, R2C is a C1-C4 alkyl or a C3-C5 cycloalkyl, each substituted with one, two, three, or four RCs; and each RC is independently -CN or a C3-C6 cycloalkyl. In some embodiments, R2C is a C1-C4 alkyl or a C3-C5 cycloalkyl, each substituted with one or more RCs; and each RC is independently -CN or a C3-C6 cycloalkyl. In some embodiments, R2C is a cyclobutyl group substituted with one -CN. In some embodiments, R2C is a C1-C3 alkyl group substituted with one -CN and one C3-C5 cycloalkyl. In some embodiments, R2C is a C1-C2 alkyl group substituted with one -CN and one C3-C4 cycloalkyl. In some embodiments, R2C is a C1-C2 alkyl group substituted with one -CN and one cyclopropyl. In some embodiments, R2C is a C1-C3 alkyl group substituted with one -CN.

[0204] In some embodiments, R2C is ethyl, isopropyl, methyl, cyclobutyl, oxacyclobutyl-3-yl or tetrahydro-2H-piperan-4-yl, each unsubstituted or substituted by one or more groups independently selected from the group consisting of cyclopropyl and -CN.

[0205] In some embodiments, R2C is methyl, cyano(cyclopropyl)methyl, 2-cyanopropyl-2-yl, cyanomethyl, 1-cyanoethyl, 1-cyanocyclobutyl, oxacyclobutyl-3-yl or 4-cyanotetrahydro-2H-piperan-4-yl.

[0206] In some embodiments, R2C is methyl. In some embodiments, R2C is cyano(cyclopropyl)methyl. In some embodiments, R2C is 2-cyanopropyl-2-yl. In some embodiments, R2C is cyanomethyl. In some embodiments, R2C is 1-cyanoethyl. In some embodiments, R2C is 1-cyanocyclobutyl. In some embodiments, R2C is oxacyclobutyl-3-yl. In some embodiments, R2C is 4-cyanotetrahydro-2H-piperan-4-yl.

[0207] In some embodiments, R1 is methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, prop-2-yl, 1,1,1-trifluoropropyl-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 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyethyl, cyanomethyl, 2-(dimethylamino)-2-sideoxyethyl, 2-(methylamino)-2-sideoxyethyl, 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-sideoxyethyl, 3-(methylsulfonylurea)propyl, (N,N-dimethylaminosulfonylurea)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-( N-(trifluoromethyl)propyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxacyclobutyl-3-yl, oxacyclopentyl-3-yl (tetrahydrofuran-3-yl), 2-sideoxy-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylacetyl-3-yl, (1-((methylsulfony)oxy)cyclopropyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (1-(methylsulfony)cyclopropyl)methyl, (1-(trifluoromethyl)cyclopentyl)methyl, (1,1- Dioxane-tetrahydro-2H-thiaran-4-yl)methyl, (1,2,4-diazol-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (1-cyanopiperidin-4-yl)methyl, (1-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazol-2-yl)methyl, (1H-tetrazole-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylacetate-3-yl)methyl, (2-ethylcyclopropyl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pentyl-1-yl)methyl, (3-fluorobicyclo[1.1.1]pentyl-1-yl)methyl, (3-fluorobicyclo[1.1.1]pentyl-1-yl)methyl.1] Pentyl-1-yl)methyl, (3-fluorooxetane-3-yl)methyl, (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl, (4,4-difluoro-1-hydroxycyclohexyl)methyl, (5-cyanofuran-2-yl)methyl, (5-cyanopyridin-2-yl)methyl, (5-methyl-1,3-azol-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, ( 6-Fluoro-1,4-dioxane-6-yl)methyl, (isoazol-3-yl)methyl, (isoazol-5-yl)methyl, (azol-4-yl)methyl, (oxacyclobut-2-yl)methyl, (oxacyclobut-3-yl)methyl, (pyridin-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-(1H-imidazol-1-yl)ethyl, 2-(3,3-difluoropyridine) (1-yl)ethyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl, cyclopropylmethyl, pyrimidin-2-ylmethyl, (2-cyanopropyl-2-yl)oxy)ethyl, 2-((4-cyanotetrahydro-2H-piperan-4-yl)oxy)ethyl, 2-(1-cyanobutoxy)ethyl, 2-(1-cyanoethoxy)ethyl, 2-(cyano(cyclopropyl)methoxy)ethyl, 2-(cyanomethoxy)ethyl, 2-(oxacyclobut-3-yloxy)ethyl, 2-methoxyethyl, 5,5,5-trifluoropentyl, 3-cyanobenzyl, 4-fluorophenylethyl, cyclobutylmethyl, 4,4,4-trifluorobutyl or (2,2-difluorocyclopropyl)methyl.

[0208] In some embodiments, R1 is methylallyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, ethyl, 2-fluoroethyl, 3-fluoropropyl, prop-2-yl, 1,1,1-trifluoropropyl-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-sideoxyethyl, 2-(methylamino)-2-sideoxyethyl, 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-sideoxyethyl, 3-(methylsulfonylurea)propyl, (N,N-dimethylaminesulfonylurea)methyl, 2-methoxypropyl, 2-ethyl-2-hydroxybutyl, 3-chloro-3,3-difluoropropyl, 2-hydroxy-3-( N-(trifluoromethyl)propyl, cyclopropyl, cyclobutyl, 4-(trifluoromethyl)cyclohexyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, oxacyclobutyl-3-yl, oxacyclopentyl-3-yl (tetrahydrofuran-3-yl), 2-sideoxy-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl, 1-methylacetyl-3-yl, 5,5,5-trifluoropentyl or 4,4,4-trifluorobutyl.

[0209] In some embodiments, R1 is (1-((methanesulfonyl)oxy)cyclopropyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (1-(methanesulfonyl)cyclopropyl)methyl, (1-(trifluoromethyl)cyclopentyl)methyl, (1,1-dioxo-tetrahydro-2H-thiaran-4-yl)methyl, (1,2,4-diazol-5-yl)methyl, (1-cyanocyclobutyl)methyl, (1-cyanocyclopropyl)methyl, (1-cyanopiperidin-4-yl)methyl, (1 (-fluorocyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (1H-imidazol-2-yl)methyl, (1H-tetrazole-5-yl)methyl, (1-hydroxycyclobutyl)methyl, (1-methylacetate-3-yl)methyl, (2-ethylcyclopropyl)methyl, (3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl, (3-fluorobicyclo[1.1.1]pent-1-yl)methyl, (3-fluorooxocyclobutyl-3-yl)methyl, (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl, (4,4-difluoro-1-hydroxycyclohexyl)methyl )methyl, (5-cyanofuran-2-yl)methyl, (5-cyanopyridin-2-yl)methyl, (5-methyl-1,3-acetazol-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (6-fluoro-1,4-dioxane-6-yl)methyl, (isoazol-3-yl)methyl, (isoazol-5-yl)methyl, (acetazol-4-yl)methyl, (oxacyclobut-2-yl)methyl, (oxacyclobut-3-yl)methyl, (pyridin-3-yl)methyl, 2-(1-cyanocyclopropyl)ethyl, 2-(1H-imidazol-1 -yl)ethyl, 2-(3,3-difluoropyrrolidin-1-yl)ethyl, 2-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorobenzyl, 4-((difluoromethyl)sulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethyl)phenethyl, 4-fluorobenzyl, benzyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, oxacyclobutyl-3-yl, oxacyclopent-3-yl (tetrahydrofuran-3-yl), pyrimidin-2-ylmethyl, 3-cyanobenzyl, 4-fluorophenylethyl, cyclobutylmethyl or (2,2-difluorocyclopropyl)methyl.

[0210] In some embodiments, R1 is (2-cyanopropyl-2-yl)oxy)ethyl, 2-((4-cyanotetrahydro-2H-piperan-4-yl)oxy)ethyl, 2-(1-cyanocyclobutoxy)ethyl, 2-(1-cyanoethoxy)ethyl, 2-(cyano(cyclopropyl)methoxy)ethyl, 2-(cyanomethoxy)ethyl, 2-(oxacyclobut-3-yloxy)ethyl or 2-methoxyethyl.

[0211] In some embodiments, R1 is methylallyl. In some embodiments, R1 is 2,2,2-trifluoroethyl. In some embodiments, R1 is 2,2-difluoroethyl. In some embodiments, R1 is 2,2-difluoropropyl. In some embodiments, R1 is 3,3,3-trifluoropropyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is 2-fluoroethyl. In some embodiments, R1 is 3-fluoropropyl. In some embodiments, R1 is prop-2-yl. In some embodiments, R1 is 1,1,1-trifluoroprop-2-yl. In some embodiments, R1 is 2-hydroxy-2-methylpropyl. In some embodiments, R1 is 3,3,3-trifluoro-2-hydroxypropyl. In some embodiments, R1 is 3,3-difluoro-2-hydroxypropyl. In some embodiments, R1 is methyl. In some embodiments, R1 is 2-hydroxypropyl. In some embodiments, R1 is 2-hydroxybutyl. In some embodiments, R1 is 4,4,4-trifluoro-2-hydroxybutyl. In some embodiments, R1 is 3,3,3-trifluoro-2-hydroxy-2-methylpropyl. In some embodiments, R1 is 2,3-dihydroxypropyl. In some embodiments, R1 is 3-hydroxypropyl. In some embodiments, R1 is 2-hydroxyethyl. In some embodiments, R1 is cyanomethyl. In some embodiments, R1 is 2-(dimethylamino)-2-sideoxyethyl. In some embodiments, R1 is 2-(methylamino)-2-sideoxyethyl. In some embodiments, R1 is 2-hydroxy-3-methoxypropyl. In some embodiments, R1 is 2-chloro-2,2-difluoroethyl. In some embodiments, R1 is 2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl. In some embodiments, R1 is 2-(methyl(2,2,2-trifluoroethyl)amino)-2-sideoxyethyl. In some embodiments, R1 is 3-(methylsulfonylurea)propyl. In some embodiments, R1 is (N,N-dimethylaminosulfonylurea)methyl. In some embodiments, R1 is 2-methoxypropyl. In some embodiments, R1 is 2-ethyl-2-hydroxybutyl. In some embodiments, R1 is 3-chloro-3,3-difluoropropyl. In some embodiments, R1 is 2-hydroxy-3-(N-hydroxylinyl)propyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is 4-(trifluoromethyl)cyclohexyl. In some embodiments, R1 is 2-fluorocyclopentyl. In some embodiments, R1 is 3,3-difluorocyclopentyl. In some embodiments, R1 is oxacyclobut-3-yl. In some embodiments, R1 is oxacyclopent-3-yl (tetrahydrofuran-3-yl). In some embodiments, R1 is 2-sideoxy-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl. In some embodiments, R1 is 1-methylacetyl-3-yl.In some embodiments, R1 is (1-((methanesulfonyl)oxy)cyclopropyl)methyl. In some embodiments, R1 is (1-(cyanomethyl)cyclopropyl)methyl. In some embodiments, R1 is (1-(difluoromethyl)cyclopropyl)methyl. In some embodiments, R1 is (1-(methanesulfonyl)cyclopropyl)methyl. In some embodiments, R1 is (1-(trifluoromethyl)cyclopentyl)methyl. In some embodiments, R1 is (1,1-dioxo-tetrahydro-2H-thiaran-4-yl)methyl. In some embodiments, R1 is (1,2,4-diazol-5-yl)methyl. In some embodiments, R1 is (1-cyanocyclobutyl)methyl. In some embodiments, R1 is (1-cyanocyclopropyl)methyl. In some embodiments, R1 is (1-cyanopiperidin-4-yl)methyl. In some embodiments, R1 is (1-fluorocyclobutyl)methyl. In some embodiments, R1 is (1-fluorocyclopropyl)methyl. In some embodiments, R1 is (1H-imidazol-2-yl)methyl. In some embodiments, R1 is (1H-tetrazole-5-yl)methyl. In some embodiments, R1 is (1-hydroxycyclobutyl)methyl. In some embodiments, R1 is (1-methylacartan-3-yl)methyl. In some embodiments, R1 is (2-ethylcyclopropyl)methyl. In some embodiments, R1 is (3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl. In some embodiments, R1 is (3-fluorobicyclo[1.1.1]pent-1-yl)methyl. In some embodiments, R1 is (3-fluorooxocyclobutyl-3-yl)methyl. In some embodiments, R1 is (3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl. In some embodiments, R1 is (4,4-difluoro-1-hydroxycyclohexyl)methyl. In some embodiments, R1 is (5-cyanofuran-2-yl)methyl. In some embodiments, R1 is (5-cyanopyridin-2-yl)methyl. In some embodiments, R1 is (5-methyl-1,3-acetazol-2-yl)methyl. In some embodiments, R1 is (6-cyanopyridin-2-yl)methyl. In some embodiments, R1 is (6-fluoro-1,4-dioxane-6-yl)methyl. In some embodiments, R1 is (isoazol-3-yl)methyl. In some embodiments, R1 is (isoazol-5-yl)methyl. In some embodiments, R1 is (acetazol-4-yl)methyl. In some embodiments, R1 is (oxacyclobut-2-yl)methyl. In some embodiments, R1 is (oxacyclobut-3-yl)methyl. In some embodiments, R1 is (pyridin-3-yl)methyl. In some embodiments, R1 is 2-(1-cyanocyclopropyl)ethyl. In some embodiments, R1 is 2-(1H-imidazol-1-yl)ethyl. In some embodiments, R1 is 2-(3,3-difluoropyrrolidin-1-yl)ethyl. In some embodiments, R1 is 3-fluorobenzyl.In some embodiments, R1 is 4-((difluoromethyl)sulfonyl)benzyl. In some embodiments, R1 is 4-(trifluoromethyl)benzyl. In some embodiments, R1 is 4-(trifluoromethyl)phenethyl. In some embodiments, R1 is 4-fluorobenzyl. In some embodiments, R1 is benzyl. In some embodiments, R1 is cyclopropylmethyl. In some embodiments, R1 is pyrimidin-2-ylmethyl. In some embodiments, R1 is (2-cyanopropyl-2-yl)oxy)ethyl. In some embodiments, R1 is 2-((4-cyanotetrahydro-2H-piperan-4-yl)oxy)ethyl. In some embodiments, R1 is 2-(1-cyanocyclobutoxy)ethyl. In some embodiments, R1 is 2-(1-cyanoethoxy)ethyl. In some embodiments, R1 is 2-(cyano(cyclopropyl)methoxy)ethyl. In some embodiments, R1 is 2-(cyanomethoxy)ethyl. In some embodiments, R1 is 2-(oxacyclobut-3-yloxy)ethyl. In some embodiments, R1 is 2-methoxyethyl. In some embodiments, R1 is 5,5,5-trifluoropentyl. In some embodiments, R1 is 3-cyanophenylmethyl. In some embodiments, R1 is 4-fluorophenylethyl. In some embodiments, R1 is cyclobutylmethyl. In some embodiments, R1 is 4,4,4-trifluorobutyl. In some embodiments, R1 is (2,2-difluorocyclopropyl)methyl. It should be understood that when the R1 group has an anticoarticulated carbon, the anticoarticulated carbon can be (R) or (S). In some embodiments, when the R1 group has an anticoarticulated carbon, the anticoarticulated carbon is (R). In some embodiments, when the R1 group has an anticoarticulated carbon, the anticoarticulated carbon is (S). Furthermore, it should be understood that when the R1 group has two anticoarticulated carbons, these anticoarticulated carbons can be independently (R) or (S). In some embodiments, when the R1 group has two anticoarticulated carbons, both anticoarticulated carbons are (R). In some embodiments, when the R1 group has two anticoarticulated carbons, both anticoarticulated carbons are (S). In some embodiments, when the R1 group has two opposing carbons, one opposing carbon is (R) and the other opposing carbon is (S).

[0212] In some embodiments, R1 is -CH3. In some embodiments, R1 is -CD3. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is -CD2CD3. In some embodiments, R1 is -CH2CH2OCH3, -CH2CH(OH)CH3, -CH2CH(OH)CF3, -CH2CF3, -CH2CF2H, -CH2CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, or -CH(CH3)(CF3). In some embodiments, R1 is -CH2CF3, -CH2CF2H, -CH2CH2CF3, or -CH2CH2CHF2.

[0213] In some embodiments, R1 is -CH2CH3, -CH(CH3)2, -CH2CN, -CH2CF3, -CH(CH3)(CF3), -CH2CF2H, -CH2CF2H, -CH2CF2CH3, -CH2CH2CF3, -CH2CH2CH2H, -CH2CH2OCH3.

[0214] In some embodiments, R1 is -CH2CH3, -CH(CH3)2, -CH2CF3, -CH(CH3)(CF3), -CH2CF2H, -CH2CF2H, -CH2CF2CH3, -CH2CH2CF3, -CH2CH2CH2H, -CH2CH2OCH3.

[0215] In some embodiments, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, etc.

[0216] Some embodiments include each combination of compounds selected from one or more of the groups shown in Table A below, and their pharmaceutically acceptable salts. Some embodiments include each combination of compounds selected from one or more of the groups shown in Table A below. Table A Compound numbering Chemical structure Chemical name 4-1 (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 4-2 (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 4-3 (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 4-4 (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 4-5 (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 4-6 (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 4-7 (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 4-8 (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 4-9 (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 4-10 (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 4-11 (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 4-12 (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 4-13 (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 4-14 (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 4-15 (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 4-16 (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 4-17 (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 4-18 (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 4-19 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(3-fluorooxycyclobut-3-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-20 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[2-(oxocyclobut-3-yloxy)ethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-21 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-oxocyclobut-2-ylmethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-22 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxocyclobut-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-23 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)cyclobutane-1-carboxynitrile 4-24 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 4-25 (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 4-26 (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 4-27 (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 4-28 (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 4-29 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-carboxynitrile 4-30 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetanebut-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-31 (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 4-32 (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 4-33 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 4-34 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-(1H-imidazol-1-yl)ethoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-35 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 4-36 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(5-methyl-1,3-azol-2-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-37 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylacetyl-3-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-38 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(propyl-2-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-39 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1,1,1-trifluoroprop-2-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-40 (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 or (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-( 2 H5) Ethoxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-41 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)oxocyclohexane-4-carboxynitrile 4-42 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)cyclobutane-1-carboxynitrile 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-cyclopropylacetonitrile 4-44 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-methylpropionitrile 4-45 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-carboxynitrile 4-46 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 4-47 (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 4-48 (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 4-49 (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 4-50 (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 4-51 (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 4-52 (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 or (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(²H3)methoxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-53 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxacyclopentan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-54 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3S)-oxacyclopentan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-55 (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 4-56 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2-methylprop-2-en-1-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-57 (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 4-58 (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 4-59 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-carboxynitrile 4-60 (2R,3R,11bR)-9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-61 (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 4-62 (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 4-63 (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 4-64 (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 4-65 (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 4-66 (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 4-67 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]methoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-68 (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 4-69 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-acezo-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-70 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 4-71 (2R,3R,11bR)-9-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-72 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(6-fluoro-1,4-dioxane-6-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-73 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-carboxynitrile 4-74 (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 4-75 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,3-acezo-4-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-76 (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 4-77 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-carboxynitrile 4-78 (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 4-79 ((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 4-80 (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 4-81 (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 4-82 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-carboxynitrile 4-83 (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 4-84 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 4-85 (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 4-86 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 4-87 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)pyrrolidone-2-one 4-88 (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 4-89 (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 4-90 (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 4-91 (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 4-92 (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 4-93 (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 4-94 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 methanesulfonate 4-95 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2,4-diazol-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-96 (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 4-97 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)-1λ 6 -Tetrahydrothiaran-1,1-dione 4-98 (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 4-99 (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 4-100 (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 4-101 (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 4-102 (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 4-103 (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 4-104 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylacetyl-3-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-105 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)propionitrile 4-106 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-({3-fluorobicyclo[1.1.1]pent-1-yl}methoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-107 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyridin-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-108 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyrimidin-2-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-109 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-acezo-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-110 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(1H-imidazol-2-ylmethoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-111 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1H-1,2,3,4-tetrazol-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-112 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxy-3-methoxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-113 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-hydroxy-3-(furrin-4-yl)propoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-114 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-115 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(5,5,5-trifluoropentyl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-116 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}methyl)benzonitrile 4-117 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-(4-fluorophenyl)ethoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-118 (2S,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 4-119 (2R,3R,11bR)-9-(cyclobutylmethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-120 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 4-121 (2R,3R,11bR)-9-[(2,2-difluorocyclopropyl)methoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 5-1 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 5-2 (2S,3R,11bR)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 5-3 (2S,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 5-4 (2R,3S,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol

[0217] Each compound of formula (I), method, composition or use described herein also includes, where applicable, compounds of formula (I) not limited to 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.

[0218] Some embodiments provide a compound of Table 10A and / or Table 10B, or a pharmaceutically acceptable salt thereof. Some embodiments provide a compound having the following structure: or a pharmaceutically acceptable salt thereof.

[0219] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0220] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0221] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0222] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0223] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0224] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0225] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0226] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0227] Some embodiments provide compounds having the following structures:; or pharmaceutically acceptable salts thereof.

[0228] Intermediates applicable to the preparation of compounds of formula (I) are novel and applicable to compounds of formula (I) as described above and below.

[0229] In some embodiments, the compound is selected from the group consisting of: 9-(benzoxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-one (compound 1-B); 9-(benzoxy)-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-one (compound 1-B); Isoquinoline-2-ol (compound 1-C); 10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D); and 9-hydroxy-10-methoxy-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2-one (compound 2-B), or salts thereof.

[0230] In some embodiments, the compound is: 9-(benzoxy)-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-(benzoxy)-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-(benzoxy)-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-(benzoxy)-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:

[0231] In some embodiments, the compound is: 9-(benzoxy)-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-(benzoxy)-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:

[0232] 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 selected from the group consisting 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)); (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)); (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 salts 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:

[0233] 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:

[0234] It should be further understood that certain features described in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, various features described in the context of a single embodiment may also be provided individually or in any suitable sub-combination.

[0235] Pharmaceutical Compositions, Formulations and Dosage Forms The present invention 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.

[0236] The present invention further provides a pharmaceutical composition comprising any of the VMAT2 inhibitor compounds described herein (e.g., compounds of formula (I), including specific compounds described herein); and at least one pharmaceutically acceptable excipient used in the methods described herein, such as for treating hyperkinetic disorders. Pharmaceutically acceptable excipients are physiologically and pharmaceutically suitable, non-toxic and non-inactivating materials or components that do not interfere with the activity of the pharmaceutical substance; excipients may also be referred to as carriers. The formulation methods and excipients described herein are illustrative and not limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005)).

[0237] The composition may also be formulated as pills, capsules, granules or tablets, which, in addition to the VMAT2 inhibitor, also contain diluents, dispersants and surfactants, binders and lubricants. Those skilled in the art can further formulate the VMAT2 inhibitor in an appropriate manner and in accordance with recognized standards (such as those disclosed in Remington above).

[0238] Administration methods include systemic administration of the VMAT2 inhibitor described herein, preferably in the form of the pharmaceutical composition discussed above. As used herein, systemic administration includes oral and non-enteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules, as well as liquids, syrups, suspensions, and emulsions.

[0239] Pharmaceutical preparations for oral administration can be obtained by any suitable method, usually by uniformly mixing the compound with a liquid or fine powdered solid carrier or both in the desired proportion, and then, if necessary, treating the mixture by adding a suitable adjuvant, and if necessary, shaping the resulting mixture into the desired shape to obtain a tablet or sugar-coated pill core.

[0240] Conventional excipients, such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tablet lubricants, and disintegrants, can be used in tablets and capsules for oral administration. Liquid formulations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral formulations may be in the form of dry powders, which can be reconstituted with water or other suitable liquid media prior to use. Non-enteric dosage forms can be prepared by dissolving the compounds described herein in a suitable liquid media and sterilizing the solution by filtration prior to lyophilization or simple filling and sealing of appropriate vials or ampoules.

[0241] Some embodiments provide a method for preparing a pharmaceutical composition, comprising the step of blending a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0242] The preparation suitable for vaginal administration may be in the form of a pessary, tampon, cream, gel, paste, foam or spray, and in addition to containing a pharmaceutical substance, it may also contain a carrier such as that known in this art as appropriate.

[0243] In the preparation of pharmaceutical compositions, the pharmaceutical substance is typically mixed (i.e., blended) with an excipient, which is then diluted or encapsulated within such a carrier, in the form of, for example, capsules, pouches, paper, or other containers. When the excipient acts as a diluent, it can be a solid, semi-solid, or liquid material, serving as a medium, carrier, or medium for the pharmaceutical substance. Therefore, the composition can be in the form of lozenges, powders, tablets, pouches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile encapsulated powders.

[0244] For the preparation of solid pharmaceutical compositions, such as powders, tablets, capsules, suppositories, and dispersible granules, the excipients may be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. This also includes solid formulations intended to be converted into liquid form immediately before use for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0245] To prepare the suppository, a low-melting-point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredient is uniformly dispersed therein (e.g., by stirring). The molten, homogeneous mixture is then poured into a mold of suitable size and allowed to cool and solidify.

[0246] Liquid formulations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions. Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, non-enteric-acceptable diluents or solvents.

[0247] The pharmaceutical composition may be in the form of a suspension, solution or emulsion, such as in an oily or aqueous medium, and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the pharmaceutical composition may be in powder form, obtained by aseptic separation of sterile solids or by lyophilization from solution, and reconstituted with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0248] Pharmaceutical compositions can be formulated as aqueous solutions, water-alcohol solutions, solid suspensions, emulsions, liposome suspensions, or lyophilized powders for reconstitution. Such pharmaceutical compositions can be administered directly or as admixtures for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, perfusion, and infusion.

[0249] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding appropriate colorants, flavoring agents, stabilizers and thickeners as needed.

[0250] Aqueous suspensions suitable for oral use can be prepared by dispersing finely powdered drug substances in water containing viscous materials.

[0251] For topical administration to the epidermis, the compounds described herein and their pharmaceutically acceptable salts may be formulated as gels, ointments, creams or emulsions or transdermal patches. Furthermore, formulations suitable for topical administration into the oral cavity include lozenges containing the medicinal substance in flavoring bases.

[0252] The solution or suspension can be applied directly to the nasal cavity by conventional methods, such as using a dropper, pipette, or nebulizer. The preparation can be provided in single or multiple dosage forms. In the case of a dropper or pipette, this can be achieved by administering an appropriate predetermined volume of solution or suspension to the patient. In the case of a nebulizer, this can be achieved, for example, by means of a metering nebulizer pump.

[0253] Administration to the respiratory tract can also be achieved by means of an aerosol formulation provided in a pressurized package with a suitable propellant. If the compound described herein or its pharmaceutically acceptable salt or pharmaceutical composition containing the compound is administered in the form of an aerosol (e.g., a nasal aerosol) or by means of an inhaler, this can be done, for example, using a nebulizer, a pump nebulizer, an inhalation device, a metered inhaler or a dry powder inhaler.

[0254] Alternatively, the pharmaceutical composition may be provided in dry powder form (e.g., a powder mixture of the compound in a suitable powder base (such as lactose, starch, starch derivatives)). The powder carrier should preferably form a gel in the nasal cavity. The powder composition may be presented, for example, in capsules or cartridges of gelatin, or in unit dosage forms in blister packs, from which the powder may be administered by means of an inhaler.

[0255] Compounds of formula (I) or their pharmaceutically acceptable salts may also be administered via rapidly dissolving or slowly releasing compositions, wherein the compositions include biodegradable rapidly dissolving or slowly releasing carriers.

[0256] Pharmaceutical preparations are preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the pharmaceutical substance. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and powder in vials or ampoules. The unit dosage form may also be a capsule, tablet, lozenge, or oral tablet itself, or any of these unit dosage forms in appropriate quantities. In some embodiments, the pharmaceutical preparation is a tablet or capsule for oral administration. In some embodiments, the pharmaceutical preparation is a liquid prepared for intravenous administration.

[0257] The composition may be formulated in unit dosage forms, each dose containing a pharmaceutical substance or an equivalent mass of a pharmaceutical substance. The term "unit dosage form" means a physically discrete unit of formulation suitable for unit doses in human individuals and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with a suitable excipient as described herein.

[0258] Liquid forms of pharmaceutical substances, including aqueous solutions, appropriately flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils, may be included for oral or injectable administration.

[0259] The pharmaceutical compositions described herein may be sterilized by conventional sterilization techniques or by aseptic filtration. Aqueous solutions may be used as is or lyophilized, with the lyophilized formulation being combined with a sterile aqueous carrier prior to administration.

[0260] 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 excipients as described herein. In some embodiments, the composition is administered via the oral or nasal airway for local or systemic action. The composition may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer or the nebulizer may be connected to a mask holder or an intermittent positive pressure ventilator. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the preparation in a suitable manner.

[0261] The composition may, if necessary, be presented in a package or dispenser device containing one or more unit dosage forms of pharmaceutical substances. The package may, for example, contain metal or plastic foil, such as blister packs. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notification associated with the container, in a form prescribed by the government agency regulating the manufacture, use, or sale of the pharmaceutical product, reflecting that the agency has approved the form of the drug for human or veterinary administration. Such notification may, for example, be a prescription drug label approved by the US Food and Drug Administration or an approved product insert. Compositions comprising the compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0262] In order to prepare solid compositions such as tablets, pharmaceutical substances may be mixed with excipients to form a solid preformed composition containing a homogeneous mixture of components. When such preformed compositions are homogeneous, the pharmaceutical substances are generally uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets and capsules.

[0263] Kits are provided containing one or more of the compounds described herein or their pharmaceutically acceptable salts in unit dose (usually in oral or injectable doses). Such kits may include: containers containing unit doses; informational package inserts describing the use of the medicine in relation to the treatment of the relevant pathological condition and associated benefits; and, where appropriate, apparatus or devices for delivering the composition.

[0264] The compounds described herein or their pharmaceutically acceptable salts are effective over a wide dose range and are generally administered at therapeutically effective doses. However, it should be understood that the actual amount of compound administered will usually be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the individual's age, weight and response, the severity of the individual's symptoms and similar factors.

[0265] The amount of compound or composition administered to an individual will also vary depending on the substance administered, the purpose of administration (such as prevention or treatment), the individual's condition, the manner of administration, and the like. In therapeutic applications, the composition may be administered to an individual already suffering from the disease in an amount sufficient to cure or at least partially inhibit the symptoms and / or lesions of the disease and its complications. The therapeutically effective dose will depend on the condition of the disease being treated and will be determined by the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition, and similar factors.

[0266] The required dose may be presented as a single dose or as a series of doses administered at appropriate time intervals (e.g., two, three, four, or more sub-dose per day). The sub-dose itself may be further divided into, for example, many loosely spaced discrete doses. The daily dose may be divided into several (e.g., two, three, or four) doses, especially when a relatively large dose is considered appropriate. Where appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the specified daily dose.

[0267] Those skilled in this art will readily recognize that the dosage forms described herein may contain the compounds described herein or their pharmaceutically acceptable salts.

[0268] As used herein, a "formulation" is the product of a procedure for preparing or isolating a compound as disclosed and described herein, wherein the formulation contains at least one other component in addition to the compound. In some embodiments, the formulation comprises a chemical entity.

[0269] As used herein, a “chemical entity” as defined in the context of a “formulation” means a compound as disclosed and described herein and at least one other component besides that compound. For example, a chemical entity may be a eutectic or salt of a compound as disclosed and described herein.

[0270] Some embodiments provide a formulation comprising a compound as disclosed and described herein. In some embodiments, the compound is a component of a chemical entity. In some embodiments, the chemical entity is a salt of a compound as disclosed and described herein. In some embodiments, the chemical entity is a (2S,3S)-2,3-bis(4-methylbenzooxy)succinic acid (DPTTA) salt of a compound as disclosed and described herein.

[0271] In some embodiments, the compound of the formulation is present in an excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% of a mirror-isomer, or in an excess of a mirror-isomer within the range defined by any of the foregoing numbers. In some embodiments, the compound of the formulation is present in an excess of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of a mirror-isomer, or in an excess of a mirror-isomer within the range defined by any of the foregoing numbers.

[0272] In some embodiments, the compound of the formulation is present in an excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% of the non-mirror image isomer, or in an excess of the non-mirror image isomer within the range defined by any of the foregoing numbers. In some embodiments, the compound of the formulation is present in an excess of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of the non-mirror image isomer, or in an excess of the non-mirror image isomer within the range defined by any of the foregoing numbers.

[0273] In some embodiments, the formulation comprises 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 of the compound, or by weight within the range defined by any of the foregoing figures. In some embodiments, the formulation comprises at most 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, or 93% by weight of the compound, or by weight within the range defined by any of the foregoing figures. In some embodiments, the formulation comprises at most 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 93% by weight, or 95% by weight of the compound, or by weight within the range defined by any of the foregoing figures.

[0274] In some embodiments, the formulation comprises at least 50% by weight of the compound. In some embodiments, the formulation is in solid form, i.e., a solid dosage form. In some embodiments, the formulation is used to prepare a pharmaceutical composition.

[0275] The method of use is as follows: The compound of formula (I) disclosed and described herein is a VMAT2 inhibitor. Therefore, the present invention includes a method for inhibiting VMAT2 (i.e., reducing at least one function of VMAT2 or reducing VMAT2 expression) by contacting VMAT2 with a compound disclosed and described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact may be performed in vitro, such as when VMAT2 is present in a purified formulation or in cells outside a living organism (e.g., in a tissue sample or cell preparation). In some embodiments, the contact may be performed in vivo, such as when VMAT2 is present in a living organism.

[0276] The VMAT2 inhibitors described herein can reduce the levels of monoamines in the central nervous system. Therefore, the present invention includes a method for reducing the levels of monoamines in the central nervous system of an individual, comprising administering to the individual an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such amount being sufficient to reduce the monoamine levels relative to the levels prior to administration.

[0277] It is believed that VMAT2 inhibitors as disclosed and described herein are effective in a wide range of therapeutic applications and can be used to treat or prevent a variety of conditions caused by or associated with the inhibition of human vesicular monoamine transporter isoform 2. These conditions include neurological and psychiatric disorders, such as hyperactivity, 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. Similarly, (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 treatment methods disclosed and described herein. In some embodiments, isotopic variants of compound 5-A (3R, 11bR) or compound 5-A (3S, 11bS) may contain deuterium at three or more positions, exhibiting an isotopic distribution in proportions different from those normally found in nature. In some embodiments, compound 5-A (3R, 11bR) or compound 5-A (3S, 11bS) may have at least 95%, 97%, 99%, 99.5%, or 99.9% deuterium incorporation at three or more positions, or may have deuterium incorporation at three or more positions within the range defined by any of the foregoing figures.

[0278] Therefore, in the various embodiments disclosed herein, methods are provided for treating or preventing neurological and / or mental illnesses or conditions in an individual of need by administering to an individual a pharmaceutically effective amount of a VMAT2 inhibitor as described herein or a pharmaceutically acceptable salt thereof. Neurological and / or mental illnesses or conditions may be, for example, hyperactivity disorder, schizophrenia, affective schizophrenia, mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Leni syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-linked tremor-dysregulation syndrome, autism spectrum disorder (e.g., restrictive and repetitive behaviors associated with autism spectrum disorder (ASD), Rett syndrome, or chorea-like acanthosis.

[0279] In various other embodiments as revealed herein, a method of treating or preventing a vesicular monoamine transporter protein-2 (VMAT2) disease or condition in an individual in need is provided by administering to an individual a medically effective amount of a VMAT2 inhibitor as described herein or a medically acceptable salt thereof. VMAT2 disorders or conditions can be, for example: arrhythmia or spinal muscular atrophy;chorea;congenital malformations, deformities, or abnormalities;dementia;disorders of the mouth, salivary glands, or jaws;movement difficulties;muscle dystonia;endocrine, nutritional, or metabolic diseases;epilepsy;habit or impulsivity disorders;Handington's disease or phase related disorders;mood or psychotic disorders;neurotic stress-related and somatization-like disorders mental disorders;basal ganglia degenerative disorders;extrapyramidal and motor disorders;neurological or psychiatric disorders or conditions;neural system or motor dysfunction;Parkinson's / parkinsonism disorder);pediatric-onset behavioral and mood disorders;pervasive developmental disorders;and substance abuse or dependence conditions.

[0280] Accordingly, in various embodiments as revealed herein, methods are provided to treat or prevent hyperkinetic dyskinesia in an individual in need by administering a medically effective amount of a VMAT2 inhibitor described herein or a medically acceptable salt thereof to an individual in need. In some embodiments, the hyperkinetic movement disorder is tardive dyskinesia, Tourette's syndrome, Huntington's syndrome, chorea associated with Huntington's, or convulsions. In other embodiments, the hyperkinetic movement disorder is ataxia, chorea, muscle hypotonia, hemifacial spasm, myoclonus, restless leg syndrome, or tremor.

[0281] In some embodiments, a method of treating or preventing a mood disorder in an individual in need is provided by administering a medically effective amount of a VMAT2 inhibitor described herein or a medically acceptable salt thereof to an individual in need. In some embodiments, the mood disorder is bipolar disorder, severe depression, mania in mood disorder, or depression in mood disorder.

[0282] In some embodiments as revealed herein, a method is provided to treat or prevent schizophrenia or affective schizophrenia in an individual in need by administering a medically effective amount of a VMAT2 inhibitor described herein or a medically acceptable salt thereof to an individual in need.

[0283] In some embodiments, the neurological or psychiatric disorder or condition is a hyperkinetic movement disorder.

[0284] In some embodiments, the hyperkinetic dyskinesia is tardive dyskinesia.

[0285] In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome.

[0286] In some embodiments, the hyperkinetic movement disorder is Huntington's disease.

[0287] In some embodiments, the hyperkinetic movement disorder is convulsions.

[0288] In some embodiments, hyperkinetic movement disorder is a chorea associated with Huntington's disease.

[0289] In some embodiments, the hyperkinetic movement disorder is catatonia, chorea, muscle hypotonia, hemifacial spasm, Hangington's disease, myoclonus, restless leg syndrome, or tremor.

[0290] In some embodiments, the neurological or psychiatric disorder or condition is restrictive and repetitive sexual behavior associated with pan-autistic disorder (ASD).

[0291] In some embodiments, the neurological or psychiatric disorder or condition is distress and obsessive-compulsive disorder in partial and nonresponders (or complete refractory) suffering from obsessive-compulsive disorder (OCD). In some embodiments, the neurological or psychiatric disorder or condition is distress and obsessive-compulsive disorder in partial and non-responders (or complete refractory) suffering from obsessive-compulsive disorder (OCD), and the compounds described herein are administered as adjunctive therapy. In some embodiments, compounds described herein are administered as adjuvant therapy together with primary treatment treated with antidepressants.

[0292] In some embodiments, the neurological or psychiatric disorder or condition is Bipolar I Disorder. In some embodiments, the compounds described herein are administered as monotherapy for the treatment of type I bipolar mood disorder. In some embodiments, compounds described herein are administered as maintenance therapy for the treatment of type I bipolar mood disorder. In some embodiments, the compounds described herein are administered as monotherapy maintenance therapy for the treatment of type I bipolar mood disorder.

[0293] In some embodiments, a VMAT2 inhibitory compound of formula (I) or a medically acceptable salt thereof is administered to a patient to treat or prevent a disease or condition selected from: dystrophy or spinal muscular dystrophy, such as spinocerebellar arrhythmia type 17 (SCA17) / HDL4, arrhythmia, spinal muscular dystrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal bulbar muscular dystrophy, dentate nucleus erythroid glomerulus Lewy body atrophy, hereditary motor neuron amputation disease and hereditary motor neuron amputation; Chorea, such as benign hereditary chorea, chorea, chorea associated with mitochondrial disease / etiology, chorea associated with Wilson's disease, chorea of ​​pregnancy, chorea choroidocytosis, drug-induced chorea, miasma, rheumatoid / Sydenham's chorea and thyrotoxic chorea, Angel's syndrome of congenital chorea, chorea malformation of Mann / hyperthyroidism syndrome), congenital neurological conditions, Aicardi's syndrome, neurofibroma, congenital facial nerve hypoplasia, Moebius II syndrome, Cockayne's syndrome, Sjogren-Larsson syndrome, and Laurence-Mooniedl syndrome syndrome), dyskinesia, such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonate), dyskinesia (esophagus), levodopa-induced dyskinesia, sudden motor-induced dyskinesia, sudden non-exercise-induced dyskinesia and respiratory dyskinesia; syndrome), drug-induced acute dystonia, dystonia, early-onset primary dystonia, hereditary torsion muscle hypotonia, hand muscle hypotonia / writing spasms, idiopathic nonfamilial muscle dystonia, idiopathic oral and maxillofacial muscle hypotonia / Meige's disease, laryngeal muscle hypotonia, oral and mandibular dystonia and spastic torticollis;Endocrine, nutritional, and metabolic disorders, such as Wilson's disease, diabetes, obesity, syndrome X, and Lesch-Nyhan syndrome; epilepsy, such as Baltic myoclonic epilepsy, benign familial neonatal seizures, epilepsy, congenital epilepsy, Lafora's myoclonic epilepsy, severe infantile myoclonic epilepsy, and seizures; habitual and impulsive disorders, such as bulimia, kleptomania, impulse control disorders, trichotillomania, intermittent explosive disorder, pathological gambling, and pyrokinesis; Huntington's disease or related disorders, such as Huntington's disease, Huntington's syndrome 1-3, Huntington's disease, and X-linked McLeod neuroacanthocytosis syndrome; Mood or psychotic disorders, such as schizophrenia, psychosis, mania, bipolar disorder, depression, and mood disorders; other diseases or conditions, such as fumbling disorder, hypokinesis, hypokinesis (neonatal), movement disorders, rabbit meat syndrome, spasms, up-and-down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders, and rheumatoid arthritis; neurogenic stress-related and somatization disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and psychomotor disorders; other degenerative diseases of the basal ganglia, such as pantothenic kinase-related neurodegeneration, progressive supranuclear palsy, multiple systemic atrophy, dyslexia, basal ganglia degeneration, and neuroferritinopathy; Other extrapyramidal and motor disorders, such as unilateral tic, extrapyramidal symptoms, essential tremor, geniospasm, hyperexplexia, akathisia, ballismus / hemispheric twitching, myoclonus, and restless legs syndrome / Willis-Ekbom's syndrome;Other neurological or motor dysfunctions, such as sleep-related bruxism, abnormal involuntary movement disorders, extralimb syndrome, Alzheimer's disease (agitation), clumsiness, spastic hemifacial spasm, olfactory dysplasia, congenital cranial nerve palsy, ataxia syndrome, familial periodic paralysis, congenital hemiparesis, fine motor delay, fine motor skill dysfunction, gross motor delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, childhood alternating hemiparesis, motor developmental delay, cerebral palsy, choreoathetoid cerebral palsy, posturing, pseudoparalysis, psychomotor hyperactivity, bradykinesia, synkinesis, akinesis, Riley-Day syndrome, and choreoathetosis; Parkinson's disease, including Parkinson's syndrome, drug-induced Parkinson's disease, micrographia, and Parkinson's disease; episodic behavioral and emotional disorders in children, such as attention deficit hyperactivity disorder (ADHD), attention deficit disorder, hyperkinesis, hyperkinesis (neonatal), oppositional defiant disorder, transient tic disorders, persistent (long-term) motor or vocal tic disorders, stereotyped movement disorders, stereotyped disorders, and Tourette syndrome; pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, and Asperger's syndrome. (syndrome), pervasive developmental disorder (NOS) and dyslexia; and substance abuse or dependence, such as addiction, alcoholism, cocaine dependence, illicit drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine analogue abuse, nicotine dependence, multiple substance abuse, and prescription drug abuse.

[0294] In some embodiments, the patient undergoing treatment has been determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is susceptible to mental illness due to having 22q11.2 deletion syndrome. In some embodiments, the patient has been determined to have COMT haploinadequacy. In some embodiments, the patient is susceptible to mental illness due to having COMT haploinadequacy.

[0295] In another embodiment, the VMAT2 inhibitors described herein can be hydrolyzed in mammals to compounds that inhibit human vesicular monoamine transporter isoform 2. Therefore, such VMAT2 inhibitors may have additional utility in altering the in vivo properties of the metabolites in mammals, such as maximum concentration or duration of action.

[0296] Any of the VMAT2 inhibitors described herein can be characterized using the methods described herein and the methods of this technique. For example, dopamine depletion can be measured using a motor activity (LMA) assay. Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds.

[0297] Combination Therapy The compounds of the present invention or their pharmaceutically acceptable salts may be used as a monotherapy or in combination with one or more other agents. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered together (simultaneously or sequentially) with one or more agents selected from: antidepressants, antipsychotics (typical or atypical), antiepileptics, antibacterial agents, antiarrhythmics, mood stabilizers, and gastrointestinal drugs. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is used in adjunctive therapy, which refers to treatment used in conjunction with initial treatment and intended to assist the initial treatment. Adjunctive therapy is generally a co-administration therapy. As an example of adjunctive therapy, if obsessive-compulsive disorder is being treated, the initial treatment may be, for example, an antidepressant, and co-administration with the compound described herein would be considered adjunctive therapy.

[0298] Compound Synthesis Detailed methods for the synthesis of compounds are described in the examples herein. Generally, the starting components are commercially available chemicals, or can be prepared using commercially available chemicals and / or compounds described in chemical literature as starting materials, based on organic synthesis techniques known to those skilled in the art.

[0299] Generally, the compounds used in the reactions described herein can be manufactured using commercially available chemicals and / or compounds described in chemical literature as starting materials, according to organic synthesis techniques known to those skilled in the art. Methods known to those skilled in the art can be determined through various reference books and databases. Suitable references and papers detailing the synthesis of reactants that can be used to prepare the compounds of this invention, or referring to articles describing the preparation, 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; TL 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.

[0300] Certain and similar reactants can also be identified using the Known Chemicals Index compiled by the American Chemical Society's Chemical Abstracts Service (available in most public and university libraries) and online databases (for further details, contact the American Chemical Society in Washington, D.C.). Known but not listed in the commercial catalogues can be prepared by custom chemical synthesis facilities using known methods, many of which provide custom synthesis services to standard chemical suppliers (such as those listed above).

[0301] The term "reducing agent" refers to a compound that contributes a hydride to an electrophilic position of a reactant compound, such as an unsaturated carbon (e.g., the carbon of the carbonyl group), such as converting a reactant compound containing a ketone into an alcohol product compound or a reactant compound containing an ester into an alcohol product compound. The reducing agent may be a hydride reducing agent. Examples of hydride reducing agents include, but are not limited to, diborane, borane (e.g., boranetetrahydrofuran complex), 9-boronbicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminum hydride, diisobutyl-tertiarybutoxyaluminum hydride, tri-tertiarybutoxyaluminum hydride, tri-[(3-ethyl-3-pentyl)oxy]aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminum, sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, and borohydride. Tetraethylammonium borohydride, tetramethylammonium borohydride, bis(triphenylphosphine)copper borohydride (I), 9-boronbicyclo[3.3.1]nonane lithium hydride, triethoxysodium borohydride, tri-dibutylborohydride potassium, tri-dibutylborohydride sodium, tripentylborohydride potassium, triethylbolane lithium, triethylbolane potassium, triethylbolane sodium, triphenylbolane potassium, dimethylaminobolane lithium, pyrrolidinylbolane lithium, cyanobolane sodium, trimethoxysodium borohydride, sodium borohydride and similar compounds.

[0302] The term "halogenating agent" refers to a compound that contributes halogen atoms to a reactant compound, such as converting an alcohol reactant compound into an alkyl halide product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, acetic acid chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonyl chloride and NaI, p-toluenesulfonyl chloride and NaI, phosphorus tribromide, triphenylphosphine dibromide, phosphorus pentabromide, or thionyl bromide and their analogues.

[0303] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0304] The base can be an inorganic base or an organic base.

[0305] 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.

[0306] 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.

[0307] The term “acid” refers to a compound that is an electron pair acceptor in an acid-base reaction.

[0308] The acid can be an inorganic acid or an organic acid.

[0309] The term "inorganic acid" refers to an acid that does not contain carbon bonds. Inorganic acids can be strong or weak acids.

[0310] The term "organic acid" refers to an acid that includes at least one CH bond, CF bond or CC bond.

[0311] Certain Abbreviations This manual includes many abbreviations, the definitions of which are listed in the table below: abbreviation definition ACN Acetonitrile aq. Aqueous / aqueous solution EtOAc Ethyl acetate DCM Dichloromethane (methylene chloride) d sky de Excess of non-mirror isomers DPTTA (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinic acid ee Excess of mirror isomers EtOH ethanol h Hour HPLC High performance liquid chromatography i-PrOH Isopropanol min. minute MeOH methanol MTBE Methyl tributyl ether RT room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran

[0312] Examples include the following examples to illustrate embodiments of the present invention. However, according to the present invention, those skilled in the art should understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention and still obtaining the same or similar results.

[0313] Analytical HPLC analysis was performed on an LC-MS system equipped with a UV detector (Dionex™ UVD 170u UV / VIS detector), a corona array detector (Thermo™ Veo™ RS), and a mass spectrometer (Dionex MSQ Plus™). Reverse-phase preparative HPLC purification was performed using an ACN / water gradient containing 0.05% TFA, at 1.1 mL / min and 50 °C, on a Phenomenex liquid chromatography-mass spectrometry (LCMS) system C18 Kinetix 5μ 100 A 150 x 21.2 mm column. Supercritical fluid chromatography (SFC) purification was performed using a Waters™ Prep 100q™ system equipped with a UV detector (Waters™ 2998 Photodiode Array Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Waters™ Viridis™ BEH 2-ethylpyridine 130 Å 5 µm 30 mm x 100 mm column with CO2 and 0.3% NH4OH / MeOH gradients was used, run at 100 mL / min, 40 °C, and a 105 bar back pressure regulator. All final compounds were analyzed by analytical HPLC-MS, and peaks were monitored by mass spectrometry at 220, 212, 270, and 254 nm in UV, with purity monitored via an electrosol detector. ¹H NMR in suitable NMR solvents (such as dimethyl sulfoxide-d6 (DMSO-d6)) was recorded on a Bruker 400 MHz spectrometer equipped with a broadband NMR probe or on a Bruker 500 MHz spectrometer equipped with a 5 mm QNP probe with a Z gradient. ¹H NMR chemical signals are given in parts per million (ppm), with residual solvent signals used as a reference. Chemical shifts are expressed in ppm (δ), and coupling constants (J) are reported in Hertz (Hz). Unless otherwise stated, the reaction is carried out under a dry nitrogen atmosphere.

[0314] I. A general synthetic procedure for preparing compounds of formula (I) is shown in Figure 6, wherein X is a halogroup (e.g., I, Cl, or Br), OS(O)₂OR₁, or OS(O)₂R₂, wherein R₂ is a C₁-C₆ alkyl, a halo-C₁-C₆ alkyl, or a phenyl group, which is unsubstituted or substituted with one or more halogroups, nitrogroups, C₁-C₆ alkyl groups, halo-C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, or halo-C₁-C₆ alkoxy groups. Alternatively, R₁-X (where X is I, Cl, or Br) can be prepared by reacting a commercially available HO-R₁ with a halogenating agent.

[0315] According to Figure 6, the compound of general formula (I) as described herein can be synthesized from compound 1-A in several steps. In one case, the sequence of forming the compound of general formula (I) includes, as appropriate, condensing compound 1-A with 3-[(dimethylamino)methyl]-5,5-dimethylhexane-2-one in a solvent or solvent mixture (such as i-PrOH / water and the like) in the presence of an acid and an additive (such as NaI) to give compound 1-B. In a solvent or solvent mixture (such as methanol, MTBE and the like), compound 1-B is reduced in the presence of a reducing agent, and, if applicable, in the presence of an additive (such as acetic acid), to obtain compound 1-C. The reducing agent may be: sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, tetramethylammonium borohydride, bis(triphenylphosphine)copper (I) borohydride, lithium 9-boronbicyclo[3.3.1]nonane hydride, sodium triethoxyborohydride, lithium tri-2-butylborohydride, potassium tri-2-butylborohydride, potassium tri-2-butylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidinylborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium borohydride and the like. Compound 1-D can be prepared by hydrogenolysis or solvent decomposition, for example by treating compound 1-C with an acid in a solvent (such as methanol and the like). Finally, compound 1-D can be treated in a solvent (such as DMF, acetone and the like) in the presence of a base with R1-X (where X is a leaving group, such as I, Br, Cl, trifluoromethanesulfonate and the like) or an epoxide to give compound of general formula (I).

[0316] 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.

[0317] Step 1: Synthesis of 9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 1-B). A suspension of 6-(benzoxy)-7-methoxy-3,4-dihydroisoquinoline (compound 1-A, 25 g, 93.5 mmol, 1.2 eq) in water (63 mL) was prepared and cooled to 0 °C. Then, an aqueous solution of HCl (6.7 mL, 12.1 N, 1.05 eq) was added, followed by the addition of sodium iodide (5.83 g, 38.9 mmol, 0.5 eq), and the resulting mixture was heated to room temperature. Finally, 3-[(dimethylamino)methyl]-5,5-dimethylhexane-2-one (14.4 g, 77.9 mmol, 1.0 eq) was added to a solution of i-PrOH (22 mL), 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 solids, and concentrated under vacuum. Using DCM-supported silicone columns (220 g × 2, 120 g × 1) and running with an increasing gradient of EtOAc (0–40%, over 20 min) / hexane, we obtained 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, 71%).

[0318] Step 2: Synthesize 9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C). Solid sodium borohydride (2.3 g, 61.0 mmol, 1.1 eq) was carefully added fractionally to a solution of 9-(benzoxy)-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 eq) in MTBE:MeOH (4:1, 113 mL) and acetic acid (3.2 mL, 55.5 mmol, 1.0 eq). The reaction progress was monitored hourly by LC / MS. Subsequently, 4:1 MTBE:MeOH (56 mL), 0.5 eq of acetic acid, and an additional 2.0 eq of sodium borohydride were added to the stirred mixture. After stirring overnight at room temperature, 1N NaOH (180 mL) was added, and the resulting mixture was heated to 50 °C for 3 h. The mixture was then cooled to room temperature and allowed to stand for 1 h. The precipitate was collected by vacuum filtration, washed with excess water (~600 mL) until pH < 10, and finally washed with MTBE. The filter cake was dried to give 9-(benzoxy)-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%).

[0319] Step 3: Synthesize (2R,3R,11bR)-9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (also known as compound 4-60 in Table A of compound 1-C (2R,3R,11bR)). Add (2S,3S)-2,3-bis(4-methylbenzooxy)succinic acid (DPTTA, 17.9 g, 46.3 mmol, 1.1 eq) participle to a suspension of 9-(benzoxy)-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 eq) in MeOH (150 mL). Additional MeOH (100 mL) and heating (65 °C) are required to dissolve the solid. Cool the resulting solution to 60 °C, inoculate with the previously prepared compound 1-C (2R,3R,11bR)∙(DPTTA) (138 mg, see Example 1B, for example), and stir at 60 °C for 30 min. The mixture was then cooled to room temperature at a rate of 4 °C / h, followed by stirring overnight at room temperature. The precipitate was collected by vacuum filtration and dried to give a white solid compound 1-C∙(2R,3R,11bR) (DPTTA) (14.7 g, 18.5 mmol, 44%). The optical purity as a single non-mirror image is determined by palmar supercritical fluid chromatography (SFC). Palmar purity analysis was performed using a Waters™ Ultra-Performance Convergence Chromatography (UPC2)™ system equipped with a UV detector (Waters™ Acquity UPC2 PDA Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Chiral Technologies Inc™ ChiralPakTMIC / SFC 1.6 µm, 2.1 mm x 50 mm column with isocratic gradients of 85% CO2 and 15% 0.5% DMEA / MeOH was used at 1.5 mL / min, 55 °C, and a 1500 psi back pressure regulator. An extraction wavelength of 285 nm was used for ee% quantification and analysis.

[0320] The antagonistic salt pair was suspended in DCM and water was added. The mixture was alkalized with a saturated aqueous solution of NH4OH until pH ~ 10. The mixture was extracted three times with DCM. The organic extract was dried over MgSO4, filtered and concentrated under vacuum to give (2R,3R,11bR)-9-(benzoxy)-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%).

[0321] Step 4: Synthesize (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)). After 30 min, 37% HCl aqueous solution (34 mL) was added dropwise to a solution of (2R,3R,11bR)-9-(benzoxy)-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 eq) in MeOH (68 mL). The mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 30 min, 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. Then, saturated aqueous solution of NaHCO3 was added dropwise until pH ~ 8, with additional DCM added as needed to assist stirring. The precipitate was collected by vacuum filtration, washed with water and MTBE, dried, and set aside. The filtrate was extracted with 5:1 DCM:i-PrOH. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. The resulting solids were combined with the filter cake to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 5.5 g, 17.2 mmol), in almost quantitative yield.

[0322] Example 1B: Preparation of salts of (2R,3R,11bR)-9-(benzoxy)-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-methylbenzoxy)succinic acid (compound 1-C∙(2R,3R,11bR) (DPTTA)), see Figure 8.

[0323] (2S,3S)-2,3-bis(4-methylbenzooxy)succinic acid (DPTTA, 494 mg, 1.24 mmol, 1.0 eq) was added fractionally to a suspension of 9-(benzoxy)-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 eq) in MeOH (7 mL). The resulting mixture was heated to 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 h. The precipitate was collected by vacuum filtration, washed with methanol (1 mL), and dried to obtain a white solid compound 1-C∙(2R,3R,11bR) (DPTTA) (365 mg, 37%). Optical purity (90% ee) was determined by palmarity SFC analysis. Palmarity purity analysis was performed using a Waters™ Ultra-Performance Convergence Chromatography (UPC2)™ system equipped with a UV detector (Waters™ Acquity UPC2 PDA Detector™) and a mass spectrometer (Waters™ Acquity QDa Detector™). A Chiral Technologies Inc™ ChiralPakTMIC / SFC 1.6 µm, 2.1 mm x 50 mm column with an isocratic gradient of 85% CO2 and 15% 0.5% DMEA / MeOH was used at 1.5 mL / min, 55 °C, and a 1500 psi back pressure regulator. An extraction wavelength of 285 nm was used for ee% quantification and analysis. 20 mg of the solid sample was allowed to recrystallize further, and the mother liquor and remaining white solid were recombined and concentrated under vacuum. This mixture was suspended in MeOH (5 mL) and heated to reflux to obtain a clear solution. Stirring was stopped, and the mixture was cooled to 60 °C and inoculated with 2 mg of the previously prepared 90% ee compound 1-C∙(2R,3R,11bR) (DPTTA) solid. The mixture was allowed to stand at 60 °C for 1 h, then the temperature was decreased at 5 °C per hour until room temperature was reached, and then allowed to stand for 16 h. The precipitate was collected by vacuum filtration, washed with methanol (1 mL) and dried to give compound 1-C∙(2R,3R,11bR) (DPTTA) (200 mg, 20%). The optical purity of 100% ee as a single non-mirror image is determined by palmar SFC analysis.

[0324] 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.

[0325] 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). [2-(2,2-dimethylpropyl)-3-sideoxybutyl]trimethylammonium iodide (11.1 g, 33.9 mmol, 1.0 eq) was added to a solution of 7-methoxy-3,4-dihydroisoquinoline-6-ol (compound 2-A, 7.2 g, 40.7 mmol, 1.2 eq) in EtOH (66 mL), and the mixture was stirred under reflux for 3 days. The mixture was cooled, diluted with an aqueous solution of NaHCO3, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was dried and loaded onto diatomaceous earth, and chromatographically analyzed on a silicone column (220 g) with an increasing gradient of EtOAc (0-60%, over 20 min) / hexane. Due to co-dissolved impurities, the material was dried and loaded onto diatomaceous earth again, and chromatographically analyzed on a silicone column (80 g) with a shallower gradient of EtOAc (0-45%, over 20 min) / hexane, yielding a 7:1 mixture of racemic, non-mirror image isomers 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, 4.2 g, 13.3 mmol, 39%).

[0326] Step 2: Separate (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)). The separation of mirror isomers 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 solutions in very small volumes of MeOH and performing preparative palmar supercritical fluid chromatography (SFC). Palmar isomers were separated using a Pic Solution™ SFC-PICLAB-Prep 200™ supercritical fluid chromatography (SFC) system equipped with a UV detector and Advion™ mass spectrometer. A Chiral Technologies Inc™ ChiralPak™ IG / SFC 5 µm, 20 mm x 250 mm column with isocratic gradients of 80% CO2 and 20% 0.5% DMEA / MeOH was used 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 separated.

[0327] Suitable crystals were produced by slow evaporation of a solution of compound 2-B (3S,11bS) in acetone. The absolute stereochemistry was confirmed by obtaining the small molecule crystal structure of compound 2-B (3S,11bS).

[0328] Single-crystal X-ray structure of compound 2-B (3S,11bS). 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 is specified correctly, the absolute configuration parameter (Flack parameter) is almost zero; when the configuration is incorrect, the parameter is almost +1. For this dataset, the Flack parameter is 0.06(3) for the specification shown in Figure 1A. Crystallization information is shown in Table 1. Table 1: Crystal data of compound 2-B (3S, 11bS) Molecular formula C 19 H 27 NO3 Molecular weight (g / mol) 317.41 wavelength 1.54178 Å Radiation (Å) Cu Kα (λ = 1.54178 Å) instrument Bruker Microstar APEX II CCD Crystal system Monoclinic crystal Space Group P 1 211 Temperature (K) 100.0 unit cell size a = 6.8023(2) Å α = 90° b = 8.9511(3) Å β = 94.837(3)° c = 13.9008(5) Å γ = 90° volume 843.38(5) Ǻ3 Z, Z' 2 Density (calculated value) 1.250 Mg / m 3 F(000) 344 Crystal size 0.18 × 0.12 × 0.02 mm 3

[0329] Example 3: Alternative preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR)) and preparation of (2S,3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2S,3S,11bS)), see Figure 10.

[0330] 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)). Sodium borohydride (131 mg, 3.46 mmol, 1.5 eq) was added 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 eq) in MeOH (5 mL). The mixture was stirred at room temperature for 16 h, at which point additional sodium borohydride (44 mg, 1.16 mmol, 0.5 eq) was added. The mixture was stirred at room temperature for an additional 3 h. 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 solids were suspended in MTBE (5.9 mL) and MeOH (1.5 mL), and the mixture was heated to 50 °C with stirring for 1 h. The suspension was cooled to room temperature, and the solids were collected by filtration. The filter cake was washed with MTBE (2.2 mL), and the solid was collected to give (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 567 mg, 1.77 mmol, 35:1 dr, 77%).

[0331] Single-crystal X-ray structure of compound 1-D (2R,3R,11bR). Crystals of compound 1-D (2R,3R,11bR) were grown using the CrystalBreeder system. 0.25 mL of DMF (~20 mg / mL) containing approximately 5 mg of compound 1-D (2R,3R,11bR) was slowly cyclicated several times from 5°C to 80°C. Multiple vials were used. After cyclic heating, large needle-like structures formed on the sides of the vials. The solvent was decanted, and the crystals were analyzed. Suitable crystals were selected for single-crystal X-ray structure determination. Crystals were also obtained using a similar preparation method with ACN, but crystals grown from DMF provided better candidates for further analysis.

[0332] The crystal structure of compound 1-D (2R,3R,11bR) was determined. The structure was determined to be anhydrous and unsolvated; all three palmar centers at C2, C3, and C11b were determined to have the R configuration. For the asymmetric units of the crystal structure, see Figure 1B. Crystal data, unit system, and space group of compound 1-D (2R,3R,11bR) are shown in Table 2. Data collection and refinement parameters for compound 1-D (2R,3R,11bR) are shown in Table 3. Table 2: Crystal data for compound 1-D (2R, 3R, 11bR) Chemical formula C 19 H 29 NO3 Mr 319.43 Crystal system, space group Orthorhombic crystal, P212121 Data collection temperature (K) 150 a(Å) 9.1345 (3) b(Å) 12.3990 (4) c(Å) 14.9842 (6) Volume (Å3) 1697.09 (10) Z 4 Radiation type Cu Kα Crystal shape disc color colorless Crystal size (mm) 0.13 × 0.11 × 0.04 Table 3: Data collection and refinement parameters for compound 1-D (2R, 3R, 11bR) diffractometer Bruker AXS D8 Quest diffractometer with PhotonIII_C14 charge-integrated and photon-counting pixel array detector radiation source I-mu-S Micro-source X-ray tube Absolute structural parameters 0.03 (10)

[0333] 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)). Using a method similar to that used to prepare compound 1-D (2R,3R,11bR), (3S,11bS)-3-(2,2-dimethylpropyl)-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, (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.

[0334] 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.

[0335] 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)). 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 eq) in THF (0.75 mL) was cooled to 0 °C. Next, a solution of tri-dibutylborohydride (1M THF, 0.30 mL, 0.30 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 3 h. 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. A DCM-supported silicone column (4 g) was used, and the column was run with an increasing gradient of EtOAc (0-60%, over 30 min) / hexane. Fractions were separated between the pure product (compound 1-D (2S,3R,11bR), 16 mg) and the product with minor non-mirror image isomers (28 mg, between compound 1-D (2S,3R,11bR): compound 1-D (2R,3R,11bR), 10:1 non-mirror image isomer ratio). In summary, (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 (compound 1-D (2S,3R,11bR), 44 mg) with a combined yield of 91%.

[0336] 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)). Using a method similar to that used to prepare compound 1-D (2S,3R,11bR), (3S,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 2-B (3S,11bS)) was used as the starting material and lithium tri-dibutylborohydride as the reducing agent to prepare (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))-9-hydroxy-10-methoxy-1H,2H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3S,11bS))-9-hydroxy-10-methoxy-1H,2H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3S,11bS))-9-hydroxy-10-methoxy-1H,2H,7H,11bH) ...

[0337] 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.

[0338] Cesium carbonate (0.61 g, 1.9 mmol, 3.0 eq) was added 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 eq) in acetone (6.3 mL), and the mixture was stirred at room temperature for 10 min. Next, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.19 g, 0.82 mmol, 1.3 eq) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with 5:1 DCM:i-PrOH. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. Using a DCM-supported silicone column (40 g) and run with an increasing gradient of EtOAc (0–50%, for 25 min) / hexane, a white solid (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%) was obtained. 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).

[0339] 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).

[0340] At 50 °C, cesium carbonate (2.44 g, 7.50 mmol, 3.0 eq) was added to a solution of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR), 0.80 g, 2.50 mmol, 1.0 eq) in DMF (40 mL). After 6 h via syringe pump, cyclopropyl trifluoromethanesulfonate (0.60 g, 3.13 mmol, 1.25 eq) was added to a solution of DMF (3 mL). The mixture was stirred at 50 °C for another 10 h. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. Using a DCM-supported silicone column (24 g) and run with an increasing gradient of EtOAc (0-100%, for 25 min) / hexane, an 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) was obtained as a grayish-white solid. To remove trace impurities, the crude compound 4-27 (0.83 g, 2.31 mmol, 1.0 eq) was dissolved in anhydrous THF (14 mL) at 0 °C under a nitrogen atmosphere with stirring. Lithium aluminum hydride was added dropwise to a 2M solution of THF (2.3 mL, 4.62 mmol, 2.0 eq) over 10 min. The temperature was raised to 60 °C and stirred for 16 h. The mixture was cooled to 0 °C, and then sodium sulfate dodecahydrate (0.65 g, 2.02 mmol, 0.9 eq) was added over 10 min, followed by stirring for 20 min. The mixture was filtered through diatomaceous earth, and the filter cake was washed with acetone, MeOH, and DCM. The filtrate was concentrated under vacuum, then dissolved in a 1:1 DCM / EtOAc solution and washed three times with 1M NaOH aqueous solution. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum.The crude material was subjected to three chromatographic separations: a DCM-supported silica column (12 g) with an increasing gradient of EtOAc (0–75%, for 25 min) / hexane; a basic alumina column (24 g) with an increasing gradient of EtOAc (0–75%, for 25 min) / hexane; and a DMSO-supported reverse-phase C18 column (30 g) with an increasing gradient of MeCN (10–70%, for 20 min) / water, yielding a white solid (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%, in two steps). 1H 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).

[0341] Example 5C: Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxacyclobut-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30).

[0342] Cesium carbonate (0.61 g, 1.88 mmol, 3.0 eq) was added 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 eq) in DMF (6 mL), and the mixture was stirred at room temperature for 10 min. Then, 3-bromooxybutane (0.12 mL, 1.56 mmol, 2.5 eq) was added, and the mixture was stirred at 60 °C for 6 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude material was subjected to two chromatographic separations: a DCM-supported silicone column (4 g) with an increasing gradient of EtOAc (0–100%, for 30 min) / hexane; and a DMSO-supported reverse-phase C18 column (16 g) with an increasing gradient of MeCN (10–100%, for 25 min) / water, yielding a white solid (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxacyclobut-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%). 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).

[0343] 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 (compounds 4-50).

[0344] Cesium carbonate (0.61 g, 1.88 mmol, 3.0 eq) was added 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 eq) in DMF (6 mL), and the mixture was stirred at room temperature for 10 min. Then, (2S)-2-(trifluoromethyl)ethylene oxide (72 µL, 0.94 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 6 h. Add one part (2S)-2-(trifluoromethyl)ethylene oxide (24 µL, 0.31 mmol, 0.5 eq), and stir the mixture at room temperature for another hour. Dilute the mixture with water and extract three times with EtOAc. Wash the combined organic extracts five times with water, dry to MgSO4, filter, and concentrate under vacuum. The crude material was subjected to two chromatographic separations: using a DCM-supported silicone column (12 g) with an increasing gradient of EtOAc (0–65%, for 20 min) / hexane; and using a DMSO-supported reverse-phase C18 column (16 g) with an increasing gradient of MeCN (10–40%, for 25 min, followed by 40%–90%, for 15 min) / water, yielding a white solid (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 (compounds 4–50, 0.13 g, 0.31 mmol, 50%).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).

[0345] Example 5E: Preparation of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxacyclopentan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compounds 4-53).

[0346] Cesium carbonate (0.92 g, 2.82 mmol, 3.0 eq) was added 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 eq) in DMF (3 mL), and the mixture was stirred at room temperature for 10 min. Then, (3S)-3-iodocyclopentane (0.15 mL, 1.41 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed five times with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude material was then subjected to four chromatographic separations: a dry-loaded (diatomaceous earth) alkaline alumina column (24 g) with an increasing gradient of MeOH (0-5%, 10 min, followed by 100%, 10 min) / DCM; a dry-loaded (diatomaceous earth) silica column (4 g) with an increasing gradient of EtOAc (0-100%, 20 min) / hexane; a DMSO-loaded reverse-phase C18 column (30 g) with an increasing gradient of MeCN (10-50%, 20 min) / water; and a dry-loaded (diatomaceous earth) silica column (4 g) with an increasing gradient of EtOAc (0-100%, 20 min) / hexane. Running on hexane (min) yielded (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxacyclopentan-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.1H NMR (400 MHz, DMSO-d6): δ(ppm) 6.74 (s, 1H), 6.62 (s, 1H), 4.95 - 4.89 (m, 1H), 4.55 (d,J= 6.5 Hz, 1H), 3.86 - 3.73 (m, 4H), 3.72 (s, 3H), 3.13 - 3.04 (m, 1H), 3.01 (br d,J= 11.5 Hz, 1H), 2.95 (dd,J= 11.7, 4.2 Hz, 1H), 2.92 - 2.82 (m, 2H), 2.58 - 2.53 (m, 1H), 2.49 - 2.44 (m, 1H), 2.32 - 2.24 (m, 1H), 2.19 - 2.08 (m, 1H), 1.99 - 1.88 (m, 2H), 1.70 (d,J= 13.1 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.26 (q,J= 11.4 Hz, 1H), 0.91 (s, 9H), 0.81 (dd,J= 13.9, 7.4 Hz, 1H).

[0347] 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 (compounds 4-55), see Figure 12.

[0348] Cesium carbonate (3.06 g, 9.39 mmol, 3.0 eq) was added 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 eq) in DMF (28 mL), and the mixture was stirred at room temperature for 10 min. Then, (R)-2-methylethylene oxide (0.31 mL, 6.26 mmol, 2 eq) was added, and the mixture was stirred at 80 °C for 16 h. Add one part (R)-2-methylethylene oxide (0.16 mL, 3.13 mmol, 1 eq), and stir the mixture at 80 °C for another 4 h. Add a third part (R)-2-methylethylene oxide (39 µL, 0.78 mmol, 0.25 eq), and stir the mixture at 80 °C for another 3 h. Cool the mixture to room temperature, dilute with water, and extract three times with 5:1 DCM:i-PrOH. Wash the combined organic extracts five times with water, dry to MgSO4, filter, and concentrate under vacuum. Using a DCM-supported silicone column (24 g) and running with an increasing gradient of EtOAc (0-100%, for 20 min) / hexane, an 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) was obtained as a grayish-white solid. The crude white solid was recrystallized from 1:1 hexane / EtOAc to obtain crude 4-55 (0.70 g) as a grayish-white solid. Using a DMSO-supported reverse-phase C18 column (100 g) and running with an increasing gradient of MeCN (10-70%, for 25 min) / water, a white solid (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%) was obtained.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).

[0349] Representative reagents (i.e., R1-X) used for the synthesis of the compounds in Tables 10A and 10B include those shown in Table 8. Table 8

[0350] Representative epoxide reagents used for the synthesis of the compounds shown in Tables 10A and 10B include those shown in Table 9. Table 9 epoxides epoxides epoxides

[0351] Tables 10A and 10B shown below provide the observed (Obs) ion m / z ratios for compounds 4-1, 4-27, 4-30, 4-50, 4-55, and other representative compounds prepared using procedures similar to those described in the examples above. In many cases, dialkyl sulfates, alkyl bromides, alkyl chlorides, or alkyl iodides shown in Table 8 are used instead of trifluoromethanesulfonates. In other cases, epoxides shown in Table 9 are used instead of trifluoromethanesulfonates. The final compounds are also typically purified directly by preparative HPLC. Table 10A Compound numbering -R 1 Chemical name Observed ions (m / z) 4-1 (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 402.2 4-2 (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 384.2 4-3 (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 398.3 4-4 (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 402.2 4-5 (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 416.2 4-6 (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 384.2 4-7 (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 398.3 4-8 (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 402.2 4-9 (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 416.2 4-10 (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 384.2 4-11 (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 398.3 4-12 (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 416.2 4-13 (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 384.2 4-14 (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 398.3 4-15 (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 416.2 4-16 (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 402.2 4-17 (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 348.3 4-18 (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 366.2 4-19 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(3-fluorooxocyclobut-3-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 408.3 4-20 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[2-(oxetanebut-3-yloxy)ethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 420.3 4-21 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-oxetanebut-2-ylmethoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 390.3 4-22 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetanebut-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 390.3 4-23 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)cyclobutane-1-carboxynitrile 443.3 4-24 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 359.2 4-25 (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 404.3 4-26 (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 378.3 4-27 (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 360.3 4-28 (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 380.3 4-29 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-carboxynitrile 399.3 4-30 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetanebut-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 376.3 4-31 (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 392.3 4-32 (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 374.3 4-33 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 405.3 4-34 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-(1H-imidazol-1-yl)ethoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 414.3 4-35 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 391.3 4-36 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(5-methyl-1,3-azol-2-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 415.3 4-37 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylacetyl-3-yl)methoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 403.3 4-38 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(propyl-2-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 362.3 4-39 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1,1,1-trifluoroprop-2-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 416.2 4-40 (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 or (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(²H5)ethoxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 353.3 4-41 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)oxocyclohexane-4-carboxynitrile 473.3 4-42 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)cyclobutane-1-carboxynitrile 413.3 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-cyclopropylacetonitrile 443.3 4-44 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-methylpropionitrile 431.3 4-45 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-carboxynitrile 413.3 4-46 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 413.3 4-47 (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 392.3 4-48 (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 408.3 4-49 (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 432.2 4-50 (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 432.2 4-51 (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 414.5 4-52 (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 or (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(²H3)methoxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 337.3 4-53 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3R)-oxacyclopentan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 390.3 4-54 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(3S)-oxacyclopentan-3-yloxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 390.3 4-55 (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 378.3 Table 10B Compound numbering -R 1 Chemical name Observed ions (m / z) 4-56 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2-methylprop-2-en-1-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 374.3 4-57 (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 424.3 4-58 (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 392.3 4-59 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-carboxynitrile 425.2 4-60 (2R,3R,11bR)-9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 410.3 4-61 (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 406.3 4-62 (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 446.3 4-63 (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 428.3 4-64 (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 428.3 4-65 (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 418.2 4-66 (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 446.2 4-67 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-{[3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl]methoxy}-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 468.2 4-68 (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 392.3 4-69 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-acezo-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 401.3 4-70 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 403.3 4-71 (2R,3R,11bR)-9-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 453.3 4-72 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(6-fluoro-1,4-dioxane-6-yl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 452.3 4-73 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-carboxynitrile 442.3 4-74 (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 492.3 4-75 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,3-acezo-4-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 401.3 4-76 (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 468.3 4-77 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-carboxynitrile 436.3 4-78 (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 472.3 4-79 ((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 476.3 4-80 (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 470.3 4-81 (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 478.3 4-82 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-carboxynitrile 436.3 4-83 (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 394.3 4-84 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 473.2 4-85 (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 440.2 4-86 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 441.3 4-87 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)pyrrolidone-2-one 485.2 4-88 (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 374.3 4-89 (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 378.3 4-90 (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 402.3 4-91 (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 392.3 4-92 (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 392.3 4-93 (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 420.3 4-94 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 methanesulfonate 468.3 4-95 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2,4-diazol-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 402.3 4-96 (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 452.3 4-97 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)-1λ 6 -Tetrahydrothiaran-1,1-dione 466.3 4-98 (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 364.3 4-99 (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 470.3 4-100 (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 405.3 4-101 (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 424.3 4-102 (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 524.2 4-103 (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 431.2 4-104 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(1-methylacetyl-3-yl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 389.3 4-105 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)propionitrile 417.3 4-106 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-({3-fluorobicyclo[1.1.1]pent-1-yl}methoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 418.3 4-107 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyridin-3-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 411.3 4-108 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(pyrimidin-2-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 412.3 4-109 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1,2-acezo-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 401.3 4-110 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(1H-imidazol-2-ylmethoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 400.3 4-111 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(1H-1,2,3,4-tetrazol-5-ylmethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 402.3 4-112 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxy-3-methoxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 407.3 4-113 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-hydroxy-3-(hydroxyl-4-yl)propoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 462.3 4-114 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 378.3 4-115 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(5,5,5-trifluoropentyl)oxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 444.4 4-116 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}methyl)benzonitrile 435.3 4-117 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[2-(4-fluorophenyl)ethoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 442.3 4-118 (2S,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 392.3 4-119 (2R,3R,11bR)-9-(cyclobutylmethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 388.4 4-120 (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(4,4,4-trifluorobutoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 430.3 4-121 (2R,3R,11bR)-9-[(2,2-difluorocyclopropyl)methoxy]-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol 410.3

[0352] An overview of the representative physical properties of compound 4-1 prepared according to the method disclosed herein is provided in Tables 11 and 12, and an overview of the representative physical properties of compound 4-15 prepared according to the method disclosed herein is provided in Tables 13 and 14.

[0353] Example 6: Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis 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).

[0354] Powder X-ray diffraction (PXRD) was performed on a Rigaku Miniflex 600 powder X-ray diffractometer, serial number BD66000190-01. For the analysis, approximately 0.5–1 mg of sample was added to the zero-background sample holder. The powder was gently pressed down with a piece of weighing paper and the sample holder was placed in the sample changer. Operating parameters: Miniflex counter detector, Kb filter (x2), scan axis θ / 2θ, continuous mode, start (degrees) 2.0, end (degrees) 45.0, step size (degrees) 0.020, speed (degrees / minute) 10.0, rotation - yes, voltage (kV) 40, current (mA) 15. The reported 2θ value can vary by ±0.2° (i.e., ±0.2°).

[0355] It should be understood that, based on any number of factors known to those skilled in the art, the peak intensities of different diffraction patterns for the same crystalline form may differ. These factors include, for example, the optimal orientation effect, the preparation technique, the sample installation procedure, the instrument used, and the sample purity. Those skilled in the art should understand that, despite the differences in peak intensities, a specific crystalline form can be identified by its characteristic peaks.

[0356] Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA): DSC and TGA analyses were performed on a TA Instruments Discovery 2500 calorimeter (serial number: 2500-00547, DSC) and a Discovery 5500 calorimeter (serial number: 5500-0126, TGA). For DSC analysis, the weights of the Tzero disk and Tzero cap were obtained and recorded. Approximately 1–3 mg of material was weighed into the Tzero disk, and the Tzero cap was pressed down with tweezers. The disk was transferred to the DSC autosampler for analysis. The method used for analysis involved homogenizing to 275°C at a rate of 10°C / min. A reference disk was prepared using the same procedure in the absence of material.

[0357] For TGA analysis, a standard aluminum sample pan was placed in a platinum TGA pan and a blank control was prepared using the instrument. Approximately 1–5 mg of material was added to the standard aluminum pan and analyzed at 10 °C / min up to ~400 °C. For TGA and DSC, the temperature characteristics reported herein may vary by ±3 °C (i.e., ±3 °C).

[0358] Table 11 provides the peak positions, DSC and TGA data of the free base crystal 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) at 2θ selected powder X-ray diffraction (PXRD) pattern. Table 11 (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) PXRD Figure 2: Peaks at 10.2 ± 0.2°, 11.7 ± 0.2°, 15.2 ± 0.2° and 17.0 ± 0.2° 2θ. DSC Figure 3: Apparent initial temperature: approximately 154.7℃ TGA Figure 3: Percentage weight loss: approximately 4.0%

[0359] Table 12 provides the powder X-ray diffraction (PXRD) peak positions at 2θ 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 12 Angle 2θ(2-theta) Altitude (cps) 6.6 ± 0.2° 2546 (146) 10.2 ± 0.2° 17569 (383) 11.7 ± 0.2° 6874 (239) 13.2 ± 0.2° 3069 (160) 13.9 ± 0.2° 2883 (155) 14.1 ± 0.2° 5957 (223) 15.2 ± 0.2° 8497 (266) 16.4 ± 0.2° 1461 (110) 17.0 ± 0.2° 10114 (290) 19.1 ± 0.2° 15522 (360) 19.5 ± 0.2° 5227 (209) 19.7 ± 0.2° 4430 (192) 20.6 ± 0.2° 1622 (116) 21.6 ± 0.2° 14740 (350) 21.9 ± 0.2° 9609 (283) 22.8 ± 0.2° 13213 (332) 23.7 ± 0.2° 3139 (162) 24.0 ± 0.2° 8568 (267) 25.4 ± 0.2° 2646 (148) 25.6 ± 0.2° 5154 (207) 27.2 ± 0.2° 7410 (248) 27.6 ± 0.2° 6166 (227) 27.9 ± 0.2° 1120 (97) 29.8 ± 0.2° 1596 (115) 30.3 ± 0.2° 642 (73) 31.2 ± 0.2° 1408 (108) 31.9 ± 0.2° 1120 (97) 32.3 ± 0.2° 1013 (92) 34.0 ± 0.2° 380 (56) 34.9 ± 0.2° 1948 (127) 35.4 ± 0.2° 750 (79) 35.8 ± 0.2° 617 (72) 37.6 ± 0.2° 431 (60) 39.3 ± 0.2° 566 (69) 40.2 ± 0.2° 251 (46) 41.2 ± 0.2° 1987 (129) 41.6 ± 0.2° 1642 (117) 42.0 ± 0.2° 550 (68) 43.1 ± 0.2° 1155 (98) 44.4 ± 0.2° 507 (65)

[0360] Table 13 provides the peak positions, DSC and TGA data of the selected powder X-ray diffraction (PXRD) pattern at 2θ for (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-15) free base crystalline form I. Table 13 (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 (compounds 4-15) PXRD Figure 4: Peaks at 11.4 ± 0.2°, 14.1 ± 0.2°, 15.7 ± 0.2° and 18.9 ± 0.2° 2θ. DSC Figure 5: Apparent initial temperatures: approximately 146.2℃ and approximately 153.4℃ TGA Figure 5: Percentage weight loss: 0.17%

[0361] Table 14 provides the powder X-ray diffraction (PXRD) peak positions at 2θ 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 14 Angle 2θ(2-theta) Altitude (cps) 5.6 ± 0.2° 1248 (102) 6.7 ± 0.2° 1744 (121) 7.1 ± 0.2° 1151 (98) 8.4 ± 0.2° 2630 (148) 9.2 ± 0.2° 5583 (216) 10.6 ± 0.2° 8271 (263) 11.4 ± 0.2° 13856 (340) 12.3 ± 0.2° 1809 (123) 12.8 ± 0.2° 1234 (101) 13.3 ± 0.2° 4742 (199) 14.1 ± 0.2° 12229 (319) 14.6 ± 0.2° 489 (64) 15.7 ± 0.2° 24533 (452) 16.0 ± 0.2° 4993 (204) 16.9 ± 0.2° 8830 (271) 17.3 ± 0.2° 2584 (147) 17.6 ± 0.2° 8835 (271) 17.9 ± 0.2° 8446 (265) 18.5 ± 0.2° 5690 (218) 18.9 ± 0.2° 16374 (369) 19.6 ± 0.2° 11400 (308) 20.1 ± 0.2° 13479 (335) 20.4 ± 0.2° 6903 (240) 21.2 ± 0.2° 10829 (300) 21.9 ± 0.2° 6742 (237) 22.4 ± 0.2°° 1919 (126) 22.9 ± 0.2° 15091 (355) 23.1 ± 0.2° 19640 (405) 23.7 ± 0.2° 3951 (181) 24.6 ± 0.2° 3618 (174) 24.9 ± 0.2° 3464 (170) 25.2 ± 0.2° 957 (89) 26.1 ± 0.2° 2206 (136) 27.1 ± 0.2° 6631 (235) 27.9 ± 0.2° 3317 (166) 28.4 ± 0.2° 2722 (151) 29.9 ± 0.2° 3566 (172) 30.9 ± 0.2° 794 (81) 31.7 ± 0.2° 2852 (154) 32.6 ± 0.2° 1383 (107) 33.1 ± 0.2° 1610 (116) 33.8 ± 0.2° 558 (68) 34.3 ± 0.2° 1942 (127) 35.2 ± 0.2° 418 (59) 36.6 ± 0.2° 1069 (94) 37.1 ± 0.2° 921 (88) 37.7 ± 0.2° 481 (63) 38.4 ± 0.2° 1013 (92) 40.0 ± 0.2° 675 (75) 40.3 ± 0.2° 989 (91) 41.0 ± 0.2° 563 (68) 42.1 ± 0.2° 854 (84) 44.2 ± 0.2° 1678 (118)

[0362] 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.

[0363] Step 1: Synthesize (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)). Cesium carbonate (0.19 g, 0.60 mmol, 2.0 eq) was added 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 eq) in acetone (1.5 mL), and the mixture was stirred at room temperature for 10 min. Next, dimethyl sulfate (17 µL, 0.18 mmol, 0.6 eq) was added, and the mixture was stirred at room temperature for 1 h. Then, 0.1 eq of dimethyl sulfate was added, and the mixture was stirred again for 30 min. The resulting suspension was filtered to remove solids and concentrated under vacuum. The crude material was redissolved in DCM, quenched with 1M NaOH aqueous solution, and extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. Using a DCM-supported silicone column (12 g) and an increasing gradient of EtOAc (0–40%), after 25 min / hexane run, (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%) was obtained.

[0364] 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). Sodium borohydride (7.4 mg, 0.20 mmol, 2.0 eq) was added to 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 eq) in EtOH (0.6 mL) cooled to 0 °C. The mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 1 h. The mixture was diluted with DCM, washed twice with a saturated aqueous solution of K₂CO₃, 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. Using a DCM-supported silicone column (12 g) and running with an increasing gradient of EtOAc (0-60%) / hexane for 15 min, a white solid (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%) was obtained. 10 mg was dissolved in MeOH (1 mL) and purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6): δ(ppm) 6.72 (s, 1H), 6.64 (s, 1H), 4.55 (d,J= 6.4 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.13 - 3.05 (m, 1H), 3.01 (d,J= 11.2 Hz, 1H), 2.95 (dd,J= 11.8, 4.2 Hz, 1H), 2.91 - 2.82 (m, 2H), 2.58 - 2.54 (m, 1H), 2.48 - 2.43 (m, 1H), 2.33 - 2.25 (m, 1H), 1.93 (t,J= 11.4 Hz, 1H), 1.70 (d,J= 12.8 Hz, 1H), 1.48 - 1.39 (m, 1H), 1.25 (q,J= 12.8 Hz, 1H), 0.91 (s, 9H), 0.81 (dd,J= 13.6, 7.6 Hz, 1H).The observed m / z ratio of (Obs) ions in compound 5-1 is 334.2.

[0365] 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.

[0366] 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)). Compound 5-A (3S,11bS) was prepared by replacing compound 2-B (3R,11bR) with compound 2-B (3S,11bS) according to the same procedure used to prepare compound 5-A (3R,11bR) (see Example 7, Step 1), as shown in Figure 13.

[0367] 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). Compound 5-3 was prepared using the same procedure as for preparing 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 of compound 5-3 was 334.2.

[0368] 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.

[0369] 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 eq) in THF (0.6 mL) was prepared and cooled to 0 °C. Then, tri-dibutylborohydride (1 M THF, 0.16 mL, 0.16 mmol, 2.0 eq) was added dropwise. Excess reagent was quenched with water. The resulting aqueous mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated under vacuum. Using a DCM-supported silicone column (4 g) and running with an increasing gradient of EtOAc / hexane, we obtained (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%). 1H NMR (400 MHz, DMSO-d6): δ(ppm) 6.64 (s, 1H), 6.63 (s, 1H), 4.46 (d,J= 4.0 Hz, 1H), 3.84 - 3.80 (m, 1H), 3.70 (s, 6H), 3.38 (d,J= 11.2 Hz, 1H), 2.94 - 2.83 (m, 2H), 2.56 - 2.46 (m, 2H), 2.41 - 2.26 (m, 3H), 1.72 - 1.65 (m, 1H), 1.50 - 1.43 (m, 2H), 0.90 (s, 9H), 0.84 (dd,J= 14.2, 4.6 Hz, 1H). The observed m / z ratio of (Obs) ions in compound 5-2 is 334.2.

[0370] 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.

[0371] Following the same procedure used to prepare compound 5-2 (see Example 9), compound 5-A (3S,11bS) was used instead of compound 5-A (3R,11bR) to prepare (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). The observed (Obs) ion m / z ratio of compound 5-4 was 334.2.

[0372] Example 11: Method for determining the VMAT2 inhibitory activity of a compound. An example of a technique for determining the ability of a compound to inhibit VMAT2 is provided below. The procedure is modified from a previously described procedure (see, for example, Near, (1986), Mol. Pharmacol. 30: 252-57; Teng et al., J. Neurochem. 71, 258-65, 1998). A homogenate from human platelets is prepared by homogenization and then washed by centrifugation, as previously described (see, for example, Hoare et al. (2003) Peptides 24:1881-97).

[0373] The human VMAT2 Ki values ​​of the compounds listed in Tables 15A and 15B were determined using the following procedure. A series of compound dilutions were generated in DMSO, either artificially from the powder stock solution, or by serial dilution from the DMSO stock solution on Vantage (Hamilton), or by direct dilution using an Echo 655 (Beckman). Twelve concentrations of the test compound were competitively reacted against 10 nM 3H-dihydrotetraphenylquinazon (American Radiolabeled Chemicals) on human platelet homogenate (30 µg membrane protein per well) in a total volume of 0.145 to 0.150 mL in a low-binding 96-well plate (Corning #3605) with VMAT2 binding buffer (Dulbecco's phosphate buffered saline, 1 mM EDTA, pH 7.4). After incubation at 25°C for 90 minutes, bound radioligands were collected by rapid filtration onto GF / B or GF / C glass fiber filters pretreated with 0.1% polyethyleneimine using a Unifilter-96 collector (PerkinElmer) or Microlab Star (Hamilton). Following collection, the filter tray was washed with 0.8 mL of VMAT2 binding buffer, and bound radioligands were quantified by scintillation counting using Topcount NXT or Microplate Counter Microbeta (PerkinElmer). Data from 12-point concentration-response curves were analyzed, and IC50 was calculated using a four-parameter logistic regression algorithm with a maximum constraint of 100 and a minimum constraint of 0. Ki values ​​for each compound were calculated using the Cheng-Prusoff equation with Kd of 2.5 nM or 4.06 nM against 3H-dihydrotetraphenylquinazine (depending on the platelet batch and the radiolabeling used in each experiment).

[0374] The Ki(nM) values ​​for compounds are provided in Tables 15A and 15B. Table 15A Compound numbering VMAT2 K i (nM) Compound numbering VMAT2 K i (nM) Compound numbering VMAT2 K i (nM) 4-1 2.4 4-21 28 4-41 238 4-2 467 4-22 14 4-42 35 4-3 152 4-23 0.41 4-43 4.8 4-4 170 4-24 35 4-44 2.4 4-5 135 4-25 5.5 4-45 7.3 4-6 860 4-26 14 4-46 25 4-7 539 4-27 1.0 4-47 15 4-8 597 4-28 0.48 4-48 313 4-9 277 4-29 83 4-49 20 4-10 15 4-30 12 4-50 1.4 4-11 14 4-31 1.6 4-51 9.4 4-12 3.4 4-32 0.59 4-52 2.5 4-13 2.2 4-33 ＞ 10,000 4-53 12 4-14 2.6 4-34 ＞ 10,000 4-54 12 4-15 1.1 4-35 ＞ 10,000 4-55 4.8 4-16 22 4-36 51 5-1 6.6 4-17 1.1 4-37 > 10,000 5-2 50 4-18 5.5 4-38 3.7 5-3 700 4-19 8.1 4-39 12 5-4 > 10,000 4-20 336 4-40 1.4 Table 15B Compound numbering VMAT2 K i (nM) Compound numbering VMAT2 K i (nM) Compound numbering VMAT2 K i (nM) 4-56 0.52 4-78 92 4-100 NT 4-57 0.93 4-79 99 4-101 NT 4-58 1.1 4-80 133 4-102 NT 4-59 1.5 4-81 177 4-103 NT 4-60 3.1 4-82 198 4-104 NT 4-61 3.5 4-83 207 4-105 NT 4-62 3.7 4-84 272 4-106 NT 4-63 4.2 4-85 276 4-107 NT 4-64 5.5 4-86 287 4-108 NT 4-65 8.7 4-87 650 4-109 NT 4-66 10 4-88 0.68 4-110 NT 4-67 14 4-89 140 4-111 NT 4-68 29 4-90 0.29 4-112 NT 4-69 32 4-91 28 4-113 NT 4-70 36 4-92 51 4-114 70 4-71 37 4-93 281 4-115 6.1 4-72 51 4-94 387 4-116 56 4-73 51 4-95 > 10,000 4-117 2.2 4-74 65 4-96 > 10,000 4-118 13 4-75 76 4-97 > 10,000 4-119 0.29 4-76 82 4-98 NT 4-120 1.5 4-77 85 4-99 NT 4-121 0.82 NT = Untested

[0375] Figures 15 to 21 provide VMAT2 Ki (nM) values ​​for the representative formula (I) compound and the comparative compound. The VMAT2 Ki values ​​were determined according to Example 11. The comparative compound was prepared as described in International Publication No. WO 2018 / 195121 A1, which is incorporated herein by reference in its entirety. With respect to the VMAT2 Ki value, the representative formula (I) compound is more potent than the comparative compound (e.g., 4.1 to 20.9 times).

[0376] Example 12: VMAT2 inhibitor-induced reduction of open-field hypolocomotor activity. The effect of VMAT2 inhibitors on dopamine depletion was measured using motor activity (LMA) analysis. Male Sprague-Dawley rats (200–250 g) were placed in transparent cages surrounded by photocell detectors (San Diego Instruments) after a pretreatment time of 60 or 120 minutes. Rats' motor activity was detected by interrupting the photocell beam, and activity was defined as the number of beam interruptions within 30 minutes. Data were analyzed by one-way ANOVA (SigmaStat version 3.0.1, SPSS, Chicago, IL), and significance was subsequently analyzed using the Student Newman-Keuls post-hoc test. Calculate the ED50 of compounds 4-1 (0.24 mg / kg, see Figure 22), 4-15 (0.18 mg / kg, see Figure 22), 4-27 (0.14 mg / kg, see Figure 23), 4-31 (0.31 mg / kg, see Figure 24), 4-50 (0.21 mg / kg, see Figure 23), and 4-55 (0.29 mg / kg, see Figure 23).

[0377] Example 13A: Conditioned Avoidance Response Analysis of Antipsychotic Activity. 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 in a two-chamber shuttle frame to respond to a conditioned stimulus (auditory) with negative reinforcement. If an animal fails to move to the other chamber after the auditory stimulus is presented, a mild foot shock is applied to the side where the rat was located. The rat learns to avoid the mild foot shock by moving to the other chamber after the initial auditory signal; this is called the conditioned avoidance response. Moving to the other chamber during the application of the shock is called the escape response. If a rat fails to move to the other chamber even after the application of the foot shock, the rat is considered to have failed to escape. Numerous studies have shown that typical and atypical antipsychotic drugs selectively inhibit CAR, thus making it an ideal analysis for screening potential antipsychotic compounds (see, for example, Wadenberg et al., Biobehav. Rev. (1999) 23: 851-62).

[0378] Male Wistar rats were trained daily for 3 to 4 weeks. During the training phase, rats were placed in a CAR bidirectional shuttle frame and subjected to 20 training sessions. The tests consisted of the following: 10 seconds of 80 dB white noise followed by a 0.6 mA foot shock for up to 20 seconds. The intervals between tests were 20–60 seconds. Rats learned to avoid the shock by moving from one chamber to another when the conditioned stimulus was presented (conditioned avoidance response). A rat was considered adequately trained if it avoided the shock for at least 19 / 20 tests when the conditioned stimulus was presented. Rats that did not meet these criteria were not used.

[0379] On the test day, trained animals were acclimatized to the test chamber for 30 minutes prior to the test. They were then administered the compound and placed in a CAR two-way shuttle frame. Twenty trials were performed on each rat. In each trial, a modulated stimulus (80 dB white noise presented for 10 seconds) was applied, followed by a paw shock (scrambled 0.6 mA paw shock for up to 20 seconds). If the animal moved to the other chamber upon presentation of the modulated stimulus, it was rated as a conditioned avoidance response. If it moved after the paw shock, it was rated as an escape. If it could not move after the paw shock, it was rated as an escape failure. The antipsychotic efficacy was significant with increasing escape counts. Data were analyzed using analysis of variance (ANOVA), followed by post-hoc comparisons using the Bonferroni Test where appropriate. A p < 0.05 was considered significant. Outliers defined as being two standard deviations above or below the mean were detected and removed from all analyses.

[0380] Example 13B: Analysis of Conditioned Avoidance Response (CAR) in Antipsychotic Activity.

[0381] Materials and Methods Animals: Adult male Wistar rats from Envigo (Indianapolis, IN) were used in this study. Rats weighed approximately 150 g, were assigned unique identification numbers, and were housed in ventilated cages in groups of 2–3 rats per cage. All rats were examined, handled, and weighed prior to the start of the study to ensure adequate health and fitness. A 12 / 12 light / dark cycle was maintained throughout the study. Room temperature was maintained between 20°C and 23°C, and relative humidity was approximately 50%. Food and water were provided freely during the study. All tests were performed during the rat light cycle.

[0382] Compound preparation: Compound 4-1 (0.03, 0.1, 0.3 and 1 mg / kg) was prepared in 0.25% methylcellulose and administered orally at a dose of 3 mL / kg 120 minutes before the test.

[0383] Compounds 4-15 (0.03, 0.1, 0.3 and 1 mg / kg) were prepared in 0.25% methylcellulose and administered orally at a dose of 3 mL / kg 120 minutes before the test.

[0384] Behavioral Testing – Conditioned Avoidance Response (CAR) has been shown to be an extremely reliable animal model for screening antipsychotics (see Wadenberg and Hicks, Neuroscience and Biobehavioral Reviews, (1999) 23:851-862). In the CAR paradigm, animals are trained to respond to conditioned stimuli (auditory and visual) through negative reinforcement (foot shocks). Numerous studies have shown that typical and atypical antipsychotics selectively inhibit CAR, thus making it an ideal analysis for screening potential antipsychotic compounds (Wadenberg and Hicks, Neuroscience and Biobehavioral Reviews, (1999) 23:851-862).

[0385] Rats were placed in a CAR bidirectional shuttle frame and then trained for 20 trials. The trials consisted of 10 seconds of 80 dB white noise followed by a 0.6 mA foot shock for up to 20 seconds. The intervals between trials ranged from 20 to 60 seconds. Rats learned to avoid the shock by moving from one chamber to another when prompted. If they failed to do so, they received a foot shock, during which time they were likely to cross the chamber to escape the shock. Finally, if the rat failed to leave the chamber, it endured the full 20 seconds of foot shocks. The following measurements were captured from the analysis:

[0386] Avoidance response: If a rat moves from one chamber to another during the presentation of a cue stimulus (CS). A reduced avoidance response is a typical characteristic of effective doses of antipsychotic drugs.

[0387] Escape failure: If the rat fails to move to another chamber during the 20-second foot shock.

[0388] Data analysis: Avoidance response data is presented as the number of avoidance responses and the percentage of avoidance responses based on three baseline responses prior to drug testing. Escape failures are presented as the total number of failures during the testing phase.

[0389] Weight and avoidance data were analyzed using ANOVA, followed by Dunnett's post-hoc comparison where appropriate. Escape failure was analyzed using Kruskal-Wallis nonparametric analysis, followed by Dunn's post-hoc comparison where appropriate. Results are reported as mean ± SEM. A p < 0.05 was considered statistically significant.

[0390] The ED50 of compound 4-1 (0.55 mg / kg) was calculated. The ED50 (mg / kg) of compound 4-15 (0.44 mg / kg) was also calculated. In addition, rats treated with compound 4-1 or compound 4-15 were observed to show no significant increase in avoidance reduction and escape failure at 0.3 mg / kg.

[0391] Example 14: Method for determining the stability of a compound in human liver microsomes. The test compound (0.5 µM) was incubated with combined mixed-sex human liver microsomes (0.5 mg / mL total protein) at 37 °C in the presence of an NADPH generating system containing 50 mM pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 unit / mL glucose-6-phosphate dehydrogenase. All concentrations are relative to a final incubation volume of 125 µL. Incubation was performed at 37 °C in a water bath for 0, 5, 10, 20, 40, and 60 minutes, terminated by rapid mixing with 150 µL of ice-cold internal standard containing acetonitrile. Protein precipitate was removed by centrifugation prior to LC-MS / MS analysis. Aliquots of the resulting supernatant fraction were analyzed by LC-MS / MS monitoring of parent compound consumption. Using XLfit scientific curve fitting software (IDBS Ltd., Surrey, UK), the obtained peak area ratios were fitted to nonlinear regressions relative to time data, and the elimination half-life (t1 / 2, min) was calculated based on the slope. Pharmacokinetic parameters were predicted using the method described by Obach et al. (J. Pharmcol. Exp. Ther. 1997; 283: 46.58). In short, intrinsic clearance values ​​were calculated based on the elimination half-life data and then scaled to represent the expected clearance in all animals (see Table 16 (humans)). Additional values ​​calculated included the predicted extraction rate and the predicted maximum bioavailability.

[0392] For extremely stable compounds, the in vitro half-life calculated using the HLM method is at its maximum at 420 minutes. Therefore, for such stable compounds, the in vitro half-life is at least 420 minutes, but may be greater. Furthermore, for such stable compounds, the predicted systemic clearance and scaled-adjusted intrinsic clearance are at least 2.59 and 2.97, respectively, but may be lower, and the predicted maximum bioavailability (F%) is at least 87, but may be higher. Table 16 (Human LM) Compound numbering HLM elimination half-life (t) 1 / 2 , min) HLM-predicted systemic clearance (ml / min / kg) HLM's proportionally adjusted intrinsic clearance (ml / min / kg) Predicted maximum bioavailability (F%) 4-1 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-9 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-10 342 3.09 3.65 85 4-11 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-12 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-13 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-14 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-15 308 3.37 4.05 83 4-16 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-17 38 12.44 32.9 38 4-18 155 5.74 8.05 71 4-19 88 8.3 14.18 59 4-22 130 6.49 9.6 68 4-23 21 14.9 58.49 25 4-24 117 6.97 10.7 65 4-25 109 7.26 11.41 64 4-26 88 8.32 14.24 58 4-27 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-28 39 12.28 31.79 39 4-29 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-30 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-31 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-32 19 15.38 66.53 23 4-36 93 8.02 13.39 60 4-38 58 10.35 21.46 48 4-40 52 10.88 23.86 46 4-41 28 13.87 45.21 31 4-42 51 10.98 24.33 45 4-43 18 15.5 68.8 23 4-44 46 11.47 26.9 43 4-45 129 6.53 9.7 67 4-46 28 13.86 45.1 31 4-47 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-49 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-50 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-51 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-52 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-53 146 6 8.57 70 4-54 164 5.5 7.59 73 4-55 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-56 10 17.16 120.93 14 4-57 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-58 208 4.61 5.99 77 4-59 50 11.08 24.82 45 4-60 37 12.58 33.93 37 4-61 30 13.55 42.02 32 4-62 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-63 29 13.58 42.33 32 4-64 33 13.1 37.96 35 4-65 227 4.31 5.5 78 4-66 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-67 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-68 196 4.83 6.37 76 4-69 80 8.74 15.51 56 4-70 110 7.25 11.37 64 4-71 33 13.15 38.38 34 4-72 80 8.77 15.62 56 4-73 119 6.88 10.48 66 4-74 36 12.68 34.62 37 4-75 104 7.48 11.94 63 4-76 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-77 156 5.72 8.01 71 4-78 195 4.86 6.41 76 4-79 212 4.54 5.88 77 4-88 44 11.68 28.05 42 4-90 8 17.72 155.72 11 4-91 63 9.92 19.7 50 4-92 49 11.2 25.46 44 4-114 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-115 133 6.39 9.38 68 4-116 57 10.44 21.84 48 4-117 11 16.98 112.26 15 4-118 189 4.96 6.6 75 4-119 9 17.4 133.88 13.00 4-120 ≥ 420 ≤ 2.59 ≤ 2.97 ≥ 87 4-121 280 3.64 4.46 82 5-1 80 8.77 15.63 56 5-2 38 12.39 32.56 38

[0393] The various embodiments described above may be combined to provide other embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the filing data are incorporated herein by reference in their entirety. Where necessary, the embodiments may be modified to incorporate the concepts of various patents, applications, and publications, thereby providing other embodiments.

[0394] Such and other changes may be made to the embodiments based on the detailed description above. Generally, the terminology used in the appended claims should not be construed as limiting the scope of the claims to the specific embodiments disclosed in this specification and the claims, but should be construed as including all possible embodiments and the full scope equivalent to such claims. Therefore, the scope of the claims is not limited to this invention. [Simplified Explanation of the Diagram]

[0034] Figure 1A shows 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)). Figure 1B shows the single crystal structure of (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2,9-diol (compound 1-D (2R,3R,11bR)). Figure 2 shows the powder X-ray diffraction (PXRD) 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. Figure 3 shows the DSC and TGA thermal analysis chromatograms 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. Figure 4 shows the powder X-ray diffraction (PXRD) pattern of 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) free base. Figure 5 shows the DSC and TGA thermal analysis chromatograms of 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) free base. Figure 6 shows a general synthetic procedure for preparing compounds of formula (I) and their associated intermediates, where R1 has the same meaning as described herein, and X is a detachable group, such as a halogen (e.g., I, Cl, and Br) or OS(O)2Rz (e.g., methanesulfonate (-OMs), trifluoromethanesulfonate (-OTf), and toluenesulfonate (-OTs), where Rz has the same meaning as described herein). As shown in Figure 6, the intermediates, compounds 1-B, 1-C, and 1-D (including their corresponding stereoisomers) are novel and applicable to preparing compounds of formula (I) and their pharmaceutical salts, as described herein.Figure 7 shows 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). The general synthetic procedure for (2R,3R,11bR) utilizes an eluent extraction step with (2S,3S)-2,3-bis(4-methylbenzooxy)succinic acid (DPTTA) on 9-(benzoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 1-C) to yield (2R,3R,11bR)-9-(benzoxy)-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)). This is then deprotected to give compound 1-D. (2R,3R,11bR). Figure 8 shows a representative reaction for the preparation of (2R,3R,11bR)-9-(benzoxy)-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 salts of (2S,3S)-2,3-bis(4-methylbenzooxy)succinic acid (DPTTA), see Example 1B. Figure 9 shows the general synthetic procedure for preparing (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 palmar supercritical fluid chromatography (SFC), see Example 2.Figure 10 shows 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-one (compound 2-B (3R,11bR)) from (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) from (3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH. (2R,3R,11bR)) as the representative reduction steps described in Example 3; and the representative reduction steps from (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 2-B (3S,11bS)) to prepare (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)) to (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)). Figure 11 shows 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-one (compound 2-B (3R,11bR)) from (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) from (3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH. (2S,3R,11bR)) as the representative reduction steps described in Example 4; and the representative reduction steps from (3S,11bS)-3-(2,2-dimethylpropyl)-9-hydroxy-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-one (compound 2-B (3S,11bS)) to prepare (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)) to (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)).Figure 12 shows a representative reaction in the presence of cesium carbonate and acetone 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)) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CF3CH2OTf) to (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-1) using (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 representative reaction in the presence of cesium carbonate and DMF 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)) and (R)-2-methylethylene oxide to (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compounds 4-55). See Example 5F. Figure 13 shows the representative reaction flow for 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 the representative reaction flow for 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; both reactions utilize dimethyl sulfate as the methylating agent and sodium borohydride as the reducing agent.Figure 14 shows a representative reduction reaction for 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 a representative reduction reaction for 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; both reactions were carried out in THF using tri-dibutylborohydride as a reducing agent. Figure 15 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-1, 4-13, and 4-14) and the comparison agent compounds (i.e., compounds 4-1C, 4-13C, and 4-14C). Figure 16 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-15, 4-17, and 4-18) and the comparison agent compounds (i.e., compounds 4-15C, 4-17C, and 4-18C). Figure 17 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-22, 4-26, and 4-28) and the comparison agent compounds (i.e., compounds 4-22C, 4-26C, and 4-28C). Figure 18 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-30, 4-32, and 4-38) and the comparative compounds (i.e., compounds 4-30C, 4-32C, and 4-38C). Figure 19 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-39 and 5-1) and the comparative compounds (i.e., compounds 4-39C and 5-1C). Figure 20 shows the VMAT2 Ki values ​​(nM) between the compounds provided herein (i.e., compounds 4-27, 4-88, and 4-119) and the comparative compounds (i.e., compounds 4-27C, 4-88C, and 4-119C). Figure 21 shows the VMAT2 Ki values ​​(nM) between the compounds presented herein (i.e., compounds 4-120 and 4-121) and the comparative compounds (i.e., compounds 4-120C and 4-121C). Figure 22 shows the in vivo pharmacology of compounds 4-1 and 4-15 in Sprague Dawley rats in an open-field hypocomotion model as described in Example 12.Figure 23 shows the in vivo pharmacology of compounds 4-27, 4-50, and 4-55 in Sprague Dawley rats in an open-space, low-motor model as described in Example 12. Figure 24 shows the in vivo pharmacology of compound 4-31 in Sprague Dawley rats in an open-space, low-motor model as described in Example 12.

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R1 can be -CH2CF3, -CH2CF2H, -CH2CF2CH3, ..., or ...

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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), or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-13).

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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), or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-14).

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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), or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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).

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxacyclobut-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30), or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxacyclobut-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30).

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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), or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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).

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-47), or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-47).

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-49), or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-49).

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-50), or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-50).

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-51), or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-51).

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-55); or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (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 (compounds 4-55).

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-114), or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof is: (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-114).

26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

27. A formulation comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

28. A unit dosage form comprising a compound as claimed in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

29. A kit comprising a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25.

30. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

31. A formulation comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

32. A unit dosage form comprising a compound as claimed in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

33. A kit comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

34. Use of a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating vesicle monoamine transporter-2 (VMAT2) disease or condition.

35. Use of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25 for the manufacture of an agent for treating a neurological or mental illness or condition selected from the group consisting of: hyperactivity disorder, schizophrenia, affective schizophrenia, mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, X-chromosome fragility syndrome or X-chromosome fragility-associated tremor-dysregulation syndrome, autism spectrum disorder, Rett syndrome, and chorea-acanthocytosis.

36. As used in request item 35, wherein: This neurological or mental illness or condition is a hyperkinetic disorder.

37. As used in request item 36, wherein: This hyperkinetic disorder is tardive dyskinesia.

38. As used in request item 36, wherein: This hyperkinetic disorder is a chorea associated with Huntington's disease.

39. As used in request item 35, wherein: The neurological or mental illness or condition is schizophrenia or affective schizophrenia.

40. As used in request item 35, wherein: The neurological or mental illness or condition is schizophrenia.

41. As used in request item 35, wherein: This neurological or mental illness or condition is intractable obsessive-compulsive disorder.

42. As used in request item 35, wherein: This neurological or mental illness or condition is a form of autism spectrum disorder.

43. As used in request item 35, wherein: This neurological or mental illness or condition is a mood disorder.

44. As in the purpose of request item 35, wherein: The neurological or mental illness or condition is selected from the following mood disorders: bipolar disorder, major depressive disorder, mania among mood disorders, or depression among mood disorders.

45. As used in request item 35, wherein: This treatment of neurological or mental illnesses or conditions includes the use of this medication as an adjunct therapy.

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