WO2022232380A1 - Méthodes de préparation d'un inhibiteur de vmat2 - Google Patents

Méthodes de préparation d'un inhibiteur de vmat2 Download PDF

Info

Publication number
WO2022232380A1
WO2022232380A1 PCT/US2022/026711 US2022026711W WO2022232380A1 WO 2022232380 A1 WO2022232380 A1 WO 2022232380A1 US 2022026711 W US2022026711 W US 2022026711W WO 2022232380 A1 WO2022232380 A1 WO 2022232380A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
acid
solid form
formula
Prior art date
Application number
PCT/US2022/026711
Other languages
English (en)
Inventor
Jeffrey C. Culhane
Keegan Gregory NELSON
Andrew Palmer
Donald Hettinger
Original Assignee
Neurocrine Biosciences, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Neurocrine Biosciences, Inc. filed Critical Neurocrine Biosciences, Inc.
Publication of WO2022232380A1 publication Critical patent/WO2022232380A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to processes and intermediates for preparing (3R,11bS)- 3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(3,3,3-trifluoropropoxy)- 1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline, and salts thereof, which is an inhibitor of the vesicular monoamine transporter 2 (VMAT2).
  • VMAT2 vesicular monoamine transporter 2
  • the compounds and salts, solvates, and hydrates thereof as described herein are useful in the treatment of neurological and psychiatric diseases and disorders.
  • 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.
  • 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.
  • VMAT2 inhibitors including the compound (3R,11bS)-3-(2,2-dimethylpropyl)-10- methoxy-2-methyl-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1- a]isoquinoline (Compound 1) (see PCT Publication No WO 2018/195121), are being developed for the treatment of a variety of neurological and psychiatric disorders. There is a need for improved methods of preparing VMAT2 inhibitors like Compound 1 in order, for example, to increase purity, improve reproducibility, improve efficiency, reduce costs, and allow for scale up. The present disclosure helps fulfill these and other needs, as evident in reference to the following disclosure.
  • a process for preparing Compound 1 comprising: a) coupling Compound 9 having the formula: or a salt thereof, with Compound 8 having the formula: or a salt thereof, to provide Compound 7 having the formula: or a salt thereof; b) reacting Compound 7, or a salt thereof, with a compound of Formula (i) having the formula: Formula (i), wherein X is a leaving group, in the presence of B1, wherein B1 is a base, to provide Compound 6 having the formula: or a salt thereof; c) reacting Compound 6, or a salt thereof, with A5, wherein A5 is an acid, to provide Compound 5 having the formula: or a salt thereof; d) reacting Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4, wherein A4 is an acid, and RA3, wherein RA3 is a reducing agent, to provide Compound 4 having the formula: or a salt thereof; e) reacting Compound 4, or
  • the present invention is further directed to salts of Compound 1.
  • the present invention is further directed to a hydrochloric acid salt of Compound 1.
  • the present invention is further directed to the di-hydrochloric acid salt of Compound 1.
  • the present invention is further directed to solid forms of Compound 1 and salts thereof.
  • the present invention is further directed to pharmaceutical compositions comprising a compound, salt, or solid form described herein, and at least one pharmaceutically acceptable carrier.
  • the present invention is further directed to therapeutic methods of using the compounds, salts and solid forms described herein.
  • the present disclosure also provides uses of the compounds, salts and solid forms described herein in the manufacture of a medicament for use in therapy.
  • FIG.1. depicts an X-ray powder diffraction pattern (XRPD) of a sample of Compound 1 di-HCl in crystalline Form I.
  • FIG.2. depicts an X-ray powder diffraction pattern (XRPD) of a sample of Compound 1 di-HCl in crystalline Form III.
  • DETAILED DESCRIPTION For clarity and consistency, the following definitions will be used throughout this patent document. As used herein, “about” means ⁇ 20% of the stated value, and includes more specifically values of ⁇ 10%, ⁇ 5%, ⁇ 2% and ⁇ 1% of the stated value.
  • 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, IV, IM, IP, and the like; transdermal dosage forms, including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • oral dosage forms such as, tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as, IV, IM, IP, and the like
  • transdermal dosage forms including creams, jellies, powders, and patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and the like
  • rectal suppositories rectal suppositories.
  • 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.
  • “administration” is understood to include the compound and other agents are administered at the same time or at different times. When 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.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.
  • hydrate refers to a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • in need of treatment and the term “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that 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.
  • 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.
  • composition refers to a specific composition comprising at least one drug substance; 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).
  • a mammal for example, without limitation, a human
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether a drug substance has a desired efficacious outcome based upon the needs of the artisan.
  • the terms “prevent,” “preventing,” and “prevention” refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder.
  • prevention can refer to the administration of therapy on a prophylactic or preventative basis to a subject who can 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.
  • treat refers to medical management of a disease, disorder, or condition of a subject (e.g., subject) (see, e.g., Stedman’s Medical Dictionary).
  • 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 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 the VMAT2 inhibitor 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.
  • beneficial or desired clinical results 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
  • 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
  • VMAT2 inhibitors are described in PCT Publication No WO 2018/195121, which is incorporated herein by reference in its entirety, including (3R,11bS)-3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(3,3,3- trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline, which is depicted below as Compound 1.
  • Compound 1 can be referred to as (3R,11bS)-10-methoxy-2-methyl-3- neopentyl-9-(3,3,3-trifluoropropoxy)-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1- a]isoquinoline.
  • processes for preparing Compound 1 or a salt thereof have certain advantages over the processes currently disclosed in the art. For example, the processes described herein demonstrate good scalability and yields. In particular, the reactions are easily handled because the reaction solutions and mixtures are not too viscous or too dilute. In addition, each sequence of the process can provide a filterable solid.
  • Compound 1 and its salts can be isolated as one or more solid forms.
  • the salt of Compound 1 is an acid addition salt of Compound 1.
  • the di- hydrochloric acid salt form of Compound 1 is referred to herein as “Compound 1 di-HCl,” “Compound 1 di-hydrochloric acid salt form,” “Compound 1 ⁇ 2HCl,”or “Compound 1 ⁇ dihydrochloride”.
  • a sequence for the formation of compound 1 includes coupling Compounds 8 and 9, in the presence of an amide coupling agent, such as N,N,N′,N′- tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(6- Chloro-1-H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and the like, and a base, such as DIEA, TEA and the like, in a solvent, such as CH2Cl2, dio
  • a base such as NaOH, KOH, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 and the like
  • a solvent such as DCM, or a mixture of DCM and water and the like
  • Preparation of Compound 5 can be accomplished by treating Compound 6 with an acid, such as HCl, p-TsOH and the like, in a solvent or solvent mixture, such as CH 2 Cl 2 , CPME, CH 2 Cl 2 , dioxane, THF, toluene and water and the like.
  • Preparation of Compound 4 can be accomplished by treating Compound 5 with dimethoxyacetaldehyde under reductive amination conditions.
  • Compound 5 can be treated with dimethoxyacetaldehyde in the presence of an acid, such as acetic acid, trifluoroacetic acid, boric acid, p-toluenesulfonic acid, benzoic acid and the like, and reducing agent, such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, sodium borohydride and the like, in a solvent or a solvent or solvent mixture, such as ethanol, methanol, isopropanol, MTBE, CPME, CH 2 Cl 2 , dioxane, THF, acetonitrile, MTBE and ethanol, toluene and the like.
  • an acid such as acetic acid, trifluoroacetic acid, boric acid, p-toluenesulfonic acid
  • Preparation of Compound 3 can be accomplished by treating Compound 4 with F1, wherein F1 is formalin, formaldehyde or paraformaldehyde, under reductive amination conditions.
  • Compound 4 can be treated with F1 in the presence of an acid, such as acetic acid, trifluoroacetic acid, boric acid, p-toluenesulfonic acid, benzoic acid and the like, and reducing agent, such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, sodium borohydride and the like, in a solvent or solvent mixture, such as ethanol, methanol, isopropanol, MTBE, CPME, CH2Cl2, dioxane, THF, acetonitrile, MTBE and ethanol, or toluene and the like.
  • an acid such as acetic acid, trifluoroacetic acid, boric acid, p-toluenesulf
  • Preparation of Compound 2 can be accomplished by treating Compound 3 with an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, in a solvent or a solvent mixture, such as toluene and water, DCM and water and the like.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like
  • a solvent or a solvent mixture such as toluene and water, DCM and water and the like.
  • preparation of Compound 1 can be accomplished by treating compound 2 with a reducing agent, such as lithium aluminum hydride, diisobutylaluminum hydride, lithium diisobutyl-tert-butoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tris[(3-ethyl-3-pentyl)oxy]aluminohydride, sodium bis(2-methoxyethoxy)aluminum dihydride, sodium aluminum hydride, lithium borohydride, and the like, in a solvent or a solvent mixture, such as 1,4-dioxane, THF MTBE CPME and the like.
  • a solvent or a solvent mixture such as 1,4-dioxane, THF MTBE CPME and the like.
  • Compound 1, or a salt thereof can be prepared by a process comprising reducing Compound 2 having the formula: or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 1, or a salt thereof.
  • RA1 is a hydride reducing agent.
  • RA1 is lithium aluminum hydride or lithium borohydride.
  • RA1 is lithium aluminum hydride.
  • the reducing of Compound 2 comprises using between about 1 to about 5 molar equivalents of RA1 to about one molar equivalent of Compound 2.
  • the reducing of Compound 2 comprises using between about 1 to about 3 molar equivalents of RA1 to about one molar equivalent of Compound 2. In some embodiments, the reducing of Compound 2 comprises using about 2 molar equivalents of RA1 to about 1 molar equivalent of Compound 2. In some embodiments, the reducing of Compound 2 is performed in the presence of S1, wherein S1 is a solvent. In some embodiments, S1 is an ether solvent. In some embodiments, S1 is THF or diethyl ether. In some embodiments, S1 is THF. In some embodiments, the reducing of Compound 2 is performed at a reduced temperature.
  • the reducing of Compound 2 is performed at a temperature between about -10 °C and about 30 °C. In some embodiments, the reducing of Compound 2 is performed at a temperature between about -10 °C and about 10 °C. In some embodiments, the reducing of Compound 2 is performed at 0 °C. In some embodiments, the reducing of Compound 2 is performed at a temperature between about -5 °C and about 5 °C. In some embodiments, the reducing of Compound 2 is performed from about 0 °C to room temperature. In some embodiments, the process further comprises treating Compound 1 with A1, wherein A1 is an acid. In some embodiments, A1 is an inorganic acid.
  • the acid is hydrochloric acid.
  • the treating of Compound 1 with A1 is performed in S1a, wherein S1a is a solvent.
  • S1a is an aprotic solvent.
  • S1a is acetonitrile.
  • the treating of Compound 1 with A1 is performed at an elevated temperature.
  • the treating of Compound 1 with A1 is performed at a temperature between about 30 °C and about 50 °C.
  • the treating of Compound 1 with A1 is performed at a temperature between about 35 °C to about 45 °C.
  • the treating of Compound 1 with A1 is performed at a temperature of about 40 °C.
  • the treating of Compound 1 with A1 comprises using about 1 to about 4 molar equivalents of A1 to about 1 molar equivalent of Compound 1.
  • the treating of Compound 1 with A1, wherein A1 is hydrochloric acid in the presence of S1a, wherein S1a is acetonitrile, provides the di-hydrochloric acid addition salt of Compound 1 having Form III.
  • a hydrochloric acid addition salt of Compound 1 is prepared.
  • the di-hydrochloric acid addition salt of Compound 1 is prepared.
  • the process further comprises treating Compound 1 with A1, wherein A1 is an acid.
  • the di-hydrochloric acid addition salt of Compound 1 has Form III.
  • the di-hydrochloric acid addition salt of Compound 1 having Form III is described in the embodiments and examples below.
  • the process can further comprise (i) heating a mixture of the di-hydrochloric acid addition salt of Compound 1 having Form III and S1b, wherein S1b is a solvent, to an elevated temperature; and (ii) precipitating the di-hydrochloric acid addition salt of Compound 1 having Form I from the mixture.
  • S1b is a mixture of water and an ether solvent.
  • S1b is a mixture of MTBE and water.
  • S1b is MTBE.
  • S1b is water.
  • S1b is a mixture of water and ethyl acetate. In some embodiments, S1b is ethyl acetate. In some embodiments, the elevated temperature is between about 30 °C and about 50 °C. In some embodiments, the elevated temperature is between about 40 °C and about 50 °C. In some embodiments, the elevated temperature is about 40 °C. In some embodiments, the elevated temperature is about 50 °C.
  • the di-hydrochloric acid addition salt of Compound 1 having Form I is described in the embodiments and examples below. In some embodiments, the precipitating comprises cooling the mixture to room temperature.
  • Compound 2, or a salt thereof can be prepared by a process comprising reacting Compound 3 having the formula: or a salt thereof, with A 2, wherein A2 is an acid, to provide Compound 2, or a salt thereof.
  • A2 is an inorganic acid.
  • A2 is sulfuric acid.
  • A2 is concentrated sulfuric acid.
  • the reacting of Compound 3, or a salt thereof, with A2 is performed in the presence of S2, wherein S2 is a solvent.
  • S2 is a mixture of halogenated solvent and water.
  • S2 is a mixture of dichloromethane and water.
  • the reacting of Compound 3, or a salt thereof, with A2 is performed at a reduced temperature. In some embodiments, the reacting of Compound 3, or a salt thereof, with A2 is performed at a temperature between about -10 °C and about 10 °C. In some embodiments, the reacting of Compound 3, or a salt thereof, with A2 is performed at a temperature of about 0 °C. In some embodiments, the reacting of Compound 3, or a salt thereof, with A2 comprises using about 2 to about 20 molar equivalents of A2 to about 1 molar equivalent of Compound 3.
  • the reacting of Compound 3, or a salt thereof, with A2 comprises using about 5 to about 15 molar equivalents of A2 to about 1 molar equivalent of Compound 3. In some embodiments, the reacting of Compound 3, or a salt thereof, with A2 comprises using about 8 to about 12 molar equivalents of A2 to about 1 molar equivalent of Compound 3. In some embodiments, the reacting of Compound 3, or a salt thereof, with A2 comprises using about 10 molar equivalents of A2 to about one molar equivalent of Compound 3. In some embodiments, the process further comprises treating Compound 2 with A2a, wherein A2a is an acid, to prepare an acid addition adduct, acid addition product, or acid addition salt of Compound 2.
  • A2a is di-p-toluoyl-D-tartaric acid.
  • the treating of Compound 2 with A2a is performed in the presence of S2a, wherein S2a is a solvent.
  • S2a is a mixture of an aprotic solvent and a hydrocarbon solvent.
  • S2a is a mixture of isopropyl acetate and heptane.
  • the treating of Compound 2 with A2a is performed at an elevated temperature. In some embodiments, the treating of Compound 2 with A2a is performed at a temperature between about 60 °C and about 100 °C.
  • the treating of Compound 2 with A2a is performed at a temperature between about 70 °C and about 80 °C. In some embodiments, the treating of Compound 2 with A2a is performed at a temperature of about 75 °C. In some embodiments, the treating of Compound 2 with A2a comprises using about 1 to about 2 molar equivalents of A2a to 1 molar equivalent of Compound 2. In some embodiments, the treating of Compound 2 with A2a comprises using about 1 molar equivalent of A2a to 1 molar equivalent of Compound 2. In some embodiments, the process further comprises isolating the di-p-toluoyl-D- tartaric acid adduct of Compound 2.
  • the process further comprises isolating the di-p-toluoyl-D-tartaric acid addition product of Compound 2. In some embodiments, the process further comprises isolating the di-p-toluoyl-D-tartaric acid addition salt of Compound 2.
  • a composition comprising Compound 2 and di-p-toluoyl-D-tartaric acid.
  • the acid adduct of Compound 2 is a di-p-toluoyl-D-tartaric acid adduct of Compound 2.
  • the salt of Compound 2 is the di-p- toluoyl-D-tartaric acid addition product of Compound 2.
  • the salt of Compound 2 is the di-p-toluoyl-D-tartaric acid addition salt of Compound 2.
  • Compound 3 can be prepared by a process comprising reacting Compound 4 having the formula: Compound 4, or a salt thereof, with F1, wherein F1 is formalin, formaldehyde or paraformaldehyde, in the presence of A3, wherein A3 is an acid, and RA2, wherein RA2 is a reducing agent, to provide Compound 3, or a salt thereof.
  • F1 is formalin.
  • A3 is an organic acid.
  • A3 is acetic acid.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 5 molar equivalents of A3 to about 1 equivalent of Compound 4. In some embodiments, the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 3 molar equivalents of A3 to about 1 equivalent of Compound 4. In some embodiments, the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 2 molar equivalents of A3 to about 1 equivalent of Compound 4. In some embodiments, F1 is formalin. In some embodiments, RA2 is a hydride reducing agent. In some embodiments, RA2 is sodium triacetoxyborohydride.
  • RA2 is sodium triacetoxyborohydride or sodium borohydride.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 5 molar equivalents of RA2 to about 1 equivalent of Compound 4.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 3 molar equivalents of RA2 to about 1 equivalent of Compound 4.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 2 molar equivalents of RA2 to about 1 equivalent of Compound 4.
  • F1 is formalin.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 5 molar equivalents of F1 to about 1 equivalent of Compound 4. In some embodiments, the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 3 molar equivalents of F1 to about 1 equivalent of Compound 4. In some embodiments, the reacting of Compound 4 with F1 in the presence of A3 and RA2 comprises using about 1 to about 2 molar equivalents of F1 to about 1 equivalent of Compound 4. In some embodiments, F1 is formalin.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 is performed in the presence of S3, wherein S3 is a solvent.
  • S3 is a mixture of an ether and a protic solvent.
  • S3 is a mixture of methyl t- butyl ether and ethyl alcohol.
  • F1 is formalin.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 is performed at a temperature between about 20 °C and about 30 °C.
  • the reacting of Compound 4 with F1 in the presence of A3 and RA2 is performed at room temperature.
  • F1 is formalin.
  • Compound 4 can be prepared by a process comprising reacting Compound 5, having the formula: or a salt thereof, with dimethoxyacetaldehyde in the presence of A4, wherein A4 is an acid, and RA3, wherein RA3 is a reducing agent, to provide Compound 4.
  • A4 is an organic acid.
  • A4 is acetic acid.
  • the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 1 to about 10 molar equivalents of A4 to about one molar equivalent of Compound 5.
  • the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 3 to about 8 molar equivalents of A4 to about one molar equivalent of Compound 5. In some embodiments, the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 4 to about 6 molar equivalents of A4 to about one molar equivalent of Compound 5. In some embodiments, the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 5 molar equivalents of A4 to about one molar equivalent of Compound 5.
  • RA3 is a hydride reducing agent. In some embodiments, RA3 is sodium borohydride. In some embodiments, the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 1 to about 5 molar equivalents of RA3 to about one molar equivalent of Compound 5. In some embodiments, the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 1 to about 3 molar equivalents of RA3 to about one molar equivalent of Compound 5.
  • the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 comprises using about 1 to about 2 molar equivalents of RA3 to about one molar equivalent of Compound 5.
  • the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 is performed in the presence of S4, wherein S4 is a solvent.
  • S4 is an ether solvent.
  • S4 is methyl t-butyl ether.
  • the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 is performed at a temperature between about 20 °C and about 30 °C. In some embodiments, the reacting of Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4 and RA3 is performed at room temperature.
  • Compound 5, or a salt thereof can be prepared by a process comprising reacting Compound 6 having the formula: or a salt thereof, with A5, wherein A5 is an acid, to provide Compound 5.
  • A5 is an organic acid. In some embodiments, A5 is p- toluenesulfonic acid.
  • A5 is an inorganic acid. In some embodiments, A5 is hydrochloric acid. In some embodiments, the reacting of Compound 6 with A5 is performed in the presence of S5. In some embodiments, S5 is a halogenated solvent. In some embodiments, S5 is dichloromethane. In some embodiments, S5 is a mixture of a halogenated solvent and an ether. In some embodiments, S5 is a mixture of dichloromethane and cyclopentyl methyl ether. In some embodiments, the reacting of Compound 6 with A5 is performed at a reduced temperature. In some embodiments, the reacting of Compound 6 with A5 is performed at a temperature between about -10 °C and about 30 °C.
  • the reacting of Compound 6 with A5 is performed at a temperature between about 0 °C and about 20 °C. In some embodiments, the reacting of Compound 6 with A5 is performed at a reduced temperature and A5 is hydrochloric acid. In some embodiments, the reacting of Compound 6 with A5 is performed at an elevated temperature. In some embodiments, the reacting of Compound 6 with A5 is performed at a temperature between about 30 °C and about 60 °C. In some embodiments, the reacting of Compound 6 with A5 is performed at a temperature between about 30 °C and about 50 °C.. In some embodiments, the reacting of Compound 6 with A5 is performed at a temperature of about 40 °C.
  • the salt of Compound 5 is the p-toluenesulfonic acid salt of Compound 5.
  • the process further comprises treating Compound 5 with A5a, wherein A5a is an acid, to provide an acid additional salt of Compound 5.
  • A5a is p-toluenesulfonic acid.
  • the treating of Compound 5 with A5a is performed in the presence of S5a, wherein S5a is a solvent.
  • S5a is a protic solvent.
  • S5a is methanol.
  • the treating of Compound 5 with A5a is performed at an elevated temperature.
  • the treating of Compound 5 with A5a is performed at a temperature between about 20 °C and about 60 °C. In some embodiments, the treating of Compound 5 with A5a is performed at a temperature between about 40 °C and about 60 °C. In some embodiments, the treating of Compound 5 with A5a is performed at a temperature of about 50 °C. In some embodiments, the treating of Compound 5 with A5a comprises using about 1 molar equivalent of A5a to about one molar equivalent of Compound 5. In some embodiments, the p-toluenesulfonic acid addition salt of Compound 5 is prepared.
  • composition comprising Compound 5 and p-toluenesulfonic acid.
  • Compound 6 can be prepared by a process comprising reacting Compound 7 having the formula: Compound 7, or a salt thereof, with a compound of Formula (i) having the formula: Formula (i), wherein X is a leaving group, in the presence of B1, wherein B1 is a base, to provide Compound 6.
  • X is I, Cl, Br, or OS(O2)CF3.
  • X is OS(O2)CF3.
  • the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 comprises using about 1 to about 3 molar equivalents of Formula (i) to 1 molar equivalent of Compound 7. In some embodiments, the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 comprises using about 1 to about 2 molar equivalents of Formula (i) to 1 molar equivalent of Compound 7.
  • B1 is an alkali metal hydroxide. In some embodiments, B1 is sodium hydroxide. In some embodiments, B1 is sodium hydroxide or potassium hydroxide.
  • the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 is performed in the presence of S6, wherein S6 is a solvent.
  • S6 is a halogenated solvent.
  • S6 is dichloromethane.
  • the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 is performed at a reduced temperature.
  • the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 is performed at a temperature between about -10 °C and about 10 °C.
  • the reacting of Compound 7 with the compound of Formula (i) in the presence of B1 is performed at a temperature of about 0 °C.
  • Compound 7 can be prepared by a process comprising coupling Compound 9 having the formula: Compound 9, or a salt thereof, with Compound 8 having the formula: Compound 8, or a salt thereof, to provide Compound 7.
  • the coupling of Compound 9 and Compound 8 is performed in the presence of CA1, wherein CA1 is a peptide coupling reagent.
  • CA1 is HATU.
  • the coupling of Compound 9 and Compound 8 comprises using about 1 to about 3 molar equivalents of Compound 9 to 1 molar equivalent of Compound 8.
  • the coupling of Compound 9 and Compound 8 comprises using about 1 to about 2 molar equivalents of Compound 9 to 1 molar equivalent of Compound 8. In some embodiments, the coupling of Compound 9 and Compound 8 comprises using about 1 molar equivalent of Compound 9 to 1 molar equivalent of Compound 8. In some embodiments, the coupling of Compound 9 and Compound 8 comprises using about 1 to about 3 molar equivalents of CA1 to 1 molar equivalent of Compound 8. In some embodiments, the coupling of Compound 9 and Compound 8 comprises using about 1 to about 2 molar equivalents of CA1 to 1 molar equivalent of Compound 8.
  • the coupling of Compound 9 and Compound 8 comprises using about molar equivalent of CA1 to 1 molar equivalent of Compound 8. In some embodiments, the coupling of Compound 9 and Compound 8 is performed in the presence of B2, wherein B2 is a base. In some embodiments, B2 is an amine base. In some embodiments, B2 is diisopropylethylamine. In some embodiments, the coupling of Compound 9 and Compound 8 comprises using about 1 to about 3 molar equivalents of B2 to 1 molar equivalent of Compound 8. In some embodiments, the coupling of Compound 9 and Compound 8 comprises using about 1 to about 2 molar equivalents of B2 to 1 molar equivalent of Compound 8.
  • the coupling of Compound 9 and Compound 8 is performed in the presence of S7, wherein S7 is a solvent. In some embodiments, S7 is a halogenated solvent. In some embodiments, S7 is dichloromethane. In some embodiments, the coupling of Compound 9 and Compound 8 is performed at a temperature between about 20 °C and about 30 °C. In some embodiments, the coupling of Compound 9 and Compound 8 is performed at room temperature.
  • a process for preparing Compound 1, or a salt thereof can comprise: a) reacting Compound 5 having the formula: Compound 5, or a salt thereof, with dimethoxyacetaldehyde in the presence of A4, wherein A4 is an acid, and RA3, wherein RA3 is a reducing agent, to provide Compound 4 having the formula: or a salt thereof; b) reacting Compound 4, or a salt thereof, with F1, wherein F1 is formalin, formaldehyde or paraformaldehyde, in the presence of A3, wherein A3 is an acid, and RA2, wherein RA2 is a reducing agent, to provide Compound 3 having the formula: or a salt thereof; c) reacting Compound 3, or a salt thereof, with A2, wherein A2 is an acid, to provide Compound 2 having the formula: Compound 2, or a salt thereof; and d) reducing Compound 2, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Com
  • F1 is formalin.
  • Solid Forms The present disclosure is further directed to solid forms, including crystalline forms and amorphous forms, of Compound 1 and pharmaceutically acceptable salts thereof.
  • the solid forms (e.g., crystalline forms) described herein can have certain advantages, for example, they can have desirable properties, such as ease of handling, ease of processing, storage stability, and ease of purification.
  • the crystalline forms can be useful for improving the performance characteristics of a pharmaceutical product such as dissolution profile, shelf-life and bioavailability.
  • Some embodiments provide a process of preparing a crystal form of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, comprising a) dissolving the compound in a solvent mixture including an organic solvent and aqueous solution; and b) crystallizing the compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the solvent mixture includes an organic solvent and an aqueous counter-ion solution.
  • Compound 1 di-HCl Form I Provided herein is a solid form of the di-hydrochloric acid salt of Compound 1 which is crystalline, referred to as Compound 1 di-HCl Form I, which is described below in the Examples.
  • Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.0, 9.9, 14.8, 15.4, 16.8, 19.9, 21.1, 21.4, 22.4, and 26.4 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.0, 9.9, 14.8, 15.4, 16.8, 19.9, 21.1, 21.4, 22.4, and 26.4 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having three or more characteristic XRPD peaks selected from 5.0, 9.9, 14.8, 15.4, 16.8, 19.9, 21.1, 21.4, 22.4, and 26.4 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.0, 9.9, 16.8, 19.9, and 21.4 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.0, 9.9, 16.8, 19.9, and 21.4 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having three or more characteristic XRPD peaks selected from 5.0, 9.9, 16.8, 19.9, and 21.4 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.0, 9.9, and 16.8 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.0, 9.9, and 16.8 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form I has an X-ray powder diffraction pattern having three characteristic XRPD peaks selected from 5.0, 9.9, and 16.8 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form I has an XRPD pattern substantially as shown in Fig.1.
  • Compound 1 di-HCl Form I can be prepared by a process comprising (i) heating a mixture of the di-hydrochloric acid addition salt of Compound 1 having Form III and S1b, wherein S1b is a solvent, to an elevated temperature; (ii) cooling the mixture; and (iii) precipitating the di-hydrochloric acid addition salt of Compound 1 having Form I.
  • S1b is a mixture of MTBE and water.
  • the elevated temperature is between about 30 °C and about 50 °C. In some embodiments, the elevated temperature is between about 40 °C and about 50 °C.
  • the elevated temperature is about 40 °C. In some embodiments, the elevated temperature is about 50 °C. In some embodiments, Compound 1 di-HCl Form I is a hydrate. In some embodiments, Compound 1 di-HCl Form I is a dihydrate. Compound 1 HCl Form III Provided herein is a solid form of the di-hydrochloric acid salt of Compound 1 which is crystalline, referred to as Compound 1 di-HCl Form III, which is described below in the Examples.
  • Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 14.2, 15.2, 19.6, 20.2, 22.0, and 24.2 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 14.2, 15.2, 19.6, 20.2, 22.0, and 24.2 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having three or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 14.2, 15.2, 19.6, 20.2, 22.0, and 24.2 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 19.6, and 20.2 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 19.6, and 20.2 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having three or more characteristic XRPD peaks selected from 5.7, 10.6, 13.4, 19.6, and 20.2 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having one or more characteristic XRPD peaks selected from 5.7, 10.6, and 13.4 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having two or more characteristic XRPD peaks selected from 5.7, 10.6, and 13.4 degrees two-theta ⁇ 0.2 degrees theta. In some embodiments, Compound 1 di-HCl Form III has an X-ray powder diffraction pattern having three characteristic XRPD peaks selected from 5.7, 10.6, and 13.4 degrees two-theta ⁇ 0.2 degrees theta.
  • Compound 1 di-HCl Form III has an XRPD pattern substantially as shown in Fig.2.
  • Compound 1 di-HCl Form III can be prepared by a process (i) comprising treating Compound 1 with A1, wherein A1 is hydrochloric acid, in the presence of S1a, wherein S1a is acetonitrile; and (ii) precipitating Compound 1 di-HCl Form III from a mixture comprising Compound 1 di-HCl Form III and S1a.
  • provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: p ; or a salt thereof. In some embodiments provided herein is a compound having the formula: Compound 4; or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof. In some embodiments, provided herein is a compound having the formula: or a salt thereof.
  • the reacting involves two reagents, wherein one or more equivalents of second reagent are used with respect to the first reagent.
  • the reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product.
  • the terms “protecting” and “deprotecting” as used herein in a chemical reaction refer to inclusion of a chemical group in a process and such group is removed in a later step in the process.
  • preparation of Compound 1 and its salts can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • protecting groups are described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
  • protecting groups include amino protecting groups.
  • amino protecting group refers to any protecting group for the protection of amines.
  • Example amino protecting groups include, but are not limited to, phenylsulfonyl, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2- (trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), tert-Butyloxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1- dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2- phenylsulfonylethyl (Cbz
  • leaving group refers to an electrophilic moiety that is susceptible to displacement by a nucleophilic moiety.
  • leaving groups include halogen leaving groups (-Cl, -Br, -I) and triflate (-OTf) leaving groups.
  • halogen leaving groups -Cl, -Br, -I
  • -OTf triflate
  • an alkoxide compound can react with alkyl group bearing a leaving group to form an ether.
  • coupling agent refers to a reagent that facilitates the formation of a covalent bond between two separate compounds.
  • an amide coupling agent facilitates the formation of an amide bond between two compounds (e.g., an amine compound and a carboxylic acid compound forming an amide).
  • amide coupling agents include, but not limited to, thionyl chloride oxalyl chloride phosphorus oxychloride, Vilsmeier reagent, propylphosphonic anhydride, ethylmethylphosphinic anhydride (EMPA), Ac2O, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), 2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), pentafluorophenyl trifluoroacetate, cyanuric chloride, 2- chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride,
  • base refers to a compound that is an electron pair donor in an acid-base reaction.
  • the base can be an inorganic base or an organic base.
  • organic base refers to a base including at least one C-H bond (e.g. an amine base).
  • the amine base can be a primary, secondary, or tertiary amine.
  • Examples of an amine base include, but are not limited to, methylamine, dimethylamine, diethylamine, diphenylamine, trimethylamine, triethylamine, N,N- diisopropylethylamine, diisopropylamine, piperidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-lutidine, 4-methylmorpholine, 4-ethylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,8 diazabicyclo[540]undec-7-ene, 1,4- diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene, 4-(dimethylamino)pyridine, and the like.
  • the amine base can include one alkali metal or alkaline earth metal.
  • examples of an amine base including one alkali metal include, but are not limited to, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium dicyclohexylamide, lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, and the like.
  • the organic base can be a metal alkoxide base.
  • Examples of a metal alkoxide base include, but are not limited to, barium tert-butoxide, lithium tert-amoxide, lithium tert-butoxide, lithium ethoxide, lithium isopropoxide, lithium methoxide, magnesium di-tert-butoxide, magnesium ethoxide, magnesium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-pentoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium tert-pentoxide, and the like.
  • the organic base can be an organometal base (e.g. organolithium base or organomagnesium base).
  • organolithium base examples include, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium, ethyllithium, hexyllithium, isobutyllithium, isopropyllithium, methyllithium, hexyllithium, phenyllithium, and the like.
  • organomagnesium base examples include, but are not limited to, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, ethylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride, n- propylmagnesium chloride, propylmagnesium chloride, isobutylmagnesium bromide, isobutylmagnesium chloride, butylmagnesium chloride, sec-butylmagnesium chloride, tert- butylmagnesium chloride, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, 2-pentylmagnesium bromide, 3-pentylmagnesium bromide, isopentylmagnesium bromide, pentylmagnesium bromide, phenylmagnesium bromide, phenylmag
  • inorganic base refers to a base that does not include at least one C-H bond and includes at least one alkali metal or alkaline earth metal.
  • examples of an inorganic base include, but are not limited to, sodium hydride, potassium hydride, lithium hydride, calcium hydride, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like
  • acid refers to a compound that is an electron pair acceptor in an acid-base reaction.
  • the acid can be an inorganic acid or organic acid.
  • inorganic acid refers to an acid that does not include a carbon bond.
  • Inorganic acids can be a strong acid or a weak acid. Examples of inorganic acids include, but are not limited to, sulfamic acid, hydrochloric acid, hydriodic acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid, boric acid, fluorophosphoric acid, phosphoric acid, and the like.
  • organic acid refers to an acid including at least one C-H bond, C-F bond, or C-C bond.
  • organic acid examples include but not limited to acetic acid, benzenesulfonic acid, benzoic acid, ( ⁇ )-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, (-)-camphor- 10-sulfonic acid, citric acid, difluoroacetic acid, ethanesulfonic acid, formic acid, fumaric acid, gallic acid, glycolic acid, 2-hydroxyethanesulfonic acid, 1-hydroxy-2-naphthoic acid, lactic acid, L-malic acid, maleic acid, malonic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, naphthalene-1,5-disulfonic acid, nitrilotriacetic acid, oxalic acid, phthalic acid, propionic acid, di-p-toluoyl-DL-tartaric acid, di-p-toluoyl-D-tartaric acid
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
  • Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (methylene chloride), tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, 1,1,1-trifluorotoluene, 1,2-dichloroethane, 1,2- dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof and the like.
  • halogenated solvents such as carbon tetrachloride, bromodichloromethane, di
  • Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, cyclopentyl methyl ether, 1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, mixtures thereof and the like.
  • Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, tert- pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the polar protic solvent can be an alcohol such as methanol, ethanol, 1-propanol, 2-propanol, and the like.
  • Suitable aprotic solvents can include, by way of example and without limitation, 2- butanone, acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N- methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,
  • Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.
  • reducing agent refers to a compound that contributes a hydride to an electrophilic position of a reactant compound such as an unsaturated carbon (e.g. carbon of a carbonyl moiety or imine moiety).
  • the reducing agent can contributes a hydride to a reactant compound converting an amide containing reactant compound to an amine product compound, converting an imine containing reactant compound to an amine product compound, converting a ketone containing reactant compound to an alcohol product compound or converting an ester containing reactant compound to an alcohol product compound.
  • Example hydride reducing agents include, but are not limited to, diborane, borane (e.g.
  • borane tetrahydrofuran complex 9 borabicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminum hydride, lithium diisobutyl-tert-butoxyaluminum, lithium tri- tert-butoxyaluminum, lithium tris[(3-ethyl-3-pentyl)oxy]aluminohydride, sodium bis(2- methoxyethoxy)aluminum dihydride, sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, tetramethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, lithium 9-borabicyclo[3.3.1]nonane hydride, sodium triacetoxyborohydride, potassium tri-sec-buty
  • the reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
  • the processes described herein can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry; or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • the compounds obtained by the reactions can be purified by any suitable method known in the art.
  • chromatography medium pressure
  • a suitable adsorbent e.g., silica gel, alumina and the like
  • HPLC high resolution liquid phase
  • a suitable adsorbent e.g., silica gel, alumina and the like
  • HPLC high resolution liquid phase chromatography
  • distillation sublimation, trituration, or recrystallization.
  • the purity of the compounds are determined by physical methods such as measuring the melting point (in case of a solid), obtaining a NMR spectrum, or performing a HPLC separation. If the melting point decreases, if unwanted signals in the NMR spectrum are decreased, or if extraneous peaks in an HPLC trace are removed, the compound can be said to have been purified. In some embodiments, the compounds are substantially purified.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 oC to about 30 oC.
  • reduced temperature is understood to refer generally to a temperature that is below room temperature, for example, a temperature below about 22 oC to above about ⁇ 100 oC.
  • elevated temperature is understood to refer generally to a temperature that is above room temperature, for example, a temperature above about 22 oC to below about 140 oC.
  • solid form refers to a compound provided herein in either an amorphous state or a crystalline state (“crystalline form” or “crystalline solid” or “crystalline solid form”), whereby a compound provided herein in a crystalline state can optionally include solvent or water within the crystalline lattice, for example, to form a solvated or hydrated crystalline form.
  • the compound provided herein is in a crystalline state as described herein.
  • peak or characteristic peak refers to an XRPD reflection having a relative height/intensity of at least about 3% of the maximum peak height/intensity.
  • crystalline refers to a crystalline solid form of a chemical compound, including, but not limited to, a single-component or multiple- component crystal form, e.g., including solvates, hydrates, clathrates, and a co-crystal.
  • crystalline means having a regularly repeating and/or ordered arrangement of molecules, and possessing a distinguishable crystal lattice.
  • the term “crystalline form” is meant to refer to a certain lattice configuration of a crystalline substance.
  • Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells), typically have different physical properties attributed to their different crystalline lattices, and in some instances, have different water or solvent content.
  • the different crystalline lattices can be identified by solid state characterization methods such as by XRPD. Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and the like further help identify the crystalline form as well as help determine stability and solvent/water content.
  • Different crystalline forms of a particular substance can include both anhydrous forms of that substance and solvated/hydrated forms of that substance, where each of the anhydrous forms and solvated/hydrated forms are distinguished from each other by different XRPD patterns, or other solid state characterization methods, thereby signifying different crystalline lattices.
  • a single crystalline form e.g., identified by a unique XRPD pattern
  • An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form.
  • the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters used, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks can be observed or existing peaks can disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
  • the term “peak” refers to a reflection having a relative height/intensity of at least about 3% or at least about 4% of the maximum peak height/intensity.
  • instrument variation and other factors can affect the 2-theta values.
  • peak assignments can vary by plus or minus about 0.2° (2-theta) and the term “substantially” as used in the context of XRPD herein is meant to encompass the above-mentioned variations.
  • Crystalline forms of a substance can be obtained by a number of methods, as known in the art.
  • Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, exposure to moisture, grinding and solvent-drop grinding.
  • additives such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, exposure to moisture, grinding and solvent-drop grinding.
  • amorphous or “amorphous form” is intended to mean that the substance, component, or product in question is not crystalline as determined, for instance, by XRPD or where the substance, component, or product in question, for example is not birefringent when viewed microscopically.
  • amorphous means essentially without regularly repeating arrangement of molecules or lacks the long range order of a crystal, i.e., amorphous form is non-crystalline.
  • An amorphous form does not display a defined x-ray diffraction pattern with sharp maxima.
  • a sample comprising an amorphous form of a substance can be substantially free of other amorphous forms and/or crystalline forms.
  • an amorphous substance can be identified by an XRPD spectrum having an absence of reflections.
  • 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. so 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.
  • solvate refers to a solid form of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof), which includes one or more molecules of a solvent in stoichiometric or non-stoichiometric amount. Where the solvent is water, the solvate is a hydrate.
  • the solid forms of the disclosure include hemihydrates, monohydrates, and dihydrates. In some embodiments, the solid form is anhydrous.
  • the compounds described herein can be used in a neutral form, such as, a free acid or free base form. Alternatively, the compounds can be used in the form of salts, such as pharmaceutically acceptable addition salts of bases.
  • 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, for example, a composition enriched in the compounds of the disclosure.
  • 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 disclosed herein.
  • compositions comprising any one of the compounds or solid forms described herein 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.
  • the formulation methods and excipients described herein are exemplary and are in no way limiting.
  • compositions 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, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like can be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be used.
  • acceptable carriers and/or diluents include saline and sterile water, and can optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound or solid form described herein, diluents, dispersing and surface active agents, binders, and lubricants.
  • One skilled in this art can further formulate the compounds or solid forms described herein 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 compound or solid form 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. These compositions can also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • parental administration the compounds or solid forms of the present disclosure can be prepared in aqueous injection solutions which can contain, in addition to the compound or solid form, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions. As described herein optimal doses are generally determined using experimental models and/or clinical trials.
  • the optimal dose of the compound or solid form can depend upon the body mass, weight, blood volume, or other individual characteristics of the subject. For example, a person skilled in the medical art can consider the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Subjects can generally be monitored for therapeutic effectiveness by clinical evaluation and using assays suitable for the condition being treated or prevented, which methods will be familiar to those having ordinary skill in the art and are described herein.
  • the level of a compound that is administered to a subject can be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., plasma, serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound can be used to measure the level of compound during the course of a therapeutic regimen.
  • Pharmaceutical compositions comprising a compound or solid form described herein can be formulated for timed release (also called extended release, sustained release, controlled release, or slow release). Such compositions can generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations can contain the compound or solid form dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and can also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented.
  • the pharmaceutical compositions described herein that comprise at least one of the compounds or solid forms described herein can be administered to a subject in need of treatment or prevention by any one of several routes that effectively deliver an effective amount of the compound.
  • Such administrative routes include, for example, oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, intracavernous), enteral, rectal, intranasal, buccal, sublingual, intramuscular, and transdermal.
  • Pharmaceutical preparations for oral administration can be obtained by any suitable method, typically by uniformly mixing the compound(s) or solid form 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.
  • 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. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations.
  • Parenteral dosage forms can be prepared by dissolving the compound or solid form of the disclosure in a suitable liquid vehicle and filter sterilizing the solution before lyophilization, or simply filling and sealing an appropriate vial or ampule.
  • drug substance defined in the context of a “pharmaceutical composition.” refers to a component of a pharmaceutical composition such as any one of the compounds as disclosed and described herein that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no therapeutic benefit.
  • an “excipient” refers to a substance that is added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability, etc., to the composition.
  • a “diluent” is a type of excipient, and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but can be pharmaceutically necessary or desirable.
  • a diluent can be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It can also be a liquid for the dissolution of a drug to be administered by injection, ingestion, or inhalation.
  • a pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance.
  • compositions formulated as liquid solutions include saline and sterile water, and can optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the diluents can be a buffered aqueous solution such as, without limitation, phosphate buffered saline.
  • the compositions can also be formulated as capsules, granules, or tablets which contain in addition to a compound or solid form as disclosed and described herein, diluents, dispersing and surface active agents, binders, and lubricants.
  • One skilled in this art can further formulate a compound or solid form as disclosed and described herein in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington, supra.
  • the drug substance is typically mixed 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 can 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. These preparations can contain, in addition to the drug substance, 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 drug substance is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • 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.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • 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.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the drug substance in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • the compounds and solid forms of the disclosure 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, pastilles comprising the drug substance in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes comprising the drug substance in a suitable liquid carrier.
  • Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other ingredients.
  • 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 in which the drug substance is provided in a pressurized pack with a suitable propellant.
  • the compounds of the disclosure 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.
  • Pharmaceutical forms for administration of the compounds of the present disclosure as an aerosol can be prepared by processes well known to the person skilled in the art. The dose of drug can be controlled by provision of a metered valve.
  • the compounds or solid forms of the disclosure will generally have a small particle size for example of the order of 10 microns or less.
  • the pharmaceutical composition can be provided in the form of a dry powder, for example, a powder mix of the compound or solid form in a suitable, powder base such as lactose, starch, starch derivatives.
  • a suitable, powder base such as lactose, starch, starch derivatives.
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition can be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder can be administered by means of an inhaler.
  • the compounds or solid forms of the disclosure 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 (such as a polymer carrier and the like) and a compound or solid form of the disclosure.
  • Rapid dissolving or slow release carriers are used to form complexes that capture therein a drug substance and either rapidly or slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic, etc.). Such particles are useful because they degrade/dissolve in body fluids and release the active compound(s) therein.
  • 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 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.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • compositions can contain suitable excipients as described herein.
  • the 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 can 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.
  • a "dose” or “dosage” means the measured quantity of a drug substance to be taken at one time by a patient.
  • the drug substance is mixed with an excipient to form a solid preformulation composition containing a homogeneous mixture of components.
  • a solid preformulation composition containing a homogeneous mixture of components.
  • the drug substance is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing a discrete amount of the drug substance or equivalent mass of the drug substance.
  • the amount of drug substance required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human.
  • these extrapolations can merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity efficacy pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present disclosure and as part of a drug combination.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this disclosure is selected in accordance with a variety factors as cited above.
  • kits with unit doses of one or more of the compounds or solid forms 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 is 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.
  • a “pharmaceutically acceptable salt” refers to salts of a compound having an acidic or basic moiety which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of an acidic or basic moiety (e.g. amino and/or carboxyl groups or groups similar thereto).
  • Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with inorganic acids and organic acids.
  • Inorganic acids which can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids which can be used to prepare salts include, for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed by combining a compound having an acidic moiety with inorganic and organic bases.
  • Inorganic bases which can be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like.
  • the inorganic base salt is ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates.
  • Organic bases from which can be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with at least a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN).
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN).
  • suitable salts are found in WO 87/05297; Johnston et al., published September 11, 1987; Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418; and J. Pharm.
  • 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%, or greater than about 99%.
  • Resolution of racemic or diastereomeric mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallizaion using a chiral resolving organic acid with a racemic compound containing a basic group.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-toluoyl-tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • the resolving agent is di-p-toluoyl-D-tartaric acid.
  • 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 or diastereomeric compound containing a basic group.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • 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%, 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 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%, or at least about 99.9% diastereomeric excess, or a diastereomeric excess within a range defined by any of the preceding numbers.
  • Methods of Use/Treatment The compounds of the disclosure (e.g., Compound 1) 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 of the disclosure, or a pharmaceutically acceptable salt or solid form 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 compounds and solid forms described herein can reduce the level of monoamines in the central nervous system.
  • 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 or solid form described herein, sufficient to lower the level of monoamines relative to the level prior to administration.
  • the compounds and solid forms of the disclosure are believed to have utility over a wide range of therapeutic applications, and can 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. These disorders include neurological and psychiatric disorders, for example, hyperkinetic movement disorders, schizophrenia, and mood disorders.
  • 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 compound or solid form described herein.
  • 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 syndrome,
  • a hyperkinetic movement disorder in a subject in need thereof by administering to the subject in need thereof a pharmaceutically effective amount of a compound or solid form described herein.
  • 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 compound or solid form described herein.
  • 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 compound or solid form described herein.
  • the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.
  • the hyperkinetic movement disorder is tardive dyskinesia.
  • 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 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 or solid forms described herein are administered as adjunctive therapy.
  • the compounds or solid forms 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. In some embodiments, the compound described herein is administered as maintenance therapy for the treatment of Bipolar I Disorder. In some embodiments, the compound or solid form described herein is administered as monotherapy maintenance therapy for the treatment of Bipolar I Disorder.
  • the VMAT2-inhibiting compound of the disclosure 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 patient which is treated has been determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having 22q11.2 deletion syndrome. In some embodiments, the patient has been determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to developing a psychiatric disorder due to the patient having COMT haploinsufficiency. In another embodiment, the compounds described herein can be hydrolyzed in the body of a mammal to compounds that can inhibit the human vesicular monoamine transporter isoform 2.
  • these compounds can 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 compounds described herein can be determined using methods described herein and in the art. For example, dopamine depletion can be determined using the locomotor activity (LMA) assay. Another in vivo animal model includes the conditioned avoidance response (CAR) test, which has been shown to be an effective and reliable preclinical model for assessing the antipsychotic activity of compounds.
  • CAR conditioned avoidance response
  • Combination Therapy The compounds and solid forms of the disclosure can be used as monotherapy, or in combination with one or more other pharmaceutical agents.
  • a compound or solid form of the disclosure 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 or solid form of the disclosure, or its pharmaceutically acceptable salt 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.
  • adjunctive therapy if obsessive-compulsive disorder is being treated, the primary therapy can be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy.
  • the primary therapy can be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy.
  • CERTAIN ABBREVIATIONS The specification includes numerous abbreviations, whose definitions are listed in the following Table: A A A B C E d D d D d D D D D e E g h hour(s) Abbreviation Definition H H H I J L N O r s t T T T p P The following examples are included to demonstrate embodiments of the disclosure.
  • Method A HPLC Purity method for analyzing the samples
  • System HPLC System with UV Detector (Agilent 1260 or equivalent)
  • Column Waters XSelect CSH-C18, 4.6 x 150 mm, 3.5 ⁇ m Part Number: 186005270 Wavelength : 280 nm
  • Injection Volume 5 ⁇ L
  • Flow Rate 1.0 mL/min
  • Column Temp. 50°C Auto Sampler Temp.
  • Method B HPLC Chiral Purity method for analyzing NBI-751508 System : HPLC System with UV Detector (Agilent 1260 or equivalent) Column : Phenomenex Lux Cellulose-4, 4.6 x 150mm, 3 ⁇ m Part Number: 00F-4490-E0 Wavelength : 280 nm Injection Volume : 5 ⁇ L Flow Rate : 1.0 mL/min Column Temp : 30°C Auto Sampler Temp : Ambient Sample Diluent : Water:Acetonitrile (1:1) (v:v) Sample Conc.
  • DIEA (236.5 g, 1.5 equiv) was added at a rate of about 10 mL/min for 30 minutes while maintaining the temperature between about 25 °C and 30 °C.
  • the resulting mixture was allowed to stir at 25 °C for 90 minutes.
  • the reaction was quenched with 6V of water and allowed to stir for at least 15 min. Stirring was then stopped and layers allowed to settle. Clean separation was obtained and the layers were separated and analyzed by LC.
  • the organic layer was washing with 0.5 M HCl and water.
  • the pH was adjusted to 11-12 using 45% w/v aq. KOH ( ⁇ 130 mL used). A solid came out of solution while adding base but re-dissolved immediately. Once the desired pH was obtained, the mixture was permitted to stir for 15 min.
  • the mixture was warmed to 20 °C. Brine (4V) was added, and the layers were separated. The organic layer was washed with water twice. The organic layer was concentrated from 2.8 L to 1.8 L. The organic layer was determined to contain Compound 6.
  • the solution was warmed to 40 °C, and p-toluenesulfonic acid (406 g, 1.75 equiv) was added. The mixture was allowed to stir for six hours, and another equivalent of p- toluenesulfonic acid (232 g, 1 equiv) was added. The mixture was allowed to stir overnight. The mixture was diluted with MTBE and heated to 50 °C over three hours, and then held at 50 °C for one hour.
  • the pH of the mixture was adjusted to be about 12.
  • the aqueous phase of the salt break was discarded.
  • dimethoxyacetaldehyde (286.5 g, 1.5 equiv) and acetic acid (330.46 g, 5 equiv) were added and stirred at room temperature.
  • Sodium borohydride (72.86 g, 1.75 equiv) was added in portions at room temperature. After about thirty minutes, the mixture was diluted with water and quenched with 30% aqueous potassium hydroxide.
  • the organic layer was concentrated and azeotropically dried while exchanging into acetonitrile.
  • the solution was polish filtered, diluted with acetonitrile (1.2 L) and heated to 40 °C.
  • Aqueous hydrochloric acid (37% wt, 96.74 g, 2 equiv) was charged.
  • the solution was concentrated to half the total volume and diluted back to the original volume with acetonitrile four times to azeotropically dry the solvent.
  • the suspension was cooled slowly to room temperature and filtered.
  • the solid was washed with acetonitrile and dried under vacuum to provide theoxy compound as a crystalline solid (Compound 1 ⁇ 2HCl, Form III).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des procédés et des intermédiaires pour la préparation de (3R,11bS)-3-(2,2-diméthylpropyle)-10-méthoxy-2-méthyl-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-pipérazino[2,1-a]isoquinoline, et des sels associés, laquelle préparation est un inhibiteur du transporteur de monoamine vésiculaire 2 (VMAT2). Les composés et sels, solvates et hydrates associés tels que décrits ici sont utiles dans le traitement de maladies et de troubles neurologiques et psychiatriques.
PCT/US2022/026711 2021-04-29 2022-04-28 Méthodes de préparation d'un inhibiteur de vmat2 WO2022232380A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163181262P 2021-04-29 2021-04-29
US63/181,262 2021-04-29

Publications (1)

Publication Number Publication Date
WO2022232380A1 true WO2022232380A1 (fr) 2022-11-03

Family

ID=81654593

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/026711 WO2022232380A1 (fr) 2021-04-29 2022-04-28 Méthodes de préparation d'un inhibiteur de vmat2

Country Status (1)

Country Link
WO (1) WO2022232380A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11718618B2 (en) 2021-03-22 2023-08-08 Neurocrine Biosciences, Inc. Substituted pyrido[2,1-a]isoquinolines as VMAT2 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987005297A1 (fr) 1986-03-03 1987-09-11 The University Of Chicago Derives de cephalosporines
WO2018195121A1 (fr) 2017-04-19 2018-10-25 Neurocrine Biosciences, Inc. Composés inhibiteurs de vmat2 et compositions de ceux-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987005297A1 (fr) 1986-03-03 1987-09-11 The University Of Chicago Derives de cephalosporines
WO2018195121A1 (fr) 2017-04-19 2018-10-25 Neurocrine Biosciences, Inc. Composés inhibiteurs de vmat2 et compositions de ceux-ci

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
E.L. ELIELS.H. WILENL.N. MANDER: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
FIESER, L. F.FIESER, M, REAGENTS FOR ORGANIC SYNTHESIS, 1967, pages 581 - 595
J. PHARM. SCI., vol. 66, no. 2, 1977
P. H. STAHLC. G. WERMUTH: "Handbook of Pharmaceutical Salts", 2002, VERLAG HELVETICA CHIMICA ACTA
PETURSSION ET AL.: "Protecting Groups in Carbohydrate Chemistry", J. CHEM. EDUC., vol. 74, no. 11, 1997, pages 1297
REMINGTON: "Remington: The Science and Practice of Pharmacy", 2005, MACK PUB. CO.
ROBERTSON: "Protecting Group Chemistry,", 2000, OXFORD UNIVERSITY PRESS
ROWE ET AL.: "Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety", 2006, WILEY
SMITH ET AL.: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2007, THIEME

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11718618B2 (en) 2021-03-22 2023-08-08 Neurocrine Biosciences, Inc. Substituted pyrido[2,1-a]isoquinolines as VMAT2 inhibitors

Similar Documents

Publication Publication Date Title
KR102637844B1 (ko) 키나아제를 조절하는 1h-피롤로[2,3­b]피리딘 유도체의 합성
EP2170805B1 (fr) Procédés de synthèse du cinacalcet et de ses sels
JP2007508362A (ja) Ｎ−［フェニル（ピロリジン−２−イル）メチル］ベンズアミドおよびｎ−［（アゼパン−２−イル）フェニルメチル］ベンズアミド誘導体、この調製方法および治療法における使用
JP5635181B2 (ja) ニトロイミダゾール系化合物、その製造方法および用途
WO2022232380A1 (fr) Méthodes de préparation d'un inhibiteur de vmat2
CA2758251C (fr) Inhibiteur de la recapture de la serotonine-noradrenaline
US20060270713A1 (en) 3-Aminopyrrolidines as inhibitors of monoamine uptake
CA2701638A1 (fr) Substances calcimimetiques pharmaceutiques
EP2896623A1 (fr) CRISTAL DE N-[2-({2-[(2S)-2-CYANOPYRROLIDIN-1-YL]-2- OXOÉTHYL}AMINO)-2-MÉTHYLPROPYL]-2-MÉTHYLPYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXAMIDE
CN101506156A (zh) 对GlyT1转运蛋白具有活性的吡咯烷衍生物
EP1451166B1 (fr) Sel d'acide citrique d'un compose therapeutique et compositions pharmaceutiques associees
AU2011346746A1 (en) Polymorphs of 3-chloro-4[(2R)-2
WO2011115173A1 (fr) Monomaléate de composé de benzothiazine
JP7126522B2 (ja) （＋）－３－（２，３－ジフルオロフェニル）－３－メトキシピロリジンまたはその薬学的に許容される塩、それを調製するための方法およびその使用
US20230312573A1 (en) Novel salts, crystals, and co-crystals
EP3866854B1 (fr) Dérivés de 4-pyridinylméthyl-morpholine et leur utilisation comme médicament
EP2272847A1 (fr) Enantiomères et leur utilisation comme inhibiteurs du recaptage des neurotransmetteurs monoamine
RU2325378C2 (ru) Новые производные пиперидина и их применение в качестве ингибиторов обратного захвата нейромедиаторных моноаминов
EP4334281A1 (fr) Formes solides de (r)-oxybutynine d-malate
JP2023539336A (ja) Ｇｐｒ５２モジュレーター化合物
MX2011005109A (es) Derivados de 8-azabiciclo[3.2.1]oct-2-eno y su uso como inhibidores de la re-absorcion del neurotansmisor de monoamina.
AU2010212703A1 (en) N-[(6-azabicyclo[3.2.1]oct-1-yl)-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof
FR2943056A1 (fr) Derives de n-°2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique
WO2010106269A2 (fr) Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, leur preparation et leur application en therapeutique
FR2944283A1 (fr) Derives de n-°(2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22723916

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22723916

Country of ref document: EP

Kind code of ref document: A1