EP4590676A1 - Inhibiteurs d'hexahydro-2h-pyrido[2,1-a]isoquinoline vmat2 et procédés d'utilisation - Google Patents

Inhibiteurs d'hexahydro-2h-pyrido[2,1-a]isoquinoline vmat2 et procédés d'utilisation

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Publication number
EP4590676A1
EP4590676A1 EP23786905.2A EP23786905A EP4590676A1 EP 4590676 A1 EP4590676 A1 EP 4590676A1 EP 23786905 A EP23786905 A EP 23786905A EP 4590676 A1 EP4590676 A1 EP 4590676A1
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EP
European Patent Office
Prior art keywords
methyl
methoxy
compound
cyclopropyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23786905.2A
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German (de)
English (en)
Inventor
Byron A. BOON
Nicholas PAGANO
Nicole Harriott
Jieyu Gu
Yibin Xue
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurocrine Biosciences Inc
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Neurocrine Biosciences Inc
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Application filed by Neurocrine Biosciences Inc filed Critical Neurocrine Biosciences Inc
Publication of EP4590676A1 publication Critical patent/EP4590676A1/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine

Definitions

  • VMAT2 INHIBITORS AND METHODS OF USE BACKGROUND Technical Field This disclosure relates to, inter alia, certain compounds, compositions, and pharmaceutical compositions thereof, that modulate the activity of the transporter protein vesicular monoamine transporter-2 (VMAT2) and are directed to methods useful in the treatment of transporter protein vesicular monoamine transporter-2 mediated disorders, such as, neurological or psychiatric disease or disorders, including but not limited to, hyperkinetic movement disorders (e.g., tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, ataxia, chorea (such as, chorea associated with Huntington's disease), dystonia, hemifacial spasm, myoclonus, restless leg syndrome, and tremors).
  • hyperkinetic movement disorders e.g., tardive dyskinesia, Tourette's syndrome, Huntington's disease, tics, ataxia, chorea (such as, chorea associated with Huntington's disease), dys
  • the disclosure further relates to synthetic methods and intermediates useful in the preparation of the compounds.
  • Dysregulation of dopaminergic systems is integral to several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinetic movement disorders, and conditions, such as, schizophrenia and mood disorders.
  • CNS central nervous system
  • the transporter protein vesicular monoamine transporter-2 (VMAT2) plays an important role in presynaptic dopamine release and regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.
  • ( ⁇ )-Tetrabenazine (( ⁇ )-TBZ) has been used as a drug for decades.
  • ( ⁇ )-TBZ also inhibits presynaptic and postsynaptic dopamine receptors in rat brain (see, e.g., Login et al., (1982) Ann. Neurology 12:257-62; Reches et al., J. Pharmacol. Exp. Ther. (1983) 225:515-521).
  • ( ⁇ )-TBZ exhibits extensive first pass metabolism following oral administration to humans with little or no ( ⁇ )-TBZ observed in systemic circulation. The pharmacological activity of ( ⁇ )-TBZ is therefore thought to be mediated primarily by active metabolites.
  • ( ⁇ )-TBZ has two chiral centers and is a racemic mixture of two stereoisomers.
  • ( ⁇ )-TBZ has been determined to be rapidly and extensively metabolized in vivo by carbonyl reductase to four metabolic stereoisomers of 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ).
  • DHTBZ dihydrotetrabenazine
  • the [+]-alpha-DHTBZ (2R,3R,11bR-DHTBZ) isomer was determined to be present in the least amount of all four isomers.
  • [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) appears to be the major DHTBZ isomer contributing to the pharmacological activity of ( ⁇ )-TBZ.
  • the half-life of [+]-beta-DHTBZ (2S,3R,11bR-DHTBZ) is relatively short (approximately 5 hours) which requires ( ⁇ )-TBZ to have a sub-optimal (TID) dosing regimen.
  • ( ⁇ )-TBZ has a narrow therapeutic window, and its clinical use requires careful dose titration.
  • Side effects associated with ( ⁇ )-TBZ and/or its metabolites include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, sedation, depression, akathisia, and Parkinsonism.
  • the probability of observing side effects is a function of the achieved plasma concentrations from a given dosing regimen. Compounds with a longer half-life (t 1/2 ) and lower clearance will have lower peak-to- trough fluctuations in plasma exposure given an equivalent dosing interval.
  • clearance describes the process of drug elimination from the body or from a single organ, defined as the volume of fluid cleared of drug from the body per unit of time. Clearance is a fundamental pharmacokinetic parameter and is commonly measured in drug research and development as this parameter impacts drug attributes such as half-life and, ultimately, the dosing regimen.
  • the benefits of small plasma-concentration fluctuations seen in compounds with low clearance include potentially reduced steady state peak concentrations, increased trough concentrations, and the prospect of improving medication adherence because of a possibly improved risk-benefit profile.
  • VMAT2 inhibitors including compounds, compositions, and methods related thereto.
  • the identification of long half-life / low clearance VMAT2 small molecule inhibitors is advantageous for drug development, particularly when being developed for chronic administration. In certain disease populations where patient compliance and pill burden are an ongoing challenge, reduced dosing frequency is highly desirable and offers increased patient benefit.
  • the present disclosure fulfills these, such as, improved in vitro VMAT2 potency or improved pharmacokinetics, or both, and other needs, as evident in reference to the following disclosure.
  • R 1 is selected from: C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 - alkyl-O-C 2 -C 4 -alkylene, C 3 -C 7 -cycloalkyl-O-C 2 -C 4 -alkylene, 3-7-membered-heterocyclyl, 3-7- membered-heterocyclyl-C 1 -C 4 -alkylene, C 4 -C 8 -bicycloalkyl-C 1 -C 4 -alkylene, C 4 -C 7 -cycloalkenyl, 5- 11-membered-spiro-heterocyclyl, C
  • compositions selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound, as described herein, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound, as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions comprising a compound, as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Also provided herein are methods for preparing a pharmaceutical composition comprising the step of admixing a compound, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also provided herein are methods of treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound, as described herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical product as described herein; or a pharmaceutical composition as described herein.
  • VMAT2 vesicular monoamine transporter-2
  • VMAT2 disease or disorder is selected from: an ataxias or spinal muscular atrophy; a chorea; a congenital malformation, deformation, or abnormality; a dementia; an oral cavity, salivary gland, or jaw disease; a dyskinesia; a dystonia; an endocrine, nutritional, or metabolic disease; an epilepsy; a habit or impulse disorder; a Huntington’s disease or related disorder; a mood or psychotic disorder; a neurotic, stress-related, and somatoform disorder; a degenerative disease of the basal ganglia; an extrapyramidal and movement disorder; a neurological or psychiatric disease or disorder; a nervous system or motor
  • the neurological or psychiatric disease or disorder is selected from the group consisting of: hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, a mood disorder, treatment-refractory obsessive-compulsive disorder
  • the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is treatment-refractory obsessive- compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the method comprises using the compound, salt, product, or composition in adjunctive therapy.
  • VMAT2 vesicular monoamine transporter-2
  • VMAT2 ve
  • a neurological or psychiatric disease or disorder selected from the group consisting of: hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, a mood disorder, treatment-refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer’s
  • the neurological or psychiatric disease or disorder is schizophrenia.
  • the neurological or psychiatric disease or disorder is schizoaffective disorder.
  • the neurological or psychiatric disease or disorder is obsessive-compulsive disorder.
  • the neurological or psychiatric disease or disorder is treatment-refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, treatment comprises using the compound, salt, product, or composition in adjunctive therapy. Also provided herein are compounds, as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. Also provided herein are compounds, as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder.
  • VMAT2 vesicular monoamine transporter-2
  • VMAT2 vesicular monoamine transporter-2
  • a method for treating a vesicular monoamine transporter-2 (VMAT2) disease or disorder selected from: an ataxias or spinal muscular atrophy; a chorea; a congenital malformation, deformation, or abnormality; a dementia; an oral cavity, salivary gland, or jaw disease; a dyskinesia; a dystonia; an endocrine, nutritional, or metabolic disease; an epilepsy; a habit or impulse disorder; a Huntington’s disease or related disorder; a mood or psychotic disorder; a neurotic, stress-related, and somatoform disorder; a degenerative disease of the basal ganglia; an extrapyramidal and movement disorder; a neurological or psychiatric disease or disorder; a nervous system or motor function disorder; a Parkinson’s/parkinsonism disorder; a pediatric-onset behavioral and emotional disorder; a pervasive developmental disorder; and a substance abuse or dependence disorder
  • VMAT2 ves
  • hyperkinetic movement disorder schizophrenia, schizoaffective disorder, a mood disorder, treatment-refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer’s disease, Fra
  • the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is treatment- refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the method for treating comprises using the compound, salt, product, or composition in adjunctive therapy.
  • FIG.1A shows a general synthetic scheme for the preparation of certain compounds of Formula (Ia) and intermediates related thereto, wherein R 1 is methyl.
  • R 1 is methyl and is introduced in Compound 2-3.
  • FIG.1B shows a general synthetic scheme for the preparation of certain compounds of Formula (Ia) and an intermediate related thereto, wherein R 1 is methyl.
  • compounds i.e., Compound 15, Compound 76, Compound 77, and Compounds 78
  • SFC supercritical fluid chromatography
  • FIG.2A shows a general synthetic scheme for the preparation of (2R,3R,11bR)-3-(tert- butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2- 22) utilizing intermediate ( ⁇ )-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert- butoxy)propan-2-one (Compound 2-17) and a resolution step of ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)- 10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-19) with (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid
  • FIG.2B shows a general synthetic scheme for the preparation of (2R,3R,11bR)-3-(tert- butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2- 22) utilizing intermediates 1-(tert-butoxy)propan-2-one (Compound 2-25) and 3-(tert-butoxy)-4- (dimethylamino)butan-2-one (Compound 2-26) to give ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (Compound ( ⁇ )-2-18) that is subsequently reduced to provide ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hex
  • a resolution step of Compound ( ⁇ )-2-19 with (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) is utilized to provide (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol (Compound 2-21) that is subsequently deprotected to provide Compound 2-22.
  • DPTTA (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid
  • FIG.3 shows a general synthetic scheme for the preparation of compounds of Formula (Ia) utilizing 3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol, and different alkylating agents; wherein R 1 has the same meaning as described herein, LG 1 is a Leaving Group, and R 3a can be H or C1-C4-alkyl optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6- cycloalkyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • FIG.4 shows a general synthetic scheme for the preparation of compounds of Formula (Ie) utilizing (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinoline-2,9-diol (Compound 2-22), and different alkylating agents; wherein R 1 has the same meaning as described herein, LG 1 is a Leaving Group, and R 3a can be H or C 1 -C 4 -alkyl optionally substituted with one or more substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, C 1 -C 4 - haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, C1-C
  • LG 1 can be a variety of leaving groups, such as those described herein and those known in the art.
  • FIG.5 shows in vivo pharmacology in Sprague Dawley rats for (2R,3R,11bR)-3-(tert- butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol Compound 18 and (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compound 22 in the Open Field Hypolocomotion model as described in Example 15.
  • administering refers to providing a compound described herein or other therapy to a subject in a form that can be introduced into that subject’s body in a therapeutically useful form and 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, intravenous (IV), intramuscular (IM), subcutaneous (SC), and the like; transdermal dosage forms, including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal dosages forms, such as, suppositories.
  • oral dosage forms such as, tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as, intravenous (IV), intramuscular (IM), subcutaneous (SC), and the like
  • transdermal dosage forms including creams, jellies, powders, and patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and the like
  • a health care practitioner can directly provide a compound described herein to a subject in the form of a sample or can indirectly provide a compound to a subject by providing an oral or written prescription for the compound. Also, for example, a subject can obtain a compound by themselves without the involvement of a health care practitioner.
  • the compound is administered to the subject, the body is transformed by the compound in some way.
  • administering and “administration” are understood to include the compound and at least one other agent are administered at the same time or at different times.
  • the agents of a combination are administered at the same time, they can be administered together in a single composition, or they can be administered separately.
  • composition refers to a compound or crystalline form thereof, including but not limited to, salts, solvates, and hydrates of a compound described herein, in combination with at least one additional component, such as, a composition obtained/prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), and the like.
  • additional component such as, a composition obtained/prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), and the like.
  • compound refers to all stereoisomers, geometric isomers, tautomers, and isotopic variants of the structures depicted herein.
  • the term is also meant to refer to compounds described herein, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances, such as, water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof can occur in various forms and can, e.g., take the form of co-crystals or solvates, including hydrates.
  • the compounds can be in any solid-state form, such as, a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid-state form of the compound.
  • the compounds described herein, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds described herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds described herein, or salts thereof.
  • solvate refers to a compound, as described herein, or a pharmaceutically acceptable salt thereof, which includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
  • hydrate refers to a compound, as described herein, or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • a caregiver e.g., physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • a subject or animal requires or will benefit from treatment.
  • the compound described herein can be used in a protective or preventive manner; or compound described herein can be used to alleviate, inhibit, or ameliorate the disease, condition, or disorder.
  • subject refers to any animal, including mammals, such as, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the subject can be a healthy volunteer or healthy participant without an underlying VMAT2 mediated disorder or condition or a volunteer or participant that has received a diagnosis for a disorder or condition in need of medical treatment as determined by a health care professional.
  • a subject under the care of a health care professional who has received a diagnosis for a disorder or condition is typically described as a subject.
  • the term “pediatric subject” refers to a subject under the age of 21 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)) see e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph et al., Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
  • pharmaceutically acceptable refers to compounds (and salts thereof), compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical composition refers to a specific composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds described herein, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • prevent refers to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder.
  • the terms “prevent”, “preventing”, and “prevention” can refer to the administration of therapy on a prophylactic or preventative basis to a subject who may ultimately manifest at least one symptom of a disorder but who has not yet done so.
  • Such subjects can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease, such as, the presence of a biomarker.
  • prevention therapy can be administered as a prophylactic measure without prior identification of a risk factor. Delaying the onset of the at least one episode and/or symptom of a disorder can also be considered prevention or prophylaxis.
  • the subject can be a pediatric subject.
  • the terms “treat”, “treating”, and “treatment” refer to medical management of a disease, disorder, or condition of a subject (e.g., subject) (see, e.g., Stedman’s Medical Dictionary). In general, an appropriate dose and treatment regimen provide the VMAT2 inhibitor in an amount sufficient to provide therapeutic benefit.
  • Therapeutic benefit for subjects to whom the VMAT2 inhibitor compound(s) described herein are administered includes, for example, an improved clinical outcome, wherein the object is to prevent or slow or retard (lessen) an undesired physiological change associated with the disease, or to prevent or slow or retard (lessen) the expansion or severity of such disease.
  • the effectiveness of one or more VMAT2 inhibitors can include beneficial or desired clinical results that comprise, but are not limited to, abatement, lessening, or alleviation of symptoms that result from or are associated with the disease to be treated; decreased occurrence of symptoms; improved quality of life; longer disease-free status (i.e., decreasing the likelihood or the propensity that a subject will present symptoms on the basis of which a diagnosis of a disease is made); diminishment of extent of disease; stabilized (i.e., not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission (whether partial or total), whether detectable or undetectable; and/or overall survival.
  • the subject can be a pediatric subject.
  • terapéuticaally effective amount refers to the amount of the compound described herein, or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a subject, researcher, veterinarian, medical doctor, or other clinician or caregiver, which can include one or more of the following: (1) preventing the disorder, for example, preventing a disease, condition, or disorder in a subject who can be predisposed to the disease, condition, or disorder but does not yet experience or display the relevant pathology or symptomatology; (2) inhibiting the disorder, for example, inhibiting a disease, condition, or disorder in a subject who is experiencing or displaying the relevant pathology or symptomatology (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disorder, for example, ameliorating a disease, condition, or disorder in a subject who is experiencing or displaying the relevant pathology
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the VMAT2 protein with a compound provided herein includes the administration of a compound provided herein (or a pharmaceutically acceptable salt thereof) to a subject, such as, a human, having a VMAT2 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the VMAT2 protein.
  • CHEMICAL GROUPS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety.
  • a-membered (wherein “a” is an integer) preceding the name of a group refers to the number of atoms in that group.
  • oxetanyl contains four atoms and is a 4-membered- heterocyclyl
  • 2-oxaspiro[3.3]heptanyl is an example of a 7-membered-spiro-heterocyclyl
  • piperidinyl is an example of a 6-membered-heterocyclyl ring.
  • a-b-membered (wherein “a” and “b” are integers) preceding the name of a group refers to the inclusive range of atoms in that group.
  • a “3-7-membered-heterocyclyl” group refers to all “heterocyclyl” groups having from 3 to 7 atoms (i.e., 3, 4, 5, 6, and 7 atoms), where “heterocyclyl” is defined herein; and “4-5-membered-heterocyclyl” refers to all “heterocyclyl” groups having from 4 to 5 atoms (i.e., 4 and 5 atoms).
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R, or the two R groups can be the same. Whenever a group is described as being “substituted” that group can be substituted with one or more of the indicated substituents.
  • a “C1-C4-alkyl” group refers to all alkyl groups having from 1 to 4 carbons (i.e., 1, 2, 3, and 4 carbons), such as, methyl (CH3-), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), iso-propyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), iso-butyl ((CH 3 ) 2 CHCH 2 -), sec-butyl (CH 3 CH 2 CH(CH 3 )-), and tert-butyl ((CH 3 ) 3 C-).
  • C 1 -C 4 -alkylene and “C 2 -C 4 -alkylene” refers to a straight or branched, saturated aliphatic, divalent radical having the defined number of carbons, 1 to 4 carbon atoms or 2 to 4 carbon atoms respectively. Some embodiments contain 1 to 2 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 carbon atom. Some embodiments contain 2 to 3 carbons. Some embodiments contain 2 carbon atoms.
  • Examples include, but are not limited to, methylene (i.e., -CH 2 - ), ethylene (i.e., -CH 2 CH 2 - and -CH(CH 3 )-), n-propylene, isopropylene, n-butylene, s-butylene, isobutylene, and t-butylene.
  • the substituent(s) can be bonded at any available carbon atom.
  • the substituents can be the same or different.
  • the “alkylene” group can be substituted or unsubstituted.
  • C1-C4-alkyl-O-C2-C4-alkylene refers to a radical group consisting of a “C1-C4- alkyl” group bonded to an oxygen atom and the oxygen atom is bonded to a “C2-C4 alkylene” radical, wherein “C1-C4-alkyl” and “C2-C4 alkylene” have the same definitions as described herein.
  • Examples include, but are not limited to, 1-methoxyethyl (i.e., CH3-O-CH(CH3)-), 2-methoxyethyl (i.e., CH3-O-CH2CH2-), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3- ethoxypropyl, 3-propoxypropyl, and 3-isopropoxypropyl.
  • 1-methoxyethyl i.e., CH3-O-CH(CH3)-
  • 2-methoxyethyl i.e., CH3-O-CH2CH2-
  • 2-ethoxyethyl 2-propoxyethyl
  • 2-isopropoxyethyl 3-methoxypropyl
  • 3-ethoxypropyl 3-propoxypropyl
  • 3-isopropoxypropyl 3-isopropoxypropyl.
  • C1-C4-alkyl-O-C2- C4-alkylene refers to a group selected from: 2-methoxyethyl (i.e., CH3-O-CH2CH2-), 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, and 3- isopropoxypropyl.
  • the substituent(s) can be bonded at any available carbon atom.
  • the substituents can be the same or different.
  • the “C1-C4- alkyl-O-C2-C4-alkylene” group can be substituted or unsubstituted.
  • alkoxy refers to a radical comprising an “alkyl” group attached directly to an oxygen atom, wherein “alkyl” has the same definition as found herein. Some embodiments contain 1 to 4 carbons (i.e., “C1-C4-alkoxy”). Some embodiments contain 1 to 3 carbons (i.e., “C1-C3-alkoxy”). Some embodiments contain 1 or 2 carbons.
  • alkyl refers to a fully saturated straight or branched hydrocarbon radical. In some embodiments, the alkyl group can have 1 to 6 carbons (i.e., “C1-C6-alkyl”).
  • C1-C5-alkyl Some embodiments are 1 to 5 carbons (i.e., “C1-C5-alkyl”), some embodiments are 1 to 4 carbons (i.e., C1-C4-alkyl), some embodiments are 1 to 3 carbons (i.e., “C1-C3-alkyl”), and some embodiments are 1 or 2 carbons.
  • “C1-C4-alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, and tert-butyl.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., -CH 2 CH(CH 3 )CH 2 CH 3 ], and n-hexyl.
  • the substituent(s) can be bonded at any available carbon atom.
  • the substituents can be the same or different.
  • the “alkyl” group can be substituted or unsubstituted.
  • the “alkylsulfonyl” group can have 1 to 4 carbon atoms (i.e., “C 1 -C 4 - alkylsulfonyl”).
  • Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, and t- butylsulfonyl.
  • amino refers to the group -NH 2 .
  • the term “bicycloalkyl” refers to a radical comprising two fused or bridged cycloalkyl rings. In some embodiments, the “bicycloalkyl” group contains 4 to 8 ring carbon atoms.
  • the “bicycloalkyl” group contains 5 to 8 ring carbon atoms. In some embodiments, the “bicycloalkyl” group contains 5 to 7 ring carbon atoms. In some embodiments, the “bicycloalkyl” group contains 5 or 6 ring carbon atoms. Examples include, but are not limited to, bicyclo[1.1.0]butanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl, and bicyclo[3.2.1]octyl.
  • the substituent(s) can be bonded at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the “bicycloalkyl” group can be substituted or unsubstituted.
  • the term “C4-C8-bicycloalkyl-C1-C4-alkylene” refers to a radical group consisting of a “C4- C8-bicycloalkyl” group bonded to a “C1-C4 alkylene” radical, wherein “C4-C8-bicycloalkyl” and “C1-C4 alkylene” have the same definitions as described herein.
  • Examples include, but are not limited to, (bicyclo[1.1.0]butan-1-yl)methyl (i.e., (bicyclo[1.1.0]butan-1-yl)CH2-), (bicyclo[1.1.1]pentan-1- yl)methyl (i.e., (bicyclo[1.1.1]pentan-1-yl)CH2-), (bicyclo[2.2.1]hex-1-yl)methyl, (bicyclo[2.2.1]hept- 1-yl)methyl, and (bicyclo[2.2.2]oct-1-yl)methyl.
  • the heteroatom(s) include, but are not limited to, oxygen, sulfur, and nitrogen, when more than one heteroatom is present in the ring the heteroatoms can be the same or different.
  • the “4-8-membered- heterobicyclyl” is a group selected from: 2-oxabicyclo[2.1.1]hexan-1-yl and 2- oxabicyclo[2.1.1]hexan-4-yl.
  • the substituent(s) can be bonded at any available ring atom.
  • the substituents can be the same or different.
  • the substituent(s) can be bonded at any available carbon atom. When more than one substituent is present, the substituents can be the same or different.
  • the “cycloalkenyl” group can be substituted or unsubstituted.
  • the term “cycloalkyl” refers to a fully saturated, all carbon, monocyclic ring system. In some embodiments, the cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., “C3-C7- cycloalkyl”). Some embodiments contain 3 to 6 carbons (i.e., “C3-C6-cycloalkyl”).
  • Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the substituent(s) can be bonded at any available carbon atom. When more than one substituent is present, the substituents can be the same or different.
  • the “cycloalkyl” group can be substituted or unsubstituted.
  • C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene refers to a radical group consisting of a “C 3 - C 7 -cycloalkyl” group bonded to a “C 1 -C 4 alkylene” radical, wherein “C 3 -C 7 -cycloalkyl” and “C 1 -C 4 alkylene” have the same definitions as described herein.
  • Examples include, but are not limited to, cyclopropylmethyl (cyclopropyl-CH 2 -), cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl (cyclopropyl-CH 2 CH 2 -), 2-cyclobutylethyl, 2- cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclopropylethyl (cyclopropyl-CH(CH 3 )-), 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 1-cycloheptylethyl, 3-cyclopropylpropyl, 3- cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 4-cyclopropylbut
  • C3-C7-cycloalkyl-O-C2-C4-alkylene refers to a radical group consisting of a “C3- C7-cycloalkyl” group bonded to an oxygen atom and the oxygen atom is bonded to a “C2-C4 alkylene” radical, wherein “C3-C7-cycloalkyl” and “C2-C4 alkylene” have the same definitions as described herein.
  • the chemical group “(cyclopropyl)methyl-d2” refers to the group in which the deuterium atoms are bonded to the methylene carbon (i.e., cyclopropyl-CD2-), for example, see Compound 99.
  • the substituent(s) can be bonded at any available carbon atom.
  • the substituents can be the same or different.
  • the “C3-C7-cycloalkyl-O-C2-C4- alkylene” group can be substituted or unsubstituted.
  • dialkylamino refers to an amino group (-NH2) where the nitrogen is substituted with two “alkyl” groups.
  • the two alkyl groups can be the same or different.
  • alkyl has the same definition as described herein.
  • the “dialkylamino” group can have 2 to 4 carbon atoms (i.e., “C2-C4-dialkylamino”) provided that the two alkyl groups do not exceed a total of 4 carbon atoms between the two groups.
  • haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogen atoms of the alkyl group have been replaced by a halogen atom.
  • the haloalkyl group can have 1 to 6 carbons (i.e., “C 1 -C 6 -haloalkyl”).
  • the haloC 1 -C 6 alkyl can be fully substituted in which case it can be represented by the formula CnL2n+1, wherein L is a halogen and “n” is 1, 2, 3, 4, 5, or 6.
  • L is a halogen
  • n is 1, 2, 3, 4, 5, or 6.
  • haloalkyl contains 1 to 5 carbons (i.e., “C 1 -C 5 -haloalkyl”).
  • haloalkyl contains 1 to 4 carbons (i.e., “C 1 -C 4 -haloalkyl”). In some embodiments, haloalkyl contains 1 to 3 carbons (i.e., “C 1 -C 3 - haloalkyl”). In some embodiments, haloalkyl contains 1 or 2 carbons. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, and 4,4,4-trifluorobutyl.
  • “3-7-membered-heterocyclyl” refers to a ring system containing 3 to 7 ring atoms, wherein at least one ring atom is a heteroatom.
  • “4-5- membered-heterocyclyl” refers to a ring system containing 4 or 5 ring atoms, wherein at least one ring atom is a heteroatom.
  • “4-7-membered-heterocyclyl” refers to a ring system containing 4 to 7 ring atoms, wherein at least one ring atom is a heteroatom.
  • “3-6-membered-heterocyclyl” refers to a ring system containing 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom.
  • “4-6-membered-heterocyclyl” refers to a ring system containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom.
  • the one or two heteroatoms in the ring system are selected independently from: O (oxygen) and N (nitrogen).
  • Examples include, but are not limited to, aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiopyranyl.
  • substituents can be bonded at any available carbon atom and/or heteroatom.
  • the substituents can be the same or different.
  • the “heterocyclyl” group can be substituted or unsubstituted.
  • 4-8-membered-heterobicyclyl-C1-C4-alkylene refers to a radical group consisting of a “4-8-membered-heterobicyclyl” group bonded to a “C1-C4 alkylene” radical, wherein “4-8-membered-heterobicyclyl” and “C1-C4 alkylene” have the same definitions as described herein.
  • the “4-8-membered-heterobicyclyl-C 1 -C 4 -alkylene” is a group selected from: (2-oxabicyclo[2.1.1]hexan-1-yl)methyl and (2-oxabicyclo[2.1.1]hexan-4- yl)methyl.
  • substituent(s) can be bonded at any available carbon atom.
  • substituents can be the same or different.
  • the “4-8- membered-heterobicyclyl-C 1 -C 4 -alkylene” group can be substituted or unsubstituted.
  • the term “3-7-membered-heterocyclyl-C 1 -C 4 -alkylene” refers to a radical group consisting of a “3-7-membered-heterocyclyl” group bonded to a “C 1 -C 4 alkylene” radical, wherein “3-7- membered-heterocyclyl” and “C 1 -C 4 alkylene” have the same definitions as described herein.
  • Examples include, but are not limited to, aziridin-1-ylmethyl(i.e., (aziridin-1-yl)CH 2 -), aziridin-2- ylmethyl, azetidin-2-ylmethyl (i.e., (azetidin-2-yl)CH 2 -), azetidin-3-ylmethyl (i.e., (azetidin-3-yl)CH 2 - ), piperidinylmethyl, morpholinyl, oxetan-3-ylmethyl (i.e., (oxetan-3-yl)CH 2 -), oxetan-2-ylmethyl (i.e., (oxetan-2-yl)CH 2 -), 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl)CH 2 CH 2 -), 2-oxetan-2-ylethyl (i.e., (oxe
  • “3-7-membered-heterocyclyl-C1-C4-alkylene” is a group selected from: oxetan-3-ylmethyl (i.e., (oxetan-3-yl)CH2-), oxetan-2-ylmethyl (i.e., (oxetan- 2-yl)CH2-), 2-oxetan-3-ylethyl (i.e., (oxetan-3-yl)CH2CH2-), and 2-oxetan-2-ylethyl (i.e., (oxetan-2- yl)CH2CH2-).
  • the substituent(s) can be bonded at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the “3-7- membered-heterocyclyl-C1-C4-alkylene” group can be substituted or unsubstituted.
  • spiro-cycloalkyl refers to a non-aromatic, all carbon, bicyclic ring system where both rings are linked together by a single common ring carbon.
  • C5-C11-spiro- cycloalkyl refers to a spiro ring system containing 5 to 11 ring carbons.
  • C5- C8-spiro-cycloalkyl refers to a spiro ring system containing 5 to 8 ring carbons.
  • C5-C7-spiro-cycloalkyl refers to a spiro ring system containing 5 to 7 ring carbons.
  • C7-spiro-cycloalkyl refers to a spiro ring system containing 7 ring carbons (i.e., spiro[3.3]heptanyl and spiro[2.4]heptanyl).
  • the substituent(s) can be bonded at any available carbon atom. When more than one substituent is present, the substituents can be the same or different. In some embodiments, the “spiro-cycloalkyl” group can be substituted or unsubstituted.
  • the term “spiro-heterocyclyl” refers to a bicyclic ring system containing carbon atoms and at least one heteroatom, where both rings are linked together by a single common ring carbon. In some embodiments, “5-11-membered-spiro-heterocyclyl” refers to a spiro ring system containing 5 to 11 ring atoms.
  • “5-8-membered-spiro-heterocyclyl” refers to a spiro ring system containing 5 to 8 ring atoms. In some embodiments, “5-7-membered-spiro-heterocyclyl” refers to a spiro ring system containing 5 to 7 ring atoms.
  • Examples include, but are not limited to, azaspiro[2.2]pentanyl, azaspiro[2.3]hexanyl, oxaspiro[2.3]hexanyl, oxaspiro[3.3]heptanyl, azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, azaspiro[3.5]nonanyl, and oxaspiro[3.5]nonan-9-yl.
  • the substituent(s) can be bonded at any available carbon atom and/or heteroatom. When more than one substituent is present, the substituents can be the same or different.
  • a pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance.
  • Pharmaceutically acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • Preservatives, stabilizers, dyes, buffers, and the like can be provided in the pharmaceutical composition.
  • each center can independently be the (R)-configuration, or the (S)- configuration, or a mixture thereof.
  • the compounds provided herein can be enantiomerically pure, enantiomerically enriched, a racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • Preparation of enantiomerically pure or enantiomerically enriched forms can be accomplished by resolution of racemic mixtures or by using enantiomerically pure or enriched starting materials or by stereoselective or stereospecific synthesis. Stereochemical definitions are available in E.L.
  • the compound described herein is chiral or otherwise includes one or more stereocenters
  • the compound can be prepared with an enantiomeric excess or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a chiral resolving organic acid with a racemic compound containing a basic group.
  • Other chiral resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • fractional recrystallization using a chiral resolving base can be utilized with a racemic compound containing a basic group.
  • Resolution of racemic mixtures can also be carried out by elution on a chiral column.
  • a suitable elution solvent composition can be determined by one skilled in the art.
  • a compound described herein can be prepared having 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% enantiomeric excess, or an enantiomeric excess within a range defined by any of the preceding numbers.
  • a compound described herein can be prepared having 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% enantiomeric excess, or an enantiomeric excess within a range defined by any of the preceding numbers.
  • a compound described herein can be prepared having 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% diastereomeric excess, or a diastereomeric excess within a range defined by any of the preceding numbers.
  • a compound described herein can be prepared having 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% diastereomeric excess, or a diastereomeric excess within a range defined by any of the preceding numbers.
  • Cis and trans geometric isomers of the compounds, as described herein, can be isolated as a mixture of isomers, or as separated isomeric form.
  • the compounds described herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds described herein, and their pharmaceutically acceptable salts can be found together with other substances, such as, water and solvents, for example, in the form of hydrates or solvates.
  • the compounds described herein and salts thereof can occur in various forms and can, e.g., take the form of solvates, including hydrates.
  • the compounds can be in any solid-state form, such as, a crystalline form, amorphous form, solvated form, etc. and unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as reading on any solid-state form of the compound.
  • the compounds described herein can be used in a neutral form, such as, a free acid or free base form.
  • the compounds can be used in the form of pharmaceutically acceptable salts, such as, pharmaceutically acceptable addition salts of acids or bases.
  • the compounds described herein, or salts thereof are substantially isolated.
  • the phrase “substantially isolated” refers to the compound that is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound described herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound described herein, or salt thereof.
  • ISOTOPES The compounds disclosed and described herein allow and embrace atoms at each position of the compound independently to have: 1) an isotopic distribution for a chemical element in proportional amounts to those usually found in nature or 2) an isotopic distribution in proportional amounts different to those usually found in nature unless the context clearly dictates otherwise.
  • a particular chemical element has an atomic number defined by the number of protons within the atom's nucleus. Each atomic number identifies a specific chemical element, but not the isotope; an atom of a given element can have a wide range in its number of neutrons. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number.
  • a hydrogen atom can be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be an isotopic distribution of hydrogen, including but not limited to protium ( 1 H) and deuterium ( 2 H) in proportional amounts to those usually found in nature and in proportional amounts different to those usually found in nature.
  • references herein to a compound encompasses all potential isotopic distributions for each atom unless the context clearly dictates otherwise.
  • isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and iodine.
  • any of the compounds as disclosed and described herein can include radioactive isotopes.
  • isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H).
  • Isotopes of carbon include carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), and carbon-14 ( 14 C).
  • Isotopes of nitrogen include nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), and nitrogen- 15 ( 15 N).
  • Isotopes of oxygen include oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), and oxygen-18 ( 18 O).
  • Isotopes of fluorine include fluorine-17 ( 17 F), fluorine-18 ( 18 F), and fluorine-19 ( 19 F).
  • Isotopes of phosphorus include phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), phosphorus-34 ( 34 P), phosphorus-35 ( 35 P), and phosphorus-36 ( 36 P).
  • Isotopes of sulfur include sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), and sulfur-38 ( 38 S).
  • Isotopes of chlorine include chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), and chlorine-37 ( 37 Cl).
  • Isotopes of bromine include bromine-75 ( 75 Br), bromine-76 ( 76 Br), bromine-77 ( 77 Br), bromine- 79 ( 79 Br), bromine-81 ( 81 Br), and bromine-82 ( 82 Br).
  • Isotopes of iodine include iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), iodine-131 ( 131 I), and iodine-135 ( 135 I).
  • atoms at every position of the compound have an isotopic distribution for each chemical element in proportional amounts to those usually found in nature.
  • an atom in one position of the compound has an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least two positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least five positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least six positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • Certain compounds, for example those having incorporated radioactive isotopes, such as, 3 H and 14 C, are also useful in drug or substrate tissue distribution assays.
  • Tritium ( 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Compounds with isotopes, such as, deuterium ( 2 H) in proportional amounts greater than usually found in nature can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds can generally be prepared by performing procedures routinely practiced in the chemical art. Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio- detectors used in connection with HPLC or GC.
  • isotopic variant means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35
  • an “isotopic variant” of a compound is in a stable form, that is, non-radioactive.
  • an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), and oxygen-18 ( 18 O).
  • an “isotopic variant” of a compound is in an unstable form, that is, radioactive.
  • an “isotopic variant” of a compound described herein contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), and oxygen-15 ( 15 O).
  • any hydrogen can include 2 H as the major isotopic form, as example, or any carbon include be 13 C as the major isotopic form, as example, or any nitrogen can include 15 N as the major isotopic form, as example, and any oxygen can include 18 O as the major isotopic form, as example.
  • an “isotopic variant” of a compound contains an unnatural proportion of deuterium ( 2 H).
  • deuterium 2 H
  • a position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.
  • any atomic position is designated as a specific isotope
  • the abundance of the specific isotope at that position is substantially greater than the natural abundance of that isotope.
  • a position designated as having a specific isotope typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 99.5% incorporation of the isotope at each designated position.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compound described herein and are well known in the art.
  • Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • Synthetic methods for incorporating activity levels of 125 I into target molecules include: A.
  • Aryl and heteroaryl bromide exchange with 125 I This method is generally a two-step process.
  • the first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri- alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3].
  • Pd(Ph3P)4 i.e. Pd(Ph3P)4
  • a tri-alkyltinhalide or hexaalkylditin e.g., (CH3)3SnSn(CH3)3
  • a radiolabeled form of a compound described herein can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • VMAT2 The ability of a test compound to compete with a radiolabeled form of a compound described herein for the binding to VMAT2 correlates to its binding affinity.
  • R 1 is selected from: C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 - alkyl-O-C 2 -C 4 -alkylene, C 3 -C 7 -cycloalkyl-O-C 2 -C 4 -alkylene, 3-7-membered-heterocyclyl, 3-7- membered-heterocyclyl-C 1 -C 4 -alkylene, C 4 -C 8 -bicycloalkyl-C 1 -C 4 -alkylene, C 4 -C 7 -cycloalkenyl, 5- 11-membered-spiro-heterocyclyl, C
  • R 1 is selected from: C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 - alkyl-O-C 2 -C 4 -alkylene, C 3 -C 7 -cycloalkyl-O-C 2 -C 4 -alkylene, 3-7-membered-heterocyclyl, 3-7- membered-heterocyclyl-C 1 -C 4 -alkylene, C 4 -C 8 -bicycloalkyl-C 1 -C 4 -alkylene, C 4 -C 7 -cycloalkenyl, 5- 11-membered-spiro-heterocyclyl, and C 5 -
  • the R 1 group is optionally substituted with one, two, three, four, five, six, seven, or eight substituents. In some embodiments, the R 1 group is optionally substituted with one, two, three, four, five, six, or seven substituents. In some embodiments, the R 1 group is optionally substituted with one, two, three, four, five, or six substituents. In some embodiments, the R 1 group is optionally substituted with one, two, three, four, or five substituents. In some embodiments, the R 1 group is optionally substituted with one, two, three, or four substituents. In some embodiments, the R 1 group is optionally substituted with one, two, or three substituents.
  • the R 1 group is optionally substituted with one or two substituents. In some embodiments, the R 1 group is optionally substituted with one substituent. In some embodiments, the R 1 group is not substituted. In some embodiments, the R 1 group is substituted with one, two, three, four, five, six, seven, or eight substituents. In some embodiments, the R 1 group is substituted with one, two, three, four, five, six, or seven substituents. In some embodiments, the R 1 group is substituted with one, two, three, four, five, or six substituents. In some embodiments, the R 1 group is substituted with one, two, three, four, or five substituents. In some embodiments, the R 1 group is substituted with one, two, three, four, or five substituents.
  • the R 1 group is substituted with one, two, three, or four substituents. In some embodiments, the R 1 group is substituted with one, two, or three substituents. In some embodiments, the R 1 group is substituted with one or two substituents. In some embodiments, the R 1 group is substituted with one substituent.
  • Some embodiments provide a compound of Formula (Ic): , or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definition as described herein, supra, and infra. It is understood that the stereochemistry for compounds of Formula (Ic) includes both the 2S,3R,11bR isomer and the 2R,3R,11bR isomer.
  • Some embodiments provide a compound of Formula (Ie): , or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definition as described herein, supra, and infra.
  • the stereochemistry for a compound of Formula (Ie) is the 2R,3R,11bR isomer.
  • Some embodiments provide a compound of Formula (Ig): , or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definition as described herein, supra, and infra.
  • the stereochemistry for a compound of Formula (Ig) is the 2S,3R,11bR isomer.
  • Some embodiments provide a compound of Formula (Ii): , or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definition as described herein, supra, and infra.
  • the stereochemistry for a compound of Formula (Ii) is the 2R,3S,11bS isomer.
  • Some embodiments provide a compound of Formula (Ik): , or a pharmaceutically acceptable salt thereof, wherein: R 1 has the same definition as described herein, supra, and infra.
  • the stereochemistry for a compound of Formula (Ik) is the 2S,3S,11bS isomer.
  • Some embodiments provide a compound, as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an elimination t 1/2 ⁇ 420 minutes as determined using a human liver microsomes (HLM) assay, such as, the assay as described in Example 17.
  • HLM human liver microsomes
  • the compound has an elimination t 1/2 ⁇ 400 minutes.
  • the compound has an elimination t 1/2 ⁇ 375 minutes.
  • the compound has an elimination t 1/2 ⁇ 350 minutes.
  • the compound has an elimination t 1/2 ⁇ 325 minutes.
  • the compound has an elimination t 1/2 ⁇ 300 minutes.
  • the compound has an elimination t 1/2 ⁇ 275 minutes.
  • the compound has an elimination t1/2 ⁇ 250 minutes. In some embodiments, the compound has an elimination t 1/2 ⁇ 225 minutes. In some embodiments, the compound has an elimination t 1/2 ⁇ 200 minutes.
  • Some embodiments provide a compound, as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an IC50 > 6,000 nM against CYP2D6 and CYP3A4, as determined using an IC50 method, such as, the method described in Example 18. In some embodiments, the compound has an IC50 > 5,000 nM against CYP2D6. In some embodiments, the compound has an IC50 > 4,000 nM against CYP2D6.
  • the compound has an IC50 > 3,000 nM against CYP2D6. In some embodiments, the compound has an IC50 > 2,000 nM against CYP2D6. In some embodiments, the compound has an IC 50 > 5,000 nM against CYP3A4. In some embodiments, the compound has an IC 50 > 4,000 nM against CYP3A4. In some embodiments, the compound has an IC 50 > 3,000 nM against CYP3A4. In some embodiments, the compound has an IC 50 > 2,000 nM against CYP3A4. In some embodiments, the compound is substantially inactive against CYP2D6. In some embodiments, the compound is substantially inactive against CYP3A4.
  • Some embodiments provide a compound, as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound has an IC 50 > 12,000 nM against hERG (human ether- a-go-go-related gene) as determined using an IC 50 method, such as, the method described in Example 19.
  • the compound has an IC50 > 11,000 nM against hERG.
  • the compound has an IC50 > 10,000 nM against hERG.
  • the compound has an IC50 > 9,000 nM against hERG.
  • the compound has an IC50 > 8,000 nM against hERG.
  • the compound has an IC50 > 7,000 nM against hERG. In some embodiments, the compound is substantially inactive against hERG.
  • the phrase “compound as described herein” or “compounds as described herein” refers to any compound or compounds in the present disclosure, supra, and infra.
  • the compound(s) is of Formula (Ia). In some embodiments, the compound(s) is of Formula (Ic). In some embodiments, the compound(s) is of Formula (Ie). In some embodiments, the compound(s) is of Formula (Ig). In some embodiments, the compound(s) is of Formula (Ii). In some embodiments, the compound(s) is of Formula (Ik).
  • R 1 is selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3- C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3-7-membered- heterocyclyl, 3-7-membered-heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7- cycloalkenyl, 5-11-membered-spiro-heterocyclyl, C5-C11-spiro-cycloalkyl, cubanyl-C1-C4-alkylene, and 4-8-membered-heterobicyclyl-C1-C4-alkylene; wherein each R 1 group is optionally
  • R 1 is selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3- C7-cycloalkyl, C1-C4-alkyl-O-C2-C4-alkylene, C3-C7-cycloalkyl-O-C2-C4-alkylene, 3-7-membered- heterocyclyl, 3-7-membered-heterocyclyl-C1-C4-alkylene, C4-C8-bicycloalkyl-C1-C4-alkylene, C4-C7- cycloalkenyl, 5-11-membered-spiro-heterocyclyl, and C 5 -C 11 -spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl; where
  • R 1 is selected from: C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene, C 1 -C 5 -alkyl, C 3 - C 5 -cycloalkyl, C 1 -C 3 -alkyl-O-CH 2 CH 2 -, cyclopropyl-O-CH 2 CH 2 -, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH 2 -, (C 5 -C 6 -bicycloalkyl)CH 2 -, C 4 -cycloalkenyl, 7-membered-spiro- heterocyclyl, C 7 -spiro-cycloalkyl, (cubanyl)CH 2 -, and 6-membered-heterobicyclyl-C 1 -C 4 -alkylene- CH 2 -; wherein each R 1 group is optionally substituted with one or more substituents selected from:
  • R 1 is selected from: C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene, C 1 -C 5 -alkyl, C 3 - C 5 -cycloalkyl, C 1 -C 3 -alkyl-O-CH 2 CH 2 -, cyclopropyl-O-CH 2 CH 2 -, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH 2 -, (C 5 -bicycloalkyl)CH 2 -, C 4 -cycloalkenyl, 7-membered-spiro- heterocyclyl, and C7-spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C
  • R 1 is selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3- C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered-spiro- heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered-heterobicyclyl-C1-C4-alkylene- CH2-; wherein each R 1 group is optionally substituted with one or more substituents selected from: cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cycloprop
  • R 1 is selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3- C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered-spiro- heterocyclyl, and C7-spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one or more substituents selected from: cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.
  • R 1 is selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3- C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered-spiro- heterocyclyl, C7-spiro-cycloalkyl, (cubanyl)CH2-, and 6-membered-heterobicyclyl-C1-C4-alkylene- CH2-; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: cyanomethyl, fluoro, methyl, C 1 -haloalkyl, cyan
  • R 1 is selected from: C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene, C 1 -C 5 -alkyl, C 3 - C 5 -cycloalkyl, C 1 -C 3 -alkyl-O-CH 2 CH 2 -, cyclopropyl-O-CH 2 CH 2 -, 4-5-membered-heterocyclyl, (4- membered-heterocyclyl)CH 2 -, (C 5 -bicycloalkyl)CH 2 -, C 4 -cycloalkenyl, 7-membered-spiro- heterocyclyl, and C 7 -spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: cyanomethyl, fluoro, methyl, C 1 -haloalkyl, cyano, cyclopropyl, hydroxyl, and me
  • R 1 is selected from: C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene, C 1 -C 5 -alkyl, C 3 - C 5 -cycloalkyl, C 1 -C 3 -alkyl-O-CH 2 CH 2 -, cyclopropyl-O-CH 2 CH 2 -, 4-membered-heterocyclyl, (4- membered-heterocyclyl)CH 2 -, (C 5 -C 6 -bicycloalkyl)CH 2 -, C 4 -cycloalkenyl, 7-membered-spiro- heterocyclyl, C 7 -spiro-cycloalkyl, (cubanyl)CH 2 -, and 6-membered-heterobicyclyl-C 1 -C 4 -alkylene- CH 2 -; wherein each R 1 group is optionally substituted with one, two, three, or four substituents
  • R 1 is selected from: C3-C5-cycloalkyl-C1-C2-alkylene, C1-C5-alkyl, C3- C5-cycloalkyl, C1-C3-alkyl-O-CH2CH2-, cyclopropyl-O-CH2CH2-, 4-membered-heterocyclyl, (4- membered-heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-, C4-cycloalkenyl, 7-membered-spiro- heterocyclyl, and C7-spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: cyanomethyl, fluoro, methyl, C1-haloalkyl, cyano, cyclopropyl, hydroxyl, and methoxy.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, (cyclobutyl)ethy
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one or more substituents selected from: cyan
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d 3 , ethyl, ethyl-d 5 , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclo
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, pyrrolidinyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three, or four substituents
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl, (cubanyl)
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one or more substituents selected from: cyanomethyl, fluoro,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, methyl-d 3 , ethyl, ethyl-d 5 , cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, (cyclobutyl)ethyl,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, neopentyl, cyclobutenyl, oxaspiro[3.3]heptanyl, spiro[3.3]heptanyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, three, or four substituents selected from: cyanomethyl,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2- methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3- methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2- en-1-yl, 2-
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2- cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1- yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopentyl, cyclobutyl, 2- methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d 3 , ethyl, ethyl-d 5 , cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3- methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2- en
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2- cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1- yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopentyl, cyclobutyl, 2- methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3- methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2- en-1-yl, 2-
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2- cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1- yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopentyl, cyclobutyl, 2- methoxyethyl, butyl, propyl, 2-cyclopropoxyethyl, methyl, methyl-d3, ethyl, ethyl-d5, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3- methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2- en-1-yl
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (cyclopropyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, 2- cyclopropoxyethyl, methyl, ethyl, cyclopropyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1- yl)methyl, 2-(methoxy)ethyl, neopentyl, cyclobut-2-en-1-yl, 2-oxaspiro[3.3]heptan-6-yl, spiro[3.3
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2- methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d 3 , 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl,
  • R 1 is (cyclopentyl)methyl. In some embodiments, R 1 is isobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is (cyclobutyl)methyl. In some embodiments, R 1 is (1-(cyanomethyl)cyclopropyl)methyl. In some embodiments, R 1 is isopentyl. In some embodiments, R 1 is (1-fluorocyclobutyl)methyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is 2-(cyano(cyclopropyl)methoxy)ethyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is propyl.
  • R 1 is (1-hydroxycyclobutyl)methyl. In some embodiments, R 1 is 2-cyclopropoxyethyl. In some embodiments, R 1 is 2-fluoro-2-methylpropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methyl-d3. In some embodiments, R 1 is 2,2-difluoropropyl. In some embodiments, R 1 is 2,2,2-trifluoroethyl. In some embodiments, R 1 is 3,3,3-trifluoropropyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is (1- fluorocyclopropyl)methyl. In some embodiments, R 1 is 2-hydroxypropyl.
  • R 1 is ethyl. In some embodiments, R 1 is ethyl-d5. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is 2-methoxyethyl. In some embodiments, R 1 is (cyclopropyl)methyl. In some embodiments, R 1 is (cyclopropyl)methyl-d 2 . In some embodiments, R 1 is 3-fluoropropyl. In some embodiments, R 1 is 2-fluoroethyl. In some embodiments, R 1 is 2-((2-cyanopropan-2-yl)oxy)ethyl. In some embodiments, R 1 is 1,1,1-trifluoropropan-2-yl.
  • R 1 is 2,2-difluoroethyl. In some embodiments, R 1 is oxetan-3-yl. In some embodiments, R 1 is oxetan-3-ylmethyl. In some embodiments, R 1 is (oxetan-2-yl)methyl. In some embodiments, R 1 is 3,3,3-trifluoro-2- hydroxypropyl. In some embodiments, R 1 is 4,4,4-trifluorobutyl. In some embodiments, R 1 is 3- methoxypropyl. In some embodiments, R 1 is (3,3-difluorocyclobutyl)methyl. In some embodiments, R 1 is (1-(difluoromethyl)cyclopropyl)methyl.
  • R 1 is 5,5,5-trifluoropentyl. In some embodiments, R 1 is (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is fluoromethyl. In some embodiments, R 1 is (2,2-difluorocyclopropyl)methyl. In some embodiments, R 1 is 2-(trifluoromethoxy)ethyl. In some embodiments, R 1 is neopentyl. In some embodiments, R 1 is (1-methylcyclobutyl)methyl. In some embodiments, R 1 is (2-methylcyclopropyl)methyl. In some embodiments, R 1 is (2,2-difluorocyclopentyl)methyl.
  • R 1 is 3-fluorocyclobut-2- en-1-yl. In some embodiments, R 1 is 2-oxaspiro[3.3]heptan-6-yl. In some embodiments, R 1 is 3- cyanocyclobutyl. In some embodiments, R 1 is 3-fluorocyclobutyl. In some embodiments, R 1 is 3,3- dimethylcyclobutyl. In some embodiments, R 1 is spiro[3.3]heptan-2-yl. In some embodiments, R 1 is 1-methylpyrrolidin-3-yl. In some embodiments, R 1 is (3-methyloxetan-3-yl)methyl. In some embodiments, R 1 is (1-methylcyclopropyl)methyl.
  • R 1 is 1-methylcyclobutyl. In some embodiments, R 1 is (2-fluorocyclopropyl)methyl. In some embodiments, R 1 is (2,2-difluoro-3- methylcyclopropyl)methyl. In some embodiments, R 1 is 1-cyclobutylethyl. In some embodiments, R 1 is (2,2-dimethylcyclopropyl)methyl. In some embodiments, R 1 is (3,3-difluorocyclopentyl)methyl. In some embodiments, R 1 is 3-(trifluoromethyl)cyclobutyl. In some embodiments, R 1 is 2-fluoropropyl. In some embodiments, R 1 is 3-methoxycyclobutyl.
  • R 1 is 3- (dimethylamino)cyclobutyl. In some embodiments, R 1 is cyanomethyl. In some embodiments, R 1 is (1-cyanocyclobutyl)methyl. In some embodiments, R 1 is (1-cyanocyclopropyl)methyl. In some embodiments, R 1 is 2-methoxypropyl. In some embodiments, R 1 is (1- (methylsulfonyl)cyclopropyl)methyl. In some embodiments, R 1 is 3-(methylsulfonyl)propyl. In some embodiments, R 1 is 2-(methylsulfonyl)ethyl. In some embodiments, R 1 is 3,3-difluorocyclobutyl.
  • R 1 is (2,2-difluorocyclobutyl)methyl. In some embodiments, R 1 is (cuban-1- yl)methyl. In some embodiments, R 1 is (bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is (bicyclo[2.1.1]hexan-1-yl)methyl. In some embodiments, R 1 is (1,1-dimethylsilolan-3-yl)methyl. In some embodiments, R 1 is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl. In some embodiments, R 1 is (2-oxabicyclo[2.1.1]hexan-1-yl)methyl.
  • R 1 is (2- oxabicyclo[2.1.1]hexan-4-yl)methyl.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2- methoxye
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2- methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroe
  • R 1 is (R)-2-hydroxypropyl.
  • R 1 is ((R)-oxetan-2- yl)methyl.
  • R 1 is (S)-3,3,3-trifluoro-2-hydroxypropyl.
  • R 1 is ((S)-2,2-difluorocyclopropyl)methyl.
  • R 1 is ((R)-2,2- difluorocyclopropyl)methyl. In some embodiments, R 1 is (1R,3r)-3-cyanocyclobutyl. In some embodiments, R 1 is (1r,3R)-3-fluorocyclobutyl. In some embodiments, R 1 is (1s,3S)-3- fluorocyclobutyl. In some embodiments, R 1 is ((1R,2S)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((1S,2R)-2-fluorocyclopropyl)methyl.
  • R 1 is ((1S,3R)-2,2- difluoro-3-methylcyclopropyl)methyl. In some embodiments, R 1 is ((1R,3S)-2,2-difluoro-3- methylcyclopropyl)methyl. In some embodiments, R 1 is (S)-1-cyclobutylethyl. In some embodiments, R 1 is (R)-1-cyclobutylethyl. In some embodiments, R 1 is ((1S,2S)-2-fluorocyclopropyl)methyl. In some embodiments, R 1 is ((1R,2R)-2-fluorocyclopropyl)methyl.
  • R 1 is ((S)-2,2- dimethylcyclopropyl)methyl. In some embodiments, R 1 is (1s,3S)-3-(trifluoromethyl)cyclobutyl. In some embodiments, R 1 is (R)-2-fluoropropyl. In some embodiments, R 1 is (S)-2-fluoropropyl. In some embodiments, R 1 is (1s,3S)-3-methoxycyclobutyl. In some embodiments, R 1 is (1s,3S)-3- (dimethylamino)cyclobutyl. In some embodiments, R 1 is (R)-3,3,3-trifluoro-2-hydroxypropyl.
  • R 1 is (S)-2-hydroxypropyl. In some embodiments, R 1 is (R)-2-methoxypropyl. In some embodiments, R 1 is (S)-2-methoxypropyl. In some embodiments, R 1 is (1S,3s)-3-cyanocyclobutyl. In some embodiments, R 1 is (1r,3R)-3-(trifluoromethyl)cyclobutyl. In some embodiments, R 1 is (1r,3R)- 3-methoxycyclobutyl. In some embodiments, R 1 is (1r,3R)-3-(dimethylamino)cyclobutyl.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, (1-(cyanomethyl)cyclopropyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2-(cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2- cyclopropoxyethyl, 2-fluoro-2-methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2- methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroe
  • R 1 is C3-C7-cycloalkyl-C1-C4-alkylene. In some embodiments, R 1 is C3-C7-cycloalkyl-C1-C4-alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C 1 -C 4 -alkylsulfonyl, C 3 -C 6 -cycloalkyl, hydroxyl, C 1 -C 4 -alkoxy, and C 2 -C 4 -dialkylamino.
  • R 1 is C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, hydroxyl, C1-C4-haloalkyl, C1-C4- alkyl, cyano, and C 1 -C 4 -alkylsulfonyl.
  • R 1 is C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene optionally substituted with one or more substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, hydroxyl, C 1 -C 4 -haloalkyl, C 1 -C 4 - alkyl, and cyano.
  • R 1 is C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene optionally substituted with one, two, or three substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, hydroxyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyl, and cyano.
  • R 1 is C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene optionally substituted with one, two, or three substituents selected from: cyanomethyl, halogen, hydroxyl, C 1 -haloalkyl, methyl, cyano, and methylsulfonyl.
  • R 1 is C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkylene optionally substituted with one, two, or three substituents selected from: cyanomethyl, halogen, hydroxyl, C 1 -haloalkyl, methyl, and cyano.
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl.
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, methyl, and methylsulfonyl.
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl.
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (cyclopropyl)methyl, and (cyclobutyl)ethyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, cyanomethyl, difluoromethyl, fluoro, hydroxyl, and methyl.
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3- difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1- methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1- (difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, (2- fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2- dimethylcyclopropyl)methyl, (3,3-difluorocycl
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3- difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1- methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2-dimethylcyclopropyl)
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1- (difluoromethyl)cyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, (2- fluorocyclopropyl)methyl, (2,2-difluoro-3-methylcyclopropyl)methyl, 1-cyclobutylethyl, (2,2- dimethylcyclopropyl)methyl, (3,3-difluorocycl
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3- difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2- difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2- methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)- 2-fluorocyclopropyl)methyl, ((1S,2R)-2- 2-fluoro
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1- (difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2- difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2- difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3- difluorocyclobutyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, ((S)-2,2- difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2- methylcyclopropyl)methyl, (2,2-difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)- 2-fluorocyclopropyl)methyl, ((1S,2R)-2- 2-fluoro
  • R 1 is selected from: (cyclopentyl)methyl, (cyclobutyl)methyl, (1- (cyanomethyl)cyclopropyl)methyl, (1-fluorocyclobutyl)methyl, (1-hydroxycyclobutyl)methyl, (1- fluorocyclopropyl)methyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1- (difluoromethyl)cyclopropyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2- difluorocyclopropyl)methyl, (1-methylcyclobutyl)methyl, (2-methylcyclopropyl)methyl, (2,2- difluorocyclopentyl)methyl, (1-methylcyclopropyl)methyl, ((1R,2S)-2-fluorocyclopropyl)methyl, ((1S,2R)-2-fluorocyclopropyl)methyl, ((1S,
  • R 1 is selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2- difluorocyclopropyl)methyl. In some embodiments, R 1 is selected from: (cyclopropyl)methyl, (3,3- difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2- difluorocyclopropyl)methyl. In some embodiments, R 1 is C 1 -C 6 -alkyl.
  • R 1 is C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, cyano, C 1 -C 4 - alkylsulfonyl, C 3 -C 6 -cycloalkyl, hydroxyl, C 1 -C 4 -alkoxy, and C 2 -C 4 -dialkylamino.
  • R 1 is C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from: halogen, hydroxyl, cyano, C 1 -C 4 -alkoxy, and C 1 -C 4 -alkylsulfonyl. In some embodiments, R 1 is C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from: halogen, hydroxyl, cyano, and C 1 -C 4 -alkoxy.
  • R 1 is C1-C6-alkyl optionally substituted with one, two, three, or four substituents selected from: halogen, hydroxyl, cyano, and C1-C4-alkoxy. In some embodiments, R 1 is C1-C5-alkyl optionally substituted with one, two, three, or four substituents selected from: halogen, hydroxyl, cyano, methoxy, and methylsulfonyl. In some embodiments, R 1 is C1-C5-alkyl optionally substituted with one, two, three, or four substituents selected from: halogen, hydroxyl, cyano, and methoxy.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl- d3, ethyl, ethyl-d5, isopropyl, pentyl, and neopentyl; wherein each group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl; wherein each group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, methoxy, and methylsulfonyl.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, methyl, methyl- d3, ethyl, ethyl-d5, isopropyl, pentyl, and neopentyl; wherein each group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and methoxy.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, methyl, ethyl, isopropyl, pentyl, and neopentyl; wherein each group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and methoxy.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- hydroxypropyl, ethyl, ethyl-d5, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, 2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, 2-methoxypropyl, 3-(methylsulfonyl)propyl, and 2-(methylsulfonyl)ethyl.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, methyl-d 3 , 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, and 2-methoxypropyl.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, 2-fluoropropyl, cyanomethyl, and 2-methoxypropyl.
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2- hydroxypropyl, ethyl, ethyl-d5, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluorobut
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2- hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2- hydroxypropyl, (S)
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2- hydroxypropyl, ethyl, ethyl-d5, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluorobut
  • R 1 is selected from: isobutyl, isopentyl, butyl, propyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, (R)-2- hydroxypropyl, ethyl, isopropyl, 3-fluoropropyl, 2-fluoroethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, fluoromethyl, neopentyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, cyanomethyl, (R)-3,3,3-trifluoro-2- hydroxypropyl, (S)
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, ethyl, and ethyl-d 5 . In some embodiments, R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl. In some embodiments, R 1 is C 3 -C 7 -cycloalkyl.
  • R 1 is C 3 -C 7 -cycloalkyl optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1- C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is C3-C7-cycloalkyl optionally substituted with one or more substituents selected from: cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, and C2-C4- dialkylamino. In some embodiments, R 1 is C3-C7-cycloalkyl optionally substituted with one or more substituents selected from: cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy.
  • R 1 is C3-C7-cycloalkyl optionally substituted with one or two substituents selected from: cyano, halogen, C1-C4-alkyl, C1-C4-haloalkyl, and C1-C4-alkoxy.
  • R 1 is C3-C5-cycloalkyl optionally substituted with one or two substituents selected from: cyano, halogen, methyl, C1-haloalkyl, methoxy, and dimethylamino.
  • R 1 is C3-C7-cycloalkyl optionally substituted with one or two substituents selected from: cyano, halogen, methyl, C1-haloalkyl, and methoxy.
  • R 1 is selected from: cyclopentyl, cyclobutyl, and cyclopropyl; wherein each group is optionally substituted with one or two substituents selected from: cyano, fluoro, methyl, trifluoromethyl, methoxy, and dimethylamino.
  • R 1 is selected from: cyclopentyl, cyclobutyl, and cyclopropyl; wherein each group is optionally substituted with one or two substituents selected from: cyano, fluoro, methyl, trifluoromethyl, and methoxy.
  • R 1 is selected from: cyclopentyl, cyclobutyl, cyclopropyl, 3- cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl)cyclobutyl, 3-methoxycyclobutyl, 3-(dimethylamino)cyclobutyl, and 3,3- difluorocyclobutyl.
  • R 1 is selected from cyclopentyl, cyclobutyl, cyclopropyl, 3- cyanocyclobutyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1-methylcyclobutyl, 3- (trifluoromethyl)cyclobutyl, 3-methoxycyclobutyl, and 3,3-difluorocyclobutyl.
  • R 1 is selected from: cyclopentyl, cyclobutyl, cyclopropyl, (1R,3r)-3- cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1- methylcyclobutyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (1s,3S)-3-methoxycyclobutyl, (1s,3S)-3- (dimethylamino)cyclobutyl, 3,3-difluorocyclobutyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3- (trifluoromethyl)cyclobutyl, (1r,3R)-3-methoxycyclobutyl, and (1r,3R)-3-(dimethylamino)cyclobutyl.
  • R 1 is selected from: cyclopentyl, cyclobutyl, cyclopropyl, (1R,3r)-3- cyanocyclobutyl, (1r,3R)-3-fluorocyclobutyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, 1- methylcyclobutyl, (1s,3S)-3-(trifluoromethyl)cyclobutyl, (1s,3S)-3-methoxycyclobutyl, 3,3- difluorocyclobutyl, (1S,3s)-3-cyanocyclobutyl, (1r,3R)-3-(trifluoromethyl)cyclobutyl, and (1r,3R)-3- methoxycyclobutyl.
  • R 1 is C 1 -C 4 -alkyl-O-C 2 -C 4 -alkylene. In some embodiments, R 1 is C1-C4-alkyl-O-C2-C4-alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is C1-C4-alkyl-O-C2-C4-alkylene optionally substituted with one or more substituents selected from: cyano, halogen, and C3-C6-cycloalkyl. In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene optionally substituted with one or more substituents selected from: cyano, halogen, and cyclopropyl. In some embodiments, R 1 is C1-C3-alkyl-O-C2-C3-alkylene optionally substituted with one, two, or three substituents selected from: cyano, halogen, and cyclopropyl.
  • R 1 is selected from: methoxyethyl, ((propyl)oxy)ethyl, and methoxypropyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, fluoro, and cyclopropyl.
  • R 1 is selected from: 2-(methoxy)ethyl, 2-methoxyethyl, 2-((propan-2- yl)oxy)ethyl, and 3-methoxypropyl; wherein each group is optionally substituted with one, two, or three substituents selected from: cyano, fluoro, and cyclopropyl.
  • R 1 is selected from: 2-(cyano(cyclopropyl)methoxy)ethyl, 2- methoxyethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 3-methoxypropyl, and 2-(trifluoromethoxy)ethyl.
  • R 1 is C3-C7-cycloalkyl-O-C2-C4-alkylene.
  • R 1 is C3-C7-cycloalkyl-O-C2-C4-alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is cyclopropoxyethyl.
  • R 1 is 3-7-membered-heterocyclyl.
  • R 1 is 3-7-membered-heterocyclyl optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C 1 -C 4 -alkylsulfonyl, C 3 -C 6 -cycloalkyl, hydroxyl, C 1 -C 4 -alkoxy, and C 2 -C 4 -dialkylamino.
  • R 1 is 3-7-membered-heterocyclyl optionally substituted with one or more C 1 -C 4 -alkyl substituents.
  • R 1 is 4-5-membered-heterocyclyl optionally substituted with one or more C 1 -C 4 -alkyl substituents. In some embodiments, R 1 is 4-5-membered-heterocyclyl optionally substituted with one C 1 - C 4 -alkyl substituent. In some embodiments, R 1 is 4-membered-heterocyclyl. In some embodiments, R 1 is oxetan-3-yl or pyrrolidin-3-yl; wherein each group is optionally substituted with one methyl substituent. In some embodiments, R 1 is oxetan-3-yl or 1-methylpyrrolidin-3-yl.
  • R 1 is 3-7-membered-heterocyclyl-C1-C4-alkylene. In some embodiments, R 1 is 3-7-membered-heterocyclyl-C1-C4-alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4- dialkylamino.
  • R 1 is 3-7-membered-heterocyclyl-C1-C4-alkylene optionally substituted with one or more C1-C4-alkyl substituents. In some embodiments, R 1 is (4-5-membered-heterocyclyl)CH2- optionally substituted with one or more methyl substituents. In some embodiments, R 1 is (4-membered-heterocyclyl)CH2- optionally substituted with one or more methyl substituents. In some embodiments, R 1 is (4-5-membered-heterocyclyl)CH2- optionally substituted with one methyl substituent.
  • R 1 is (4-membered-heterocyclyl)CH2- optionally substituted with one methyl substituent.
  • R 1 is (oxetanyl)methyl or (silolanyl)methyl; wherein each group is optionally substituted with one or two methyl substituents.
  • R 1 is selected from (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, and (silolan-3-yl)methyl; wherein each group is optionally substituted with one or two methyl substituents.
  • R 1 is (oxetan-3-yl)methyl or (oxetan-2-yl)methyl; wherein each group is optionally substituted with one methyl substituent.
  • R 1 is selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, (3- methyloxetan-3-yl)methyl, and (1,1-dimethylsilolan-3-yl)methyl.
  • R 1 is selected from: (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, and (3- methyloxetan-3-yl)methyl.
  • R 1 is selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (3- methyloxetan-3-yl)methyl, and (1,1-dimethylsilolan-3-yl)methyl. In some embodiments, R 1 is selected from: oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, and (3-methyloxetan-3-yl)methyl. In some embodiments, R 1 is C 4 -C 8 -bicycloalkyl-C 1 -C 4 -alkylene.
  • R 1 is C 4 -C 8 -bicycloalkyl-C 1 -C 4 -alkylene optionally substituted with one or more substituents selected from: halogen and C 1 -C 4 -haloalkyl.
  • R 1 is (C 5 -C 6 -bicycloalkyl)CH 2 - optionally substituted with one or more substituents selected from: fluoro and trifluoromethyl.
  • R 1 is (C 5 -C 6 -bicycloalkyl)CH 2 - optionally substituted with one substituent selected from: fluoro and trifluoromethyl.
  • R 1 is (bicyclo[1.1.1]pentanyl)methyl or (bicyclo[2.1.1]hexanyl)methyl; wherein each group is optionally substituted with one substituent selected from: fluoro and trifluoromethyl. In some embodiments, R 1 is (bicyclo[1.1.1]pentan-1-yl)methyl or (bicyclo[2.1.1]hexan-1- yl)methyl; wherein each group is optionally substituted with one substituent selected from: fluoro and trifluoromethyl.
  • R 1 is selected from: (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[1.1.1]pentan-1-yl)methyl, (bicyclo[2.1.1]hexan-1-yl)methyl, and (3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl.
  • R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is C4-C8-bicycloalkyl-C1-C4-alkylene optionally substituted with one or more halogen substituents.
  • R 1 is (C5-bicycloalkyl)CH2- optionally substituted with one or more fluoro substituents. In some embodiments, R 1 is (C5-bicycloalkyl)CH2- optionally substituted with one fluoro substituent. In some embodiments, R 1 is (bicyclo[1.1.1]pentanyl)methyl optionally substituted with one fluoro substituent. In some embodiments, R 1 is (bicyclo[1.1.1]pentan-1-yl)methyl optionally substituted with one fluoro substituent. In some embodiments, R 1 is C 4 -C 7 -cycloalkenyl.
  • R 1 is C4-C7-cycloalkenyl optionally substituted with one or more substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, cyano, C 1 - C 4 -alkylsulfonyl, C 3 -C 6 -cycloalkyl, hydroxyl, C 1 -C 4 -alkoxy, and C 2 -C 4 -dialkylamino.
  • R 1 is C 4 -C 7 -cycloalkenyl optionally substituted with one or more halogen substituents.
  • R 1 is C 4 -cycloalkenyl optionally substituted with one halogen substituent. In some embodiments, R 1 is cyclobutenyl optionally substituted with one fluoro substituent. In some embodiments, R 1 is cyclobut-2-en-1-yl optionally substituted with one fluoro substituent. In some embodiments, R 1 is 5-11-membered-spiro-heterocyclyl.
  • R 1 is 5-11-membered-spiro-heterocyclyl optionally substituted with one or more substituents selected from: cyano-C 1 -C 4 -alkylene, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, cyano, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is 5-11-membered-spiro-heterocyclyl.
  • R 1 is 7-membered-spiro-heterocyclyl. In some embodiments, R 1 is oxaspiro[3.3]heptanyl. In some embodiments, R 1 is C5-C11-spiro-cycloalkyl.
  • R 1 is C5-C11-spiro-cycloalkyl optionally substituted with one or more substituents selected from: cyano-C1-C4-alkylene, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C1- C4-alkylsulfonyl, C3-C6-cycloalkyl, hydroxyl, C1-C4-alkoxy, and C2-C4-dialkylamino.
  • R 1 is C5-C11-spiro-cycloalkyl.
  • R 1 is C7-spiro-cycloalkyl.
  • R 1 is spiro[3.3]heptanyl. In some embodiments, R 1 is cubanyl-C1-C4-alkylene. In some embodiments, R 1 is (cuban-1-yl)methyl. In some embodiments, R 1 is 4-8-membered-heterobicyclyl-C1-C4-alkylene. In some embodiments, R 1 is 6-membered-heterobicyclyl-CH2-. In some embodiments, R 1 is (2-oxabicyclo[2.1.1]hexanyl)methyl.
  • R 1 is (2-oxabicyclo[2.1.1]hexan-1-yl)methyl or (2- oxabicyclo[2.1.1]hexan-4-yl)methyl.
  • R 1 is selected from: C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 - alkyl-O-C 2 -C 4 -alkylene, 3-7-membered-heterocyclyl-C 1 -C 4 -alkylene, C 4 -C 8 -bicycloalkyl-C 1 -C 4 - alkylene, C 5 -C 11 -spiro-cycloalkyl, and cubanyl-C 1 -C 4 -
  • R 1 is selected from: C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkylene, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 - alkyl-O-C 2 -C 4 -alkylene, 3-7-membered-heterocyclyl-C 1 -C 4 -alkylene, C 4 -C 8 -bicycloalkyl-C 1 -C 4 - alkylene, and C 5 -C 11 -spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one or more substituents selected from: halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, C3-C6-cycloalkyl, and hydroxyl.
  • R 1 is selected from: R 1 is selected from: (C3-C5-cycloalkyl)CD2-, (C3- C5-cycloalkyl)CH2-, C1-C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, (4-membered- heterocyclyl)CH2-, (C5-C6-bicycloalkyl)CH2-, C7-spiro-cycloalkyl, and (cubanyl)CH2-; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.
  • R 1 is selected from: R 1 is selected from: (C3-C5-cycloalkyl)CH2-, C1- C5-alkyl, C3-C5-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, (4-membered-heterocyclyl)CH2-, (C5- bicycloalkyl)CH2-, and C7-spiro-cycloalkyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, spiro[3.3]heptanyl, (cubanyl)methyl, and (bicyclo[2.1.1]hexanyl)methyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, methyl, difluoromethyl, trifluoromethyl, cyano
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, ((propyl)oxy)ethyl, (oxetanyl)methyl, methoxypropyl, pentyl, (bicyclo[1.1.1]pentanyl)methyl, and spiro[3.3]heptanyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, ethyl-d 5 , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, 2-((propan-2-yl)oxy)ethyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, spiro[3.3]heptan-2-yl, (cuban-1-yl)methyl, and (bicyclo[2.1.1]hexan-1-yl)methyl; wherein each R 1 group is optionally substituted with one, two
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, 2-methoxyethyl, butyl, propyl, methyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, 2-((propan-2-yl)oxy)ethyl, (oxetan-2-yl)methyl, 3-methoxypropyl, pentyl, (bicyclo[1.1.1]pentan-1-yl)methyl, 2-(methoxy)ethyl, and spiro[3.3]heptan-2-yl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, methyl, difluoromethyl, trifluoromethyl, cyano, cyclopropyl, and hydroxyl.
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2- (cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1- fluorocyclopropyl)methyl, ethyl, ethyl-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3- fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 2,
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2- (cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1- fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2- cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, (oxetan-2
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3- difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3- fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2- difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, (2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, 3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, spiro[3.3]heptan-2-yl, (1- methylcyclopropyl)methyl, (2-fluoro
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2- (cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1- fluorocyclopropyl)methyl, ethyl, ethyl-d 5 , isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , 3- fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, but
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, (1-fluorocyclobutyl)methyl, cyclobutyl, 2- (cyano(cyclopropyl)methoxy)ethyl, butyl, propyl, (1-hydroxycyclobutyl)methyl, 2-fluoro-2- methylpropyl, methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1- fluorocyclopropyl)methyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2- cyanopropan-2-yl)oxy)ethyl, 2,2-difluoroethyl, ((R)-ox
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, ethyl-d5, isopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3-fluoropropyl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl, (3,3- difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, (1s,3S)-3-fluoro
  • R 1 is selected from: (cyclopentyl)methyl, isobutyl, cyclopentyl, (cyclobutyl)methyl, isopentyl, cyclobutyl, butyl, propyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, isopropyl, (cyclopropyl)methyl, 3-fluoropropyl, 2,2- difluoroethyl, 4,4,4-trifluorobutyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2- difluorocyclopropyl)methyl, ((R)-2,2-difluorocyclopropyl)methyl, (2-methylcyclopropyl)methyl, (1s,3S)-3-fluorocyclobutyl, 3,3-dimethylcyclobutyl, s
  • R 1 is selected from: C3-C7-cycloalkyl-C1-C4-alkylene, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4- alkyl-O-C2-C4-alkylene, 3-7-membered-heterocyclyl, 3-7-membered-heterocyclyl-C1-C4-alkylene, and C4-C8-bicycloalkyl-C1-C4-alkylene; wherein each R 1 group is optionally substituted with one or more substituents selected from: halogen, C1-C4-haloalkyl, cyano, and hydroxyl.
  • R 1 is selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-CD2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered-heterocyclyl, (4- membered-heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-; wherein each R 1 group is optionally substituted with one or more substituents selected from: halogen, C1-haloalkyl, cyano, and hydroxyl.
  • R 1 is selected from: (C3-C4-cycloalkyl)CH2-, C1-C5-alkyl, C3-C4- cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered-heterocyclyl, (4-membered- heterocyclyl)CH2-, (C5-bicycloalkyl)CH2-; wherein each R 1 group is optionally substituted with one or more substituents selected from: halogen, C1-haloalkyl, cyano, and hydroxyl.
  • R 1 is selected from: (C3-C4-cycloalkyl)CH2-, C3-C4-cycloalkyl-CD2-, C1-C5-alkyl, C3-C4-cycloalkyl, C1-C3-alkyl-O-C2-C3-alkylene, 4-membered-heterocyclyl, and (4- membered-heterocyclyl)CH2-; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: halogen, C1-haloalkyl, cyano, and hydroxyl.
  • R 1 is selected from: (C 3 -C 4 -cycloalkyl)CH 2 -, C 1 -C 5 -alkyl, C 3 -C 4 - cycloalkyl, C 1 -C 3 -alkyl-O-C 2 -C 3 -alkylene, 4-membered-heterocyclyl, (4-membered- heterocyclyl)CH 2 -, (C 5 -bicycloalkyl)CH 2 -; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: halogen, C 1 -haloalkyl, cyano, and hydroxyl.
  • R 1 is selected from: methyl, methyl-d 3 , propyl, ethyl, ethyl-d 5 , cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, and pentyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and difluoromethyl.
  • R 1 is selected from: methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, methoxyethyl, ((propyl)oxy)ethyl, oxetanyl, (oxetanyl)methyl, butyl, methoxypropyl, (cyclobutyl)methyl, pentyl, and (bicyclo[1.1.1]pentanyl)methyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and difluoromethyl.
  • R 1 is selected from: methyl, methyl-d3, propyl, ethyl, ethyl-d5, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, isopropyl, 2-methoxyethyl, 2-((propan-2- yl)oxy)ethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, butyl, 3-methoxypropyl, (cyclobutyl)methyl, and pentyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and difluoromethyl.
  • R 1 is selected from: methyl, propyl, ethyl, cyclopropyl, (cyclopropyl)methyl, isopropyl, 2-methoxyethyl, 2-((propan-2-yl)oxy)ethyl, oxetan-3-yl, (oxetan-3- yl)methyl, (oxetan-2-yl)methyl, butyl, 3-methoxypropyl, (cyclobutyl)methyl, pentyl, and (bicyclo[1.1.1]pentan-1-yl)methyl; wherein each R 1 group is optionally substituted with one, two, three, or four substituents selected from: fluoro, hydroxyl, cyano, and difluoromethyl.
  • R 1 is selected from: methyl, methyl-d3, 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, ethyl-d 5 , isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , 3- fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluor
  • R 1 is selected from: methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, 2-hydroxypropyl, ethyl, isopropyl, 2- methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, (oxetan-3-yl)methyl, (oxetan-2-yl)methyl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3,3- difluorocyclobutyl)
  • R 1 is selected from: methyl, methyl-d 3 , 2,2-difluoropropyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, ethyl-d5, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, 3- fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2-yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2- difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)-oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2- hydroxyprop
  • R 1 is selected from: methyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, (1-fluorocyclopropyl)methyl, (R)-2-hydroxypropyl, ethyl, isopropyl, 2-methoxyethyl, (cyclopropyl)methyl, 3-fluoropropyl, 2-fluoroethyl, 2-((2-cyanopropan-2- yl)oxy)ethyl, 1,1,1-trifluoropropan-2-yl, 2,2-difluoroethyl, oxetan-3-yl, oxetan-3-ylmethyl, ((R)- oxetan-2-yl)methyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluorobutyl, 3-methoxypropyl, (3
  • R 1 is selected from: C1-C6-alkyl, C3-C7-cycloalkyl, and C3-C7-cycloalkyl-C1-C4-alkylene; wherein each group is optionally substituted with one or more halogen substituents.
  • R 1 is selected from: C1-C6-alkyl, C3-C7-cycloalkyl, and C3-C7- cycloalkyl-C1-C4-alkylene; wherein each group is optionally substituted with one, two, or three halogen substituents.
  • R 1 is selected from: C 2 -C 3 -alkyl, cyclopropyl, C 3 -C 4 -cycloalkyl-CD 2 -, and C 3 -C 4 -cycloalkyl-CH 2 -; wherein each group is optionally substituted with one, two, or three halogen substituents.
  • R 1 is selected from: C 2 -C 3 -alkyl, cyclopropyl, and C 3 -C 4 -cycloalkyl- CH 2 -; wherein each group is optionally substituted with one, two, or three halogen substituents.
  • R 1 is selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two, or three halogen substituents. In some embodiments, R 1 is selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two, or three halogen substituents.
  • R 1 is selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two, or three fluoro substituents. In some embodiments, R 1 is selected from: ethyl, propyl, cyclopropyl, (cyclopropyl)methyl, and (cyclobutyl)methyl; wherein each group is optionally substituted with one, two, or three fluoro substituents.
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, and (2,2- difluorocyclopropyl)methyl.
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (cyclopropyl)methyl-d2, (3,3-difluorocyclobutyl)methyl, ((S)-2,2-difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, ethyl, (cyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, ((S)-2,2- difluorocyclopropyl)methyl, and ((R)-2,2-difluorocyclopropyl)methyl.
  • R 1 is C3-C7-cycloalkyl-C1-C4-alkylene optionally substituted with one or two halogen substituents.
  • R 1 is selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents. In some embodiments, R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents. In some embodiments, R 1 is selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two fluoro substituents.
  • R 1 is (cyclopropyl)methyl or (cyclobutyl)methyl; wherein each group is optionally substituted with one or two fluoro substituents.
  • R 1 is selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d 2 , (3,3-difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.
  • R 1 is selected from: (cyclopropyl)methyl, (3,3- difluorocyclobutyl)methyl, and (2,2-difluorocyclopropyl)methyl.
  • R 1 is selected from: (cyclopropyl)methyl, (cyclopropyl)methyl-d2, and (cyclobutyl)methyl; wherein each group is optionally substituted with one or two halogen substituents.
  • R 1 is C1-C6-alkyl optionally substituted with one, two, or three halogen substituents.
  • R 1 is ethyl or propyl; wherein each group is optionally substituted with one, two, or three halogen substituents.
  • R 1 is ethyl or propyl; wherein each group is optionally substituted with one, two, or three fluoro substituents.
  • R 1 is selected from: 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and ethyl. In some embodiments, R 1 is C3-C7-cycloalkyl. In some embodiments, R 1 is cyclopropyl. Some embodiments include every combination of one or more compounds and pharmaceutically acceptable salts thereof selected from the following group of compounds shown in Table A. Some embodiments include every combination of one or more compounds selected from the following group shown in Table A. Table A 1 Mixture of trans isomers (cyclopropyl). 2 Mixture of cis isomers (cyclopropyl).
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9- (cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1); (2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (Compound 2); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (2R,3R,
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9- (cyclopentylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 1); (2R,3R,11bR)-3-(tert-butoxy)-9-isobutoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (Compound 2); (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopentyloxy)-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 3); (2R,3R,
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group: (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy- d2)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 99); (2R,3R,11bR)-3-(tert-butoxy)-9-(cuban-1-ylmethoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (Compound 100); (2R,3R,11bR)-9-(bicyclo[1.1.1]pentan-1- ylmethoxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-
  • the compound is selected from the group consisting of: 3-(tert- butoxy)-4-(dimethylamino)butan-2-one; 1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin- 1-yl)-3-(tert-butoxy)propan-2-one; 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one; 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol; and 3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2
  • the compound is: 3-(tert-butoxy)-4-(dimethylamino)butan-2-one, or a salt thereof: .
  • the compound is: (R)-3-(tert-butoxy)-4-(dimethylamino)butan-2-one, or a salt thereof.
  • the compound is: (S)-3-(tert-butoxy)-4-(dimethylamino)butan-2-one, or a salt thereof.
  • the compound is selected from the group consisting of: 1-(6- (benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one; 9- (benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2- one; 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol; and 3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinoline-2,9-diol; or a salt thereof.
  • the compound is: 1-(6-(benzyloxy)-7-methoxy-1,2,3,4- tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one, or a salt thereof: .
  • the compound is: (R)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4- tetrahydroisoquinolin-1-yl)-3-(tert-butoxy)propan-2-one, or a salt thereof.
  • the compound is: (S)-1-(6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-(tert- butoxy)propan-2-one, or a salt thereof.
  • the compound is: 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, or a salt thereof.
  • the compound is: (3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-one, or a salt thereof: .
  • the compound is: (3S,11bS)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, or a salt thereof.
  • the compound is: 9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a salt thereof.
  • the compound is: (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-ol, or a salt thereof: .
  • the salt is a (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt.
  • the compounds is: .
  • the compound is: (2S,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a salt thereof.
  • the compound is: (2R,3S,11bS)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-ol, or a salt thereof.
  • the compound is: (2S,3S,11bS)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol, or a salt thereof.
  • the compound is: 3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol; or a salt thereof.
  • the compound is: (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinoline-2,9-diol (Compound 2-22); or a salt thereof: .
  • the compound is: (2S,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol; or a salt thereof.
  • the compound is: (2R,3S,11bS)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinoline-2,9-diol; or a salt thereof.
  • the compound is: (2S,3S,11bS)-3- (tert-butoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol; or a salt thereof. It is further appreciated that certain features, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
  • the present disclosure further provides for pharmaceutical products, such as, pharmaceutical compositions, formulations, unit dosage forms, and kits; each comprising a compound, as described herein, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical compositions comprising a compound, as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in the methods described here, such as, for treating hyperkinetic movement disorders.
  • a pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance; an excipient also can be called a carrier.
  • compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to an VMAT2 inhibitor, diluents, dispersing and surface active agents, binders, and lubricants.
  • VMAT2 inhibitor in an appropriate manner, and in accordance with accepted practices, such as, those disclosed in Remington, supra.
  • Methods of administration include systemic administration of a VMAT2 inhibitor described herein, preferably in the form of a pharmaceutical composition as discussed above.
  • systemic administration includes oral and parenteral methods of administration.
  • suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions.
  • compositions for oral administration can be obtained by any suitable method, typically by uniformly mixing the compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, processing the mixture, after adding suitable auxiliaries, if desired, forming the resulting mixture into a desired shape to obtain tablets or dragee cores.
  • Conventional excipients such as, binding agents, fillers, adjuvant, carrier, acceptable wetting agents, tableting lubricants, and disintegrants can be used in tablets and capsules for oral administration.
  • Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
  • the oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use.
  • Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filter sterilizing the solution before lyophilization, or simply filling and sealing an appropriate vial or ampule.
  • Some embodiments provide methods for preparing a pharmaceutical composition comprising the step of admixing a compound, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to the drug substance such carriers as are known in the art to be appropriate.
  • the drug substance is typically mixed (i.e., admixed) with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the drug substance.
  • compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • an excipient can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions.
  • preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • a low melting wax such as, an admixture of fatty acid glycerides or cocoa butter
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the pharmaceutical compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulatory agents, such as, suspending, stabilizing and/or dispersing agents.
  • the pharmaceutical compositions can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the pharmaceutical compositions can be formulated as an aqueous solution, an aqua- alcoholic solution, a solid suspension, an emulsion, a liposomal suspension, or a freeze-dried powder for reconstitution.
  • Such pharmaceutical compositions can be administered directly or as an admixture for further dilution/reconstitution.
  • Route of administration includes intravenous bolus, intravenous infusion, irrigation, and instillation.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided drug substance in water with viscous material.
  • the compounds described herein, or pharmaceutically acceptable salts thereof can be formulated as gels, ointments, creams, or lotions, or as a transdermal patch.
  • formulations suitable for topical administration in the mouth include lozenges comprising drug substance in a flavored base. Solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette, or spray.
  • the formulations can be provided in single or multi- dose form. In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved for example by means of a metering atomizing spray pump. Administration to the respiratory tract can also be achieved by means of an aerosol formulation provided in a pressurized pack with a suitable propellant.
  • the compounds described herein, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler, or a dry powder inhaler.
  • the pharmaceutical composition can be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable, powder base, such as, lactose, starch, starch derivatives. Conveniently the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compounds, as described herein, or pharmaceutically acceptable salts thereof, can also be administered via a rapid dissolving or a slow-release composition, wherein the composition includes a biodegradable rapid dissolving or slow-release carrier.
  • the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the drug substance.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the pharmaceutical preparation is a tablet or capsule for oral administration.
  • the pharmaceutical preparation is a liquid formulated for intravenous administration.
  • the compositions can be formulated in a unit dosage form, each dosage containing the drug substance or equivalent mass of the drug substance.
  • unit dosage forms refers to physically discrete units of a formulation suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable excipient, as described herein.
  • the liquid forms including the drug substance can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils.
  • the pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques, or can be sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable excipients as described herein.
  • compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • the compositions may, if desired, be presented in a pack or dispenser device which may contain one or more-unit dosage forms containing the drug substance.
  • the pack may for example comprise metal or plastic foil, such as, a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice for example, can be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the drug substance can be mixed with an excipient to form a solid preformulation composition containing a homogeneous mixture of components.
  • kits with unit doses of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, usually in oral or injectable doses are provided.
  • Such kits can include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating pathological condition of interest, and optionally an appliance or device for delivery of the composition.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof can be effective over a wide dosage range and are generally administered in a therapeutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like.
  • the amount of compound or composition administered to a subject will also vary depending upon what is being administered, the purpose of the administration, such as, prophylaxis or therapy, the state of the subject, the manner of administration, and the like.
  • compositions can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptomology and/or pathology of the disease and its complications.
  • Therapeutically effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors, such as, the severity of the disease, the age, weight, and general condition of the subject, and the like.
  • the desired dose may conveniently be presented in a single dose or presented as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day.
  • the sub-dose itself can be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example two, three, or four-part administrations. If appropriate, depending on individual behavior, it can be necessary to deviate upward or downward from the daily dose indicated.
  • a “preparation” is the product of a process used to make or isolate a compound as disclosed and described herein, wherein the preparation contains at least one other component in addition to the compound.
  • the preparation comprises a chemical entity.
  • a “chemical entity” defined in the context of a “preparation,” refers to a compound as disclosed and described herein and at least one other component in addition to the compound.
  • a chemical entity can be a co-crystal or salt of a compound as disclosed and described herein.
  • Some embodiments provide a preparation comprising a compound as disclosed and described herein.
  • the compound is a component of a chemical entity.
  • the chemical entity is a salt of a compound as disclosed and described herein.
  • the chemical entity is a (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid (DPTTA) salt of a compound as disclosed and described herein.
  • DPTTA (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid
  • the compound of the preparation is in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% enantiomeric excess, or an enantiomeric excess within a range defined by any of the preceding numbers. In some embodiments, the compound of the preparation is in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% enantiomeric excess, or an enantiomeric excess within a range defined by any of the preceding numbers.
  • the compound of the preparation is in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% diastereomeric excess, or a diastereomeric excess within a range defined by any of the preceding numbers. In some embodiments, the compound of the preparation is in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% diastereomeric excess, or a diastereomeric excess within a range defined by any of the preceding numbers.
  • the preparation comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 93% by weight of the compound, or a % by weight within a range defined by any of the preceding numbers. In some embodiments, the preparation comprises at least 50%, 60%, 70%, 80%, 90%, or 93% by weight of the compound, or a % by weight within a range defined by any of the preceding numbers. In some embodiments, the preparation comprises at most 50%, 60%, 70%, 80%, 90%, 93%, or 95% by weight of the compound, or a % by weight within a range defined by any of the preceding numbers. In some embodiments, the preparation comprises at least 50% by weight of the compound.
  • the preparation is in the form of a solid, i.e., a solid preparation.
  • the preparation is used to prepare a pharmaceutical composition.
  • METHODS OF USE The compounds, as described herein, are inhibitors of VMAT2.
  • the present disclosure includes a method of inhibiting VMAT2 (i.e., decreasing at least one function of VMAT2 or decreasing expression of VMAT2) by contacting the VMAT2 with a compound as disclosed and described herein, or a pharmaceutically acceptable salt thereof.
  • the contacting can occur in vitro, such as, where the VMAT2 is located in a purified preparation or in a cell outside of a living organism (e.g., in a tissue sample or a cellular preparation).
  • the contacting can occur in vivo, such as, where the VMAT2 is located in a living organism.
  • the VMAT2 inhibitors described herein can reduce the level of monoamines in the central nervous system. Accordingly, the present disclosure includes a method of reducing the level of monoamines in the central nervous system of a subject comprising administering to the subject an amount of a compound, as described herein, or a pharmaceutically acceptable salt thereof, sufficient to lower the level of monoamines relative to the level prior to administration.
  • the VMAT2 inhibitors as disclosed and described herein are believed to have utility over a wide range of therapeutic applications, and may be used to treat or prevent a variety of disorders which are caused by or linked to inhibition of the human vesicular monoamine transporter isoform 2.
  • disorders include neurological and psychiatric disorders, for example, hyperkinetic movement disorders, schizophrenia, and mood disorders.
  • a compound, as described herein, or a pharmaceutically acceptable salt thereof can be used in any of the therapeutic methods disclosed and described herein. Accordingly, in various embodiments as disclosed herein, methods are provided for treating or preventing a neurological and/or psychiatric disease or disorder in a subject in need thereof by administering to the subject a pharmaceutically effective amount of a VMAT2 inhibitor as described herein, or a pharmaceutically acceptable salt thereof.
  • the neurological and/or psychiatric disease or disorder can be, for example, a hyperkinetic movement disorder, schizophrenia, schizoaffective disorder, a mood disorder, treatment-refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer’s disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder (e.g., restricted and repetitive behaviors associated with Autism spectrum disorder (ASD)), Rett syndrome, or chorea-acanthocytosis.
  • a hyperkinetic movement disorder schizophrenia, schizoaffective disorder, a mood disorder, treatment-refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer’s disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder (e.g., restricted and repetitive behaviors associated with Autism spectrum disorder (ASD)), Rett
  • VMAT2 vesicular monoamine transporter-2
  • the VMAT2 disease or disorder can be, for example, an ataxias or spinal muscular atrophy; a chorea; a congenital malformation, deformation, or abnormality; a dementia; an oral cavity, salivary gland, or jaw disease; a dyskinesia; a dystonia; an endocrine, nutritional, or metabolic disease; an epilepsy; a habit or impulse disorder; a Huntington’s disease or related disorder; a mood or psychotic disorder; a neurotic, stress-related, and somatoform disorder; a degenerative disease of the basal ganglia; an extrapyramidal and movement disorder; a neurological or psychiatric disease or disorder; a nervous system or motor function disorder; a Parkinson’s/parkinsonism disorder; a pediatric-onset behavioral and emotional disorder; a pervasive developmental disorder; and a substance abuse or dependence disorder.
  • a chorea a congenital malformation, deformation, or abnormality
  • a dementia an oral cavity, salivary gland, or jaw disease
  • a hyperkinetic movement disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the hyperkinetic movement disorder is tardive dyskinesia, Tourette's syndrome, Huntington's disease, chorea associated with Huntington’s disease, or tics.
  • the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, myoclonus, restless leg syndrome, or tremors.
  • methods are provided for treating or preventing a mood disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the mood disorder is bipolar disorder, major depressive disorder, mania in a mood disorder, or depression in a mood disorder.
  • methods are provided for treating or preventing schizophrenia or schizoaffective disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a VMAT2 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
  • the hyperkinetic movement disorder is tardive dyskinesia. In some embodiments, the hyperkinetic movement disorder is Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder is Huntington's disease. In some embodiments, the hyperkinetic movement disorder is tics. In some embodiments, the hyperkinetic movement disorder is chorea associated with Huntington's disease. In some embodiments, the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, Huntington's disease, myoclonus, restless leg syndrome, or tremors. In some embodiments, the neurological or psychiatric disease or disorder is selected from schizophrenia and schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.
  • the neurological or psychiatric disease or disorder is schizoaffective disorder. In some embodiments, the neurological or psychiatric disease or disorder is obsessive- compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is treatment- refractory obsessive-compulsive disorder. In some embodiments, the neurological or psychiatric disease or disorder is autism spectrum disorder. In some embodiments, the neurological or psychiatric disease or disorder is restricted and repetitive behaviors associated with Autism spectrum disorder (ASD).
  • ASSD Autism spectrum disorder
  • the neurological or psychiatric disease or disorder is obsessions and compulsions in partial and non-responders (or completely refractory) with obsessive-compulsive disorder (OCD).
  • the neurological or psychiatric disease or disorder is obsessions and compulsions in partial and non-responders (or completely refractory) with obsessive- compulsive disorder (OCD) and the compounds described herein are administered as adjunctive therapy.
  • compounds described herein are useful as an adjunctive therapy or adjunctive treatment of schizophrenia.
  • the compounds described here are administered as adjunctive therapy with the primary therapy being treatment with antidepressants.
  • the neurological or psychiatric disease or disorder is Bipolar I Disorder.
  • the compound described herein is administered as monotherapy for the treatment of Bipolar I Disorder.
  • the compound described herein is administered as maintenance therapy for the treatment of Bipolar I Disorder.
  • the compound described herein is administered as monotherapy maintenance therapy for the treatment of Bipolar I Disorder.
  • the compound, as described herein, or a pharmaceutically acceptable salt thereof is administered to the patient to treat or prevent a disease or disorder selected from: ataxias or spinal muscular atrophies, such as, spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, bulbospinal muscular atrophy congenital, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia; chorea, such as, benign hereditary chorea, chorea, chorea associated with mitochondrial disease/causes, chorea associated with Wilson's disease, chorea gravidarum, chorea-acanthocytosis, drug-induced chorea, hemiballism, rheumatic/Sydenham's chorea, and thyrotoxic chorea/hyperthyroid chorea
  • the compound, as described herein, or a pharmaceutically acceptable salt thereof is administered to the patient to treat or prevent a palsy.
  • the palsy is selected from: spastic cerebral palsy (including, but not limited to, spastic hemiplegia cerebral palsy, spastic diplegia cerebral palsy, and spastic quadriplegia cerebral palsy), dyskinetic cerebral palsy, ataxic cerebral palsy, and “mixed types” cerebral palsy.
  • the palsy is spastic cerebral palsy.
  • the palsy is dyskinetic cerebral palsy.
  • the palsy is ataxic cerebral palsy.
  • the palsy is “mixed types” cerebral palsy.
  • the phrase “mixed types” cerebral palsy includes a mix of symptoms associated with other types of cerebral palsies.
  • the patient which is treated has been determined to have 22q11.2 deletion syndrome.
  • the patient is predisposed to developing a psychiatric disorder due to the patient having 22q11.2 deletion syndrome.
  • the patient has been determined to have COMT haploinsufficiency.
  • the patient is predisposed to developing a psychiatric disorder due to the patient having COMT haploinsufficiency.
  • the VMAT2 inhibitors described herein may be hydrolyzed in the body of a mammal to compounds that may inhibit the human vesicular monoamine transporter isoform 2.
  • these VMAT2 inhibitors may have additional utility in altering the in vivo properties of the metabolite in a mammal, such as, the maximum concentration or duration of action. Characterizing any of the VMAT2 inhibitors described herein may be determined using methods described herein, and those in the art. For example, dopamine depletion may be determined using the locomotor activity (LMA) assay.
  • LMA locomotor activity
  • Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has been shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds.
  • CAR conditioned avoidance response
  • a compound, as described herein, or its pharmaceutically acceptable salt is administered together with (simultaneously or sequentially) one or more pharmaceutical agents selected from antidepressants, antipsychotics (typical or atypical), antiepileptics, antimicrobials, antiarrhythmics, mood stabilizers, and gastrointestinal drugs.
  • a compound, as described herein, or a pharmaceutically acceptable salt thereof is used in adjunctive therapy which refers to a treatment that is used in conjunction with a primary treatment and its purpose is to assist the primary treatment.
  • Adjunctive therapies are typically co-administered therapies.
  • the primary therapy may be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy.
  • COMPOUND SYNTHESIS Detailed compound synthesis methods are described herein in the Examples. In general, starting components are commercially available chemicals and may be obtained from commercial sources or may be made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.
  • the compounds used in the reactions described herein may be made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. Methods known to one of ordinary skill in the art may be identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present disclosure, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A.
  • Supercritical fluid chromatography purification was performed using a Waters TM Prep 100q TM system, equipped with a UV Detector (Waters TM 2998 Photodiode Array Detector TM ) and mass spectrometer (Waters TM Acquity QDa Detector TM ).
  • a Waters TM Viridis TM BEH 2-Ethylpyridine 130 ⁇ 5 ⁇ m, 30 mm x 100 mm column was used with a CO2 and 0.3% NH 4 OH in MeOH gradient, run at 100 mL/min, 40°C, and 105 bar back pressure regulator. All final compounds were analyzed by analytical HPLC, and peaks were monitored at 210, 254, and 280 nm for purity.
  • Step 1 Preparation of N,N,N-trimethyl-3-oxobutan-1-aminium iodide (Compound 2-2).
  • a solution of 4-(dimethylamino)butan-2-one (Compound 2-1, 15.0 g, 130 mmol, 1.0 eq) in EtOAc (260 mL) was added methyl iodide (55.4 g, 390 mmol, 3.0 eq) and the mixture was stirred overnight at room temperature (RT).
  • Step 2 Preparation of ( ⁇ )-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-one (Compound 2-4).
  • MeOH 6 mL
  • N,N,N-trimethyl-3-oxobutan-1-aminium iodide Compound 2- 2, 13.3 g, 51.8 mmol, 1.5 eq
  • Step 4 Preparation of ( ⁇ )-sodium (9,10-dimethoxy-2-oxo-1,6,7,11b-tetrahydro-2H- pyrido[2,1-a]isoquinolin-3(4H)-ylidene)methanolate(Compound 2-6).
  • ( ⁇ )-3-((dimethylamino)methylene)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-one (Compound 2-5, 4.19 g, 13.2 mmol, 1.0 eq) in water (80 mL) was added aq.
  • Step 5 Preparation of ( ⁇ )-3-diazo-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-one (Compound 2-7).
  • Step 6 Preparation of ( ⁇ )-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-one (Compound ( ⁇ )-2-8).
  • Step 7 Preparation of ( ⁇ )-3-(tert-butoxy)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-9) and isolation of Compound 15, Compound 76, Compound 77, and Compound 78.
  • Chiral compound separation was performed using a Pic Solution TM SFC-PICLAB-Prep 200 TM supercritical fluid chromatography (SFC) system, equipped with a UV Detector and an Advion TM mass spectrometer.
  • SFC supercritical fluid chromatography
  • a Chiral Technologies Inc TM ChiralPak TM IG/SFC 5 ⁇ m, 20 mm x 250 mm column was used with an isocratic gradient at 85% CO 2 and 15% 0.5% DMEA in MeOH, at 150 mL/min, 55°C, and 110 bar back pressure regulator.
  • EXAMPLE 2 Preparation of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2-21).
  • Step 1 Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15). To a mixture of ethyl 4-(tert-butoxy)-3-oxobutanoate (Compound 2-14, 39.4 g, 195 mmol, 1.0 eq) and water (600 mL) was added aq.
  • Step 3A Preparation of ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-19).
  • Step 3B Preparation of ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-19).
  • Step 3C Preparation of ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-20). Diastereomerically pure Compound ( ⁇ )-2-20 could be obtained by chromatography of Compound ( ⁇ )-2-19 (0.432 g, 1.05 mmol, 1.4:1 dr).
  • Step 4 Preparation of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2-21).
  • EXAMPLE 3 Preparation of the salt of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol and (2S,3S)-2,3-bis(4- methylbenzoyloxy)butanedioic acid (Compound 2-21 ⁇ DPTTA).
  • the crystal structure of Compound 2-21 ⁇ DPTTA was determined to be a mixed ethanol and methanol solvate with formula C25H34NO4 ⁇ C20H17O8 ⁇ 0.851(C2H6O) ⁇ 0.149(CH4O).
  • the solvate was refined as disordered between majority ethanol and minority methanol.
  • Chiral centers at N1 (protonated), C2, C3, and C5 were all determined to have R configuration.
  • Chiral centers at C27 and C28 (O,O′-di-p-toluoyl-tartaric acid) both have S configuration.
  • the unit system and space group for Compound 2-21 ⁇ DPTTA are shown in Table 1.
  • Data collection and refinement parameters for Compound 2-21 ⁇ DPTTA are shown in Table 2.
  • EXAMPLE 4A Preparation of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline hydrochloride (Compound 2-16). To a solution of 6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline (23.2 g, 86.6 mmol, 1.0 eq) in 1:1 MTBE/THF (230 mL) was added HCl (4M in dioxanes, 22.7 mL, 91.0 mmol, 1.05 eq) dropwise at rt over the course of 20 minutes. The mixture was stirred 16h at RT.
  • EXAMPLE 4C Preparation of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22).
  • Step 1 Preparation of 4-(tert-butoxy)-3-oxobutanoic acid (Compound 2-15).
  • Step 3 Preparation of 3-(tert-butoxy)-4-(dimethylamino)butan-2-one (Compound 2-26).
  • 1-(tert-butoxy)propan-2-one Compound 2-25, 55.1 g, 423.3 mmol, 1.0 eq
  • EtOH 275 mL
  • dimethylamine hydrochloride 51.8 g, 635 mmol, 1.5 eq
  • paraformaldehyde (25.4 g, 847 mmol, 2.0 eq)
  • HCl (12.1 N, 1.75 mL, 21.2 mmol, 0.05 eq
  • Step 5 Preparation of ( ⁇ )-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound ( ⁇ )-2-19).
  • Step 6 Preparation of (2R,3R,11bR)-9-(benzyloxy)-3-(tert-butoxy)-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 2-21).
  • Step 6 Preparation of (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinoline-2,9-diol (Compound 2-22).
  • 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.056 g, 0.243 mmol, 1.3 eq) was added and the mixture was stirred for 3h. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
  • a solution of lithium aluminum hydride in THF (2 M, 0.40 mL, 0.810 mmol, 2.25 eq) was added dropwise over 10 min. The temperature was increased to 60°C and stirred for 3h. An additional portion of lithium aluminum hydride in THF (2 M, 0.18 mL, 0.360 mmol, 1.0 eq) was added and the mixture was stirred overnight at 60°C. The mixture was cooled to 0°C then sodium sulfate decahydrate (0.116 g, 0.360 mmol, 1.0 eq) was added over the course of 10 min then allowed to stir 20 min. The mixture was filtered over celite, the filter cake was rinsed with EtOAc, and the solvent was removed in vacuo.
  • (2R)-2-(bromomethyl)-1,1-difluorocyclopropane (0.070 g, 0.411 mmol, 1.5 eq) was added and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and rinsed five times with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
  • EXAMPLE 12 Preparation of (2R,3R,11bR)-3-(tert-butoxy)-9-(((R)-2,2- difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol (Compound 44).
  • (2S)-2-(bromomethyl)-1,1-difluorocyclopropane (0.104 g, 0.606 mmol, 1.5 eq) was added and the mixture was stirred at RT overnight.
  • the mixture was diluted with EtOAc and rinsed five times with water.
  • the organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo.
  • EXAMPLE 12A Preparation of (2R,3R,11bR)-3-(tert-butoxy)-9-isopropoxy-10-methoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 23).
  • EXAMPLE 12B Preparation of (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy-d 2 )-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 99).
  • Step 1 Preparation of (iodomethyl-d2)cyclopropane.
  • reaction mixture was stirred at RT for 30 min.
  • Imidazole (2.40 g, 35.3 mmol, 1.5 eq) and cyclopropylmethan-d2-ol (1.74 g, 23.5 mmol, 1.0 eq) were sequentially added at RT.
  • the reaction mixture was stirred at RT for 16 h.
  • the mixture was quenched with saturated aq. Na 2 S 2 O 3 .
  • the aqueous layer was extracted three times with diethyl ether.
  • the combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of (2R,3R,11bR)-3-(tert-butoxy)-9-(cyclopropylmethoxy-d 2 )-10- methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (Compound 99).
  • EXAMPLE 13 Reagents used in the preparation of certain compounds described in Table A. Additional compounds shown in Table A were prepared using similar methods as described in the above examples and the following reagents shown in Table 3. Table 3 also provides the observed (Obs) ion m/z ratio for the title compound. Table 3
  • EXAMPLE 14 Methods for Determining VMAT2 Inhibitory Activity of a Compound. Examples of techniques for determining the capability of a compound to inhibit VMAT2 are provided below. The procedure was adapted from that described previously (see, e.g., Near, (1986), Mol. Pharmacol.30: 252-57; Teng, et al., J. Neurochem.71, 258-65, 1998). Homogenates from human platelets were prepared by homogenization and then washed by centrifugation as described previously (see, e.g., Hoare et al., (2003) Peptides 24:1881-97). The human VMAT2 K i values for the compounds listed in Table A were determined using the following procedures.
  • the Ki value for each compound was calculated using the Cheng-Prusoff equation, utilizing a Kd of 4.06 nM for 3 H- dihydrotetrabenezine.
  • Compound Ki (nM) values are provided in Table 4.
  • Table 4 NT Not Tested 1 Assayed as a mixture of trans isomers (cyclopropyl). 2 Assayed as a mixture of cis isomers (cyclopropyl).
  • EXAMPLE 15 VMAT2 Inhibitor-Induced Reduction of Open-Field Hypolocomotor Activity. The effect of VMAT2 inhibitors on dopamine depletion was measured using the locomotor activity (LMA) assay.
  • Rat locomotor activity was detected by automated counting of successive beam breaks and activity is defined as the number of beam breaks in 60 min. Data was analyzed by one-way analysis of variance (ANOVA; GraphPad Prism) followed by Dunnett’s post-hoc test for significance.
  • the ED 50 was calculated for (2R,3R,11bR)-3-(tert-butoxy)-10-methoxy-9-(3,3,3-trifluoropropoxy)- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compound 18 (0.036 mg/kg, see FIG.5) and (2R,3R,11bR)-3-(tert-butoxy)-9-ethoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-ol Compound 22 (0.013 mg/kg, see FIG.5).
  • the ED50 was calculated for the following compounds: (2R,3R,11bR)-3-(tert-butoxy)-9-cyclopropoxy-10-methoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol Compound 19 (0.04 mg/kg); (2R,3R,11bR)-3-(tert-butoxy)-9-((3,3- difluorocyclobutyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compound 38 (0.06 mg/kg); (2R,3R,11bR)-3-(tert-butoxy)-9-(((S)-2,2- difluorocyclopropyl)methoxy)-10-methoxy-1,3,4,6,7,11b-hexahydro
  • EXAMPLE 16 Conditioned Avoidance Response Assay 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.
  • CAR conditioned avoidance response
  • a rat is trained in a two-chamber shuttle box to respond to a conditioned stimulus (auditory) by negative reinforcement. If the animal fails to move to the other chamber upon presentation of an auditory stimulus, a mild foot shock is applied to the side where the rat is located. The rat learns to avoid the mild foot shock by moving to the other chamber upon initiation of the auditory signal, termed a conditioned avoidance response. Crossing to the other chamber during administration of the shock is termed an escape response.
  • a rat fails to move to the other chamber even upon administration of the foot shock, the rat is considered to have an escape failure.
  • typical and atypical antipsychotic drugs selectively suppress CAR, thus making it an ideal assay to screen potential antipsychotic compounds (see, e.g., Wadenberg et al., Biobehav. Rev. (1999) 23: 851-62).
  • Male Wistar rats are trained every day for 3 to 4 weeks. In the training session, rats are placed in the CAR two-way shuttle box and the training period of 20 trials ensued.
  • a trial consisted of a 10- sec presentation of an 80 dB white noise followed by a scrambled 0.6 mA foot shock lasting up to 20 sec.
  • the inter-trial interval ranged from 20-60 sec.
  • the rat learns to avoid shock by moving from one compartment to the other when the conditioned stimulus is presented (a conditioned avoidance response).
  • a rat is deemed sufficiently trained if it avoided the shock when presented with the conditioned stimulus at least 19 times out of the 20 trials. Rats that do not pass these criteria are not used.
  • trained animals are acclimated in the test room for 30 minutes prior to testing. They are then dosed with compound and are placed in the CAR two-way shuttle box. In the test, 20 trials are performed on each rat. In each trial the conditioned stimulus is applied (10-sec presentation of 80 dB white noise), followed by the foot shock (a scrambled 0.6 mA foot shock lasting up to 20 sec).
  • test compound (0.5 ⁇ M) was incubated with pooled mixed gender liver microsomes from humans (0.5mg/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 glusose-6-phosphate, and 1 Unit/mL glucose-6-phosphate dehydrogenase. All concentrations were relative to the final incubation volume of 125 ⁇ L.
  • the values for intrinsic clearance were calculated from the elimination half-life data and were then scaled to represent the clearance expected in the entire animal, see Table 5 (human). Additional values calculated included predicted extraction ratio and predicted maximum bioavailability.
  • the in vitro half-life calculated from the HLM method is maxed at 420 minutes. Accordingly, for these stable compounds the in vitro half-life is at least 420 minutes but could be greater.
  • the predicted systemic clearance and scaled intrinsic clearance is at least 2.59 and 2.97 respectively but could be lower, and the predicted maximum bioavailability (%F) is at least 87 but could be higher.
  • EXAMPLE 18 Method to determine cytochrome P4502D63A4 (CYP3A4) and (CYP2D6) inhibition in expressed human enzymes using fluorescent marker substrates. A test compound was incubated with individually expressed human recombinant CYP enzymes systems in the presence of NADPH and IC 50 values for inhibition were determined using a marker substrate approach.
  • CYP3A4 For CYP3A4, the test compound was incubated with expressed human CYP3A4 (Gentest Supersomes (Corning, Woburn, MA)) and IC 50 values for inhibition were determined using marker substrate 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC), which is dealkylated by CYP3A4 to form the fluorescent product, 7-hydroxy-4-(trifluoromethyl)-coumarin (7-HFC). The amount of 7-HFC formed during the incubation was detected with a 96-well fluorescent plate reader (BioTek Synergy LX, Agilent, Santa Clara, CA), excitation ⁇ 400 nm and emission ⁇ 528 nm.
  • BFC marker substrate 7-benzyloxy-4-(trifluoromethyl)-coumarin
  • CYP2D6 For CYP2D6, the test compound was incubated with expressed human CYP2D6 (Gentest Supersomes, (Corning, Woburn, MA)) and IC 50 values for inhibition were determined using marker substrate, 3-[2-(N,N-diethyl-N-methylamino) ethyl]-7-methoxy-4-methylcoumarin (AMMC), which is O-demethylated by CYP2D6 to form the fluorescent product, 3-[2-(N,N-diethyl-N- methylammonium)ethyl]-7-hydroxy-4-methylcoumarin (AHMC).
  • marker substrate 3-[2-(N,N-diethyl-N-methylamino) ethyl]-7-methoxy-4-methylcoumarin (AMMC), which is O-demethylated by CYP2D6 to form the fluorescent product, 3-[2-(N,N-diethyl-N- methylammonium)ethyl]-7-hydroxy-4-methyl
  • AHMC AHMC formed during the incubation was monitored with a 96-well fluorescent plate reader (BioTek Synergy LX, Agilent, Santa Clara, CA), excitation ⁇ 360 nm and emission ⁇ 460 nm.
  • concentrations of the test compound ranging from 0.048 to 6 ⁇ M were assessed at a single concentration of the substrate (Km), 50 ⁇ M for BFC and 1.5 ⁇ M for AMMC, respectively, in duplicate.
  • Reactions included 100 ⁇ L of NADPH-generating system containing 75 mM, pH 7.4 potassium phosphate buffer, 3 mM magnesium chloride, 1 mM NADP, 5 mM glusose-6-phosphate, and 1 unit/mL glucose-6-phosphate and were initiated with 100 ⁇ L of CYP enzyme solution (10 pmol), which was added immediately before the samples were incubated at 37°C. Incubations are stopped after 30 minutes by adding 75 ⁇ L stop solution (80% acetonitrile / 20% 0.5M Tris Base). Ketoconazole and quinidine were used for positive controls of CYP3A4 and CYP2D6, respectively.
  • IC50 values for certain compounds against CYP2D6 and CYP3A4 are provided in Table 6.
  • Table 6 1 Assayed as a mixture of trans isomers (cyclopropyl).
  • 2 Assayed as a mixture of cis isomers (cyclopropyl).
  • EXAMPLE 19 Protocol for testing activity of compounds against hERG. The objective of these studies was to examine the in vitro effects of compounds on the hERG (human ether-a-go-go-related gene) channel current (a surrogate for I Kr , the rapidly activating delayed rectifier cardiac potassium current; see, e.g., Redfern et al., Cardiovascular Research (2003) 58(1):32- 45).
  • the concentration-response relationship for certain compounds on the hERG potassium channel current was evaluated at room temperature in stably transfected mammalian cells that express cloned hERG potassium channels, encoded by the KCNH2 gene.
  • the hERG potassium channels were expressed in Chinese Hamster’s Ovary (CHO) cells that lack endogenous I Kr .
  • the cardiac potassium channel hERG is responsible for a rapid delayed rectifier current (I Kr ) in human ventricles. Inhibition of I Kr is the most common cause of cardiac action potential prolongation by non-cardiac drugs (see, e.g., Brown and Rampe, Pharmaceutical News (2000) 7:15- 20; Weirich and Antoni, Basic Res. Cardiol.
  • hERG positive control Stock solutions of the positive control article were prepared in DMSO and stored at room temperature.
  • CHO/hERG Cell Line CHO Culture: CHO cells were stably transfected with hERG cDNA. Stable transfectants were maintained in the culture medium with the appropriate selection pressure and antibiotics. Test Method: 1. Cell Treatments: All experiments were performed at room temperature. Each cell was treated as its own control.
  • Compound preparation All compounds were solvated in 100% DMSO. At the day of the experiment, a serial dilution in DMSO was prepared manually.
  • the pre-diluted compounds were further diluted into external solution with a dilution factor of 1:500 (0.2% DMSO by volume).
  • d. Compound acquisition mode Single application of compounds was used with concentrations across the chip. Every well received once compound concentration followed by a full block of Verapamil to assess the leak current. Different concentrations of each compound to generate individual dose response relationships were spread across the chip.
  • Onset and block of hERG current was measured using a stimulus voltage pattern consisting of a 500ms prepulse to -40mV (leakage subtraction), a 2-second activating pulse to +40mV followed by a 2-second test pulse to -40mV followed by a 2-second test pulse to -40mV.
  • the pulse pattern was repeated continuously at 6 s intervals from a holding potential of -80 mV. Peak tail current was calculated from the current amplitude evoked by the -40 mV prepulse and subtracted from the total membrane current record. A small hyperpolarizing voltage step from -80 to -90 mV was implemented during holding potential to calculate the resistance according to Ohm’s law for quality control. 3. Data Analysis Data was stored on the Neurocrine Biosciences computer network for off-line analysis. Data acquisition and analysis was performed using Nanion Data Control software. Steady state is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after test article application was used to calculate percentage of current inhibited at each concentration.
  • Table 7 1 Assayed as a mixture of trans isomers (cyclopropyl). 2 Assayed as a mixture of cis isomers (cyclopropyl).

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Abstract

La présente invention concerne, entre autres, certains composés, compositions et compositions pharmaceutiques de ceux-ci, qui modulent l'activité du transporteur 2 de monoamine vésiculaire de protéine transporteuse (VMAT2) et sont dirigés vers des méthodes utiles dans le traitement de troubles médiés par le transporteur 2 de monoamine vésiculaire de protéine transporteuse, tels que des maladies ou des troubles neurologiques ou psychiatriques, comprenant, mais sans y être limités, des troubles de mouvement hyperkinétique (par exemple, la dyskinésie tardive, le syndrome de Tourette, la maladie de Huntington, les tics, l'ataxie, la chorée (telle que la chorée associée à la maladie de Huntington), la dystonie, le spasme hémifacial, la myoclonie, le syndrome des jambes sans repos et les tremblements). L'invention concerne en outre des procédés de synthèse et des intermédiaires utiles dans la préparation des composés.
EP23786905.2A 2022-09-21 2023-09-20 Inhibiteurs d'hexahydro-2h-pyrido[2,1-a]isoquinoline vmat2 et procédés d'utilisation Pending EP4590676A1 (fr)

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