WO2023067520A1 - Formes cristallines et processus pour la préparation de dérivés de pyrimidine utiles en tant que modulateurs du récepteur 5-ht2a de la sérotonine - Google Patents

Formes cristallines et processus pour la préparation de dérivés de pyrimidine utiles en tant que modulateurs du récepteur 5-ht2a de la sérotonine Download PDF

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Publication number
WO2023067520A1
WO2023067520A1 PCT/IB2022/060059 IB2022060059W WO2023067520A1 WO 2023067520 A1 WO2023067520 A1 WO 2023067520A1 IB 2022060059 W IB2022060059 W IB 2022060059W WO 2023067520 A1 WO2023067520 A1 WO 2023067520A1
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salt
phenyl
alkyl
ethoxy
cyclopropanecarboxamide
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PCT/IB2022/060059
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English (en)
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Anthony C. Blackburn
Jui-Chen LIN
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Arena Pharmaceuticals, Inc.
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Priority to CA3235907A priority Critical patent/CA3235907A1/fr
Publication of WO2023067520A1 publication Critical patent/WO2023067520A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present disclosure relates to crystalline forms and salts of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2 A serotonin receptor.
  • the present invention further relates to processes useful in the preparation of crystalline forms and salts of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide and pharmaceutical compositions thereof.
  • Receptors for serotonin are an important class of G protein coupled receptors. Serotonin receptors are divided into seven subfamilies, referred to as 5-HTi through 5-HT 7 , inclusive. These subfamilies are further divided into subtypes. For example, the 5-HT 2 subfamily is divided into three receptor subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C . Certain modulators of 5-HT 2A serotonin receptor activity are useful in the treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, or symptoms thereof.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)):
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide comprising the steps of: a) contacting said A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) with an acid, in the presence of a contacting-step solvent; b) crystallizing A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) to obtain a crystalline salt of A/-(3- (4,6-dimethylpyrimidin-5-
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide, wherein the process further comprises stirring after the contacting step.
  • One aspect of the present disclosure relates to processes wherein the the contacting-step solvent is selected from a group consisting of acetone, acetonitrile, 1-butanol, 2-butanol, butyl acetate, 1 ,2-dimethoxyethane, N,N-dimethylacetamide, 1 ,4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, isopropyl acetate, heptane, methyl isobutyl ketone (MIBK), 2-methyl-1 -propanol, A/-methyl pyrrolidone, 1 -propanol, 2-propanol, n-propyl acetate, te/Y-butyl methyl ether (TBME), tetra hydrofuran (THF), water, and dimethyl sulfoxide (DMSO) and combinations thereof.
  • the contacting-step solvent is selected from a group consisting of acetone,
  • One aspect of the present disclosure relates to processes wherein the acid is a mineral acid or an organic acid.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide comprising the step of: isolating said crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) from said crystallizing mixture to obtain said crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) prepared by a process as described herein.
  • compositions comprising a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein.
  • compositions comprising a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, and a pharmaceutically acceptable carrier.
  • One aspect of the present disclosure relates to processes of making a composition
  • processes of making a composition comprising mixing a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, with a pharmaceutically acceptable carrier.
  • One aspect of the present disclosure relates to methods of treating a 5HT 2 A-related disorder in an individual, comprising administering to an individual in need thereof, a therapeutically effective amount of a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to the use of a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, in the manufacture of a medicament for the treatment of a 5HT 2 A-related disorder.
  • One aspect of the present disclosure relates to a crystalline form of 5HT 2 A-related disorder as described herein, for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, for use in a method of treatment of a 5HT 2A -related disorder.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, for use in a method of treatment of a 5HT 2A -related disorder.
  • One aspect of the present disclosure relates to crystalline salts of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline citrate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline fumarate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline hydrochloride salt of A/-(3- (4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline mesylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline phosphate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline succinate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline tosylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound of Formula (la).
  • PXRD powder X-ray diffraction
  • Figure 2 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound of Formula (la).
  • FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound of Formula (la).
  • Figure 4 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Besylate Salt).
  • Figure 5 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Besylate Salt).
  • FIG. 6 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Besylate Salt).
  • Figure 7 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Citrate Salt).
  • Figure 8 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Citrate Salt).
  • FIG 9 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Citrate Salt).
  • Figure 10 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Fumarate Salt).
  • Figure 11 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Fumarate Salt).
  • Figure 12 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Fumarate Salt).
  • Figure 13 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Hydrochloride Salt).
  • Figure 14 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Hydrochloride Salt).
  • FIG 15 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Hydrochloride Salt).
  • Figure 16 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Mesylate Salt).
  • Figure 17 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Mesylate Salt).
  • FIG 18 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Mesylate Salt).
  • Figure 19 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Phosphate Salt).
  • Figure 20 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Phosphate Salt).
  • FIG 21 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Phosphate Salt).
  • Figure 22 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Succinate Salt).
  • Figure 23 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Succinate Salt).
  • FIG 24 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Succinate Salt).
  • Figure 25 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline salt of Compound la (Tosylate Salt).
  • PXRD powder X-ray diffraction
  • Figure 26 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline salt of Compound la (Tosylate Salt).
  • FIG. 27 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline salt of Compound la (Tosylate Salt).
  • agonists is intended to mean moieties that interact and activate the receptor, such as the 5-HT2A serotonin receptor, and initiate a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
  • antagonists is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • “contact or contacting” is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system.
  • “contacting” a 5-HT 2 A serotonin receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a 5-HT 2 A serotonin receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a 5-HT 2A serotonin receptor.
  • inverse agonists is intended to mean moieties that bind to the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • modulate or modulating is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • administering means to provide a compound or other therapy, remedy, or treatment such that an individual internalizes a compound.
  • a health care provider orally advises, recommends, or authorizes the use of a compound, dosage regimen, or other treatment to an individual.
  • the health care provider may or may not provide a written prescription for the compound, dosage regimen, or treatment. Further, the health care provider may or may not provide the compound or treatment to the individual. For example, the health care provider can advise the individual where to obtain the compound without providing the compound.
  • a health care provider can provide a written prescription forthe compound, dosage regimen, or treatment to the individual. A prescription can be written on paper or recorded on electronic media.
  • a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary.
  • a sample of the compound or treatment is given to the individual.
  • giving a sample of a compound constitutes an implicit prescription for the compound.
  • Different health care systems around the world use different methods for prescribing and administering compounds or treatments, and these methods are encompassed by the disclosure herein.
  • a health care provider can include, for example, a physician, nurse, nurse practitioner, or other health care professional who can prescribe or administer compounds (drugs) for the disorders disclosed herein.
  • a health care provider can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.
  • in need of treatment and “in need thereof’ when referring to treatment, are used interchangeably to mean a judgment made by a caregiver (e.g., physician, nurse, or nurse practitioner in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the disclosure. Accordingly, the compounds of the disclosure can be used in a protective or preventive manner; or compounds of the disclosure can be used to alleviate, inhibit, or ameliorate the disease, condition, or disorder.
  • a caregiver e.g., physician, nurse, or nurse practitioner in the case of humans; veterinarian in the case of animals, including non-human mammals
  • mice refers to any animal, including mammals such as mice, rats, and other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, “individual” refers to humans.
  • composition refers to a compound or crystalline form thereof, including but not limited to, salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component, such as, a composition obtained/prepared during synthesis, preformulation, in-process testing (i.e., TLC, HPLC, NMR samples), and the like.
  • additional component such as, a composition obtained/prepared during synthesis, preformulation, in-process testing (i.e., TLC, HPLC, NMR samples), and the like.
  • hydrate as used herein means a compound of the invention or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
  • composition refers to a specific composition comprising at least one active ingredient, including but not limited to, salts, solvates, and hydrates of compounds of the present disclosure, 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 an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • phrases “pharmaceutically acceptable salts, solvates, and hydrates” when referring to a compound/compounds as described herein embraces pharmaceutically acceptable solvates and/or hydrates of the compound/compounds, pharmaceutically acceptable salts of the compound/compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compound/compounds. It is also understood that when the phrase “pharmaceutically acceptable solvates and hydrates” or the phrase “pharmaceutically acceptable solvate or hydrate” is used when referring to a compound/compounds as described herein that are salts, it embraces pharmaceutically acceptable solvates and/or hydrates of such salts. It is also understood by a person of ordinary skill in the art that hydrates are a subgenus of solvates.
  • solvate means a compound or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non- covalent intermolecular forces.
  • exemplary solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • hydrate means a compound or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • compound is also meant to be agnostic as to how the compound is formed, be it synthetically or biologically.
  • a compound of the present disclosure can be produced in the body through metabolism.
  • prevention refers to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder.
  • the terms “prevent,” “preventing,” and “prevention” can refer to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disorder but who has not yet done so. Such individuals 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 the administration of therapy to an individual who already manifests, or who has previously manifested, at least one symptom of a disease, disorder, condition, dependence, or behavior.
  • “treating” can include any of the following with respect to a disease, disorder, condition, dependence, or behavior: alleviating, abating, ameliorating, improving, inhibiting (e.g., arresting the development), relieving, or causing regression.
  • “Treating” can also include treating the symptoms, preventing additional symptoms, preventing the underlying physiological causes of the symptoms, or stopping the symptoms (either prophylactically and/or therapeutically) of a disease, disorder, condition, dependence, or behavior.
  • treating in reference to a disorder means a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which can include one or more of the following:
  • preventing the disorder for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but does not yet experience or display the relevant pathology or symptomatology;
  • inhibiting the disorder for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., arresting further development of the pathology and/or symptomatology);
  • ameliorating the disorder for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., reversing the pathology and/or symptomatology).
  • the term “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which includes preventing the disorder, for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, ordisorder but does not yet experience or display the relevant pathology or symptomatology.
  • the term “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which includes inhibiting the disorder, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., arresting further development of the pathology and/or symptomatology).
  • the term “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which includes ameliorating the disorder, for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., reversing the pathology and/or symptomatology).
  • alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • alkylene means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene.
  • Alkylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkylene groups include 1 to 9 carbon atoms (for example,
  • cycloalkyl means a non-aromatic cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Cycloalkyl may include multiple fused rings. Cycloalkyl may have any degree of saturation provided that none of the rings in the ring system are aromatic. Cycloalkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, cycloalkyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.
  • aryl means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic.
  • Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, and 2,3-dihydro-IH- indenyl. In some embodiments, the aryl is phenyl.
  • halo refers to a chloro, bromo, fluoro, or iodo atom radical.
  • a halo is a chloro, bromo or fluoro.
  • a halide can be fluoro.
  • haloalkyl means a hydrocarbon substituent, which is a linear or branched alkyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s).
  • a haloalkyl is a fluoroalkyl, wherein one or more of the hydrogen atoms have been substituted by fluoro.
  • haloalkyls are of 1 to 3 carbons in length (e.g., 1 to
  • haloalkylene means a bivalent branched, or straight chain alkylene substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s), such as chloromethylene, dichloromethylene, 1 ,1 -dichloroethylene, and 1 ,2-dichloroehtylene.
  • Alkylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • heteroaryl means a mono- or bicyclic group having 5 to 10 ring atoms, such as 5, 6, 8, 9, or 10 ring atoms, such as 5, 6, 9, or 10 ring atoms; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrrolo[2,3-6]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyri
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl or “heterocycloalkyl” means a 3-14 membered, such as 3- 11 membered, such as 3-8 membered nonaromatic mono-, bi- or tricyclic group comprising at least one heteroatom in the ring system backbone.
  • Bicyclic and tricyclic heterocyclyl groups may include fused ring systems, spirocyclic ring systems, and bridged ring systems and may include multiple fused rings.
  • heterocyclyls have one to four heteroatom(s) independently selected from N, O, and S.
  • heterocyclyls have one to three heteroatom(s) independently selected from N, O, and S.
  • heterocyclyls have one to two heteroatom(s) independently selected from N, O, and S.
  • monocyclic heterocyclyls are 3-membered rings.
  • monocyclic heterocyclyls are 4-membered rings.
  • monocyclic heterocyclyls are 5- membered rings.
  • monocyclic heterocyclyls are 6-membered rings.
  • monocyclic heterocyclyls are 7-membered rings.
  • “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone.
  • heterocyclyls include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1 ,4,2-dithiazolyl, di hydro pyridinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, and thiomorpholinyl.
  • the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.
  • bicyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone.
  • bicyclic heterocyclyls examples include 2-azabicyclo[1 .1 .0] butane, 2-azabicyclo[2.1 ,0]pentane, 2- azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1 ,0]hexane, 5-azabicyclo[2.1 ,1]hexane, 3- azabicyclo[3.2.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1 ,0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1 ,1]heptane, 7- azabicyclo[4.2.0]octane, and 2-azabicyclo[2.2.2]octane.
  • spirocyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom.
  • spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 2-oxa-6-azaspiro[3.3]heptane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1 ,7-diazaspiro[3.5]nonane, 2,7- diazaspiro[3.5]nonane, 1 ,7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 1-ox
  • heterocycloalkyls examples include azetidinyl, azetidinyl-3-ol, 3-fluoroazetidinyl, pyrrolidinyl, pyrrolidinyl-3-ol, 3-methoxypyrrolidinyl, 2-(pyrrolidin-3-yl)acetic acid, piperidinyl, piperidinyl-4-ol, 2-(piperidin-4-yl)acetic acid, 4-methoxypiperidinyl, piperazinyl, piperazinyl-1- carbaldehyde, 1-methylpiperazinyl-2-one, 1 -(piperazin-1 -yl)ethan-1 -one, 1- (methylsulfonyl)piperazinyl, 2-hydroxy-1 -(piperazin-1 -yl)ethan-1 -one, 2-oxo-2-(piperazin-1 - yl)acetic acid, morpholinyl, 3-azabicyclo[3.1 .
  • the present disclosure is directed to, inter alia, processes useful in the preparation of a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide, a modulator of the 5-HT 2 A serotonin receptor.
  • the present invention provides, inter alia, processes for preparing compounds of Formula (He): comprising the step of: coupling the compound of Formula (lid) or a salt thereof: wherein R 2 is selected from 4-6 membered heterocycloalkyl, (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 membered heterocycloalkyl ring; and;
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; with an acyl chloride of Formula (Hd-1); wherein R 1 is selected from R 1 is selected from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 5-9 membered heterocycloalkyl; in the presence of a base and a solvent to form said compound of Formula (He).
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)):
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide comprising the steps of: a) contacting said A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) with an acid, in the presence of a contacting-step solvent; b) crystallizing A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) to obtain a crystalline salt of A/-(3- (4,6-dimethylpyrimidin-5-y
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the process further comprises stirring after the contacting step.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the stirring is conducted at a temperature of about 20 °C to about 75 °C.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the stirring is conducted at a temperature of about 30 °C to about 65 °C.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the stirring is conducted at a temperature of about 30 °C to about 55 °C.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the stirring is conducted at a temperature of about 30 °C to about 45 °C.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the contacting-step solvent is selected from a group consisting of acetone, acetonitrile, 1 -butanol, 2-butanol, butyl acetate, 1 ,2-dimethoxyethane, N,N-dimethylacetamide, 1 ,4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, isopropyl acetate, heptane, methyl isobutyl ketone (MIBK), 2-methyl-1 -propanol, A/- methyl pyrrolidone, 1 -propanol, 2-propanol, n-propyl
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the acid is a mineral acid or an organic acid.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the mineral acid is selected from a group consisting of hydrochloric acid, phosphoric acid, and sulfuric acid.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein the organic acid is selected from a group consisting of benzenesulfonic acid, benzoic acid, citric acid, fumaric acid, maleic acid, methanesulfonic acid, succinic acid, and p-toluenesulfonic acid.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein isolating comprises filtering said crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide from said crystallizing mixture.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein isolating comprises removing said crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide from said crystallizing mixture.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein isolating comprises drying said crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide from said crystallizing mixture.
  • drying is conducted at a temperature of about 25 °C to about 90 °C. In some embodiments, drying is conducted at a temperature of about 25 °C to about 85 °C. In some embodiments, drying is conducted at a temperature of about 35 °C to about 75 °C. In some embodiments, drying is conducted at a temperature of about 35 °C to about 45 °C.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein after isolating, said crystalline salt of A/-(3- (4 ,6-d i meth y I py ri mid i n-5-y l)-4-(2- (py rrol id i n- 1 - yl)ethoxy)phenyl)cyclopropanecarboxamide has a chemical purity of about 95% or greater.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein after isolating, said crystalline salt of A/-(3- (4 ,6-d i meth y I py ri mid i n-5-y l)-4-(2- (py rrol id i n- 1 - yl)ethoxy)phenyl)cyclopropanecarboxamide has a chemical purity of about 98% or greater.
  • One aspect of the present disclosure relates to processes for preparing a crystalline salt of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)), wherein after isolating, said crystalline salt of A/-(3- (4 ,6-d i meth y I py ri mid i n-5-y l)-4-(2- (py rrol id i n- 1 - yl)ethoxy)phenyl)cyclopropanecarboxamide has a chemical purity of about 99% or greater.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) prepared by a process described herein.
  • One aspect of the present disclosure relates to processes of making a composition
  • processes of making a composition comprising mixing a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein with a pharmaceutically acceptable carrier.
  • One aspect of the present disclosure relates to processes of making a composition further comprising forming the composition into drug product, such as, a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, a soft gelatin capsule, a hard gelatin capsule, a suppository, a sterile injectable solution, or a sterile packaged powder.
  • drug product such as, a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, a soft gelatin capsule, a hard gelatin capsule, a suppository, a sterile injectable solution, or a sterile packaged powder.
  • the present invention is directed, inter alia, to processes and intermediates useful in the preparation of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide of Formula (la) and/or salts related thereto.
  • One aspect of the present invention pertains to processes, such as those exemplified by Schemes I, II, III, and IV (supra), that involve Compounds (lib), (He), (lid), and (He).
  • One aspect of the present invention pertains to intermediates, Compounds (lib), (lie), (lid), and (lie), as exemplified in Schemes I, II, III, and IV (supra), useful in the preparation of Compounds of Formula (lie), (la) and/or a salt related thereto, a salt of compound of Formula (la).
  • R 1 is selected from R 1 is selected from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 5-9 membered heterocycloalkyl; wherein R 2 is selected from 4-6 membered heterocycloalkyl, (Ci-C 3 alkylene)-(4-10 membered heterocycloalkyl), and (Ci-C 3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (Ci-C 3 alkyl), -O-(Ci-C 3 alkyl), (Ci-C 3 alkylene)-
  • R 2A and R 2B are each independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, and C 3 - Ce cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, Ci-C 3 alkyl, (Ci-C 3 haloalkyl), -O-(Ci-C 3 alkyl), (Ci-C 3 alkylene)-C(O)OH, -C(O)H, -C(O)(Ci-C 3 alkyl), -C(O)(Ci-C 3 alkylene)-OH, -C(O)C(O)OH, and -SO 2 (Ci-C 3 alkyl), and optionally containing one additional heteroatom selected from the group of N, O, and S
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; and LG 1 comprises the groups Cl, Br, I, TfO, or TsO.
  • R 1 is selected from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, and 5-10 membered heteroaryl.
  • R 1 is selected from Ci-C 6 alkyl, and C 3 -C 6 cycloalkyl.
  • R 1 is selected C 3 -C 6 cycloalkyl and 5-10 membered heteroaryl.
  • R 1 is C 3 -C 6 cycloalkyl.
  • R 2 is selected from (Ci-C 3 alkylene)-(4-10 membered heterocycloalkyl) and (Ci-C 3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (Ci-C 3 alkyl), and -O-(Ci-C 3 alkyl);
  • R 2A and R 2B are each independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, and C 3 - C 6 cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, Ci-C 3 alkyl, (Ci-C 3 haloalkyl), and -O-(Ci-C 3 alkyl).
  • R 2 is selected from azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (Ci-C 3 alkyl), and -O-(Ci-C 3 alkyl).
  • R 2 is selected from azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more Ci-C 3 alkyl.
  • R 2 is (C1-C3 alkylene)-(4-10 membered heterocycloalkyl) and the 4-10 membered heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3-azabicyclo[3.1 .0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6- azabicyclo[3.1 ,1]heptanyl, octahydropyrrolo[1 ,2-a]pyrazinyl, hexahydro-3/7-oxazolo[3,4- a]pyrazinyl, 1 ,4-oxazepany
  • R 2 is an optionally substituted (C1-C3 alkyl)-(4-10 membered heterocycloalkyl), where the 4-10 membered heterocycloalkyl is selected from azetidinyl, azetidinyl-3-ol, 3-fluoroazetidinyl, pyrrolidinyl, pyrrolidinyl-3-ol, 3-methoxypyrrolidinyl, 2- (pyrrolidin-3-yl)acetic acid, piperidinyl, piperidinyl-4-ol, 2-(piperidin-4-yl)acetic acid, 4- methoxypiperidinyl, piperazinyl, piperazinyl-1-carbaldehyde, 1 -methylpiperazinyl-2-one, 1 - (piperazin-1 -yl)ethan-1 -one, 1 -(methylsulfonyl)piperazinyl, 2-hydroxy-1 -(piperazin-1 -(piperaz
  • R 2 is (C1-C3 alkylene)-(4-10 membered heterocycloalkyl) and the 4-10 membered heterocycloalkyl is pyrrolidinyl optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (C1-C3 alkyl), and -O-(Ci-C3 alkyl).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken togetherwith the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring.
  • R 2A and R 2B taken together with the nitrogen to which they are attached, form a pyrrolidinyl ring optionally substituted with one or more substituents independently selected from -OH, C1-C3 alkyl, and -O-(Ci-C 3 alkyl).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B .
  • R 2 is CH2-NR 2A R 2B .
  • R 2 is (CH 2 )2-NR 2A R 2B .
  • R 2 is (CH 2 )3-NR 2A R 2B .
  • R 3 and R 4 are each independently selected from H and Ci-Ce alkyl.
  • R 3 and R 4 are each Ci-C 6 alkyl.
  • R 3 and R 4 are each C1-C3 alkyl.
  • R 3 and R 4 are each methyl.
  • LG 1 is selected from the group consisting Cl, Br, I, and TfO.
  • LG 1 is selected from the group consisting Cl, Br, and I.
  • LG 1 is Br or I.
  • LG 1 is Br.
  • R 1 is C 3 -C 6 cycloalkyl
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring
  • R 1 is C 3 -C 6 cycloalkyl
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring
  • R 1 is C 3 -C 6 cycloalkyl
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring
  • R 2A and R 2B taken together with the nitrogen to which they are attached
  • R 3 and R 4 are each Ci-C 6 alkyl.
  • R 1 is cyclopropyl
  • R 3 and R 4 are each methyl.
  • One aspect of the present invention pertains to processes for preparing the intermediate compound of Formula (lib): comprising reacting (2-fluoro-5-nitrophenyl)boronic acid with a compound of Formula (Ila):
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; and LG 1 comprises the groups Cl, Br, I, TfO, or TsO; in the presence of: i) a palladium catalyst; ii) a base; and iii) a solvent; to form compound of Formula (lib).
  • R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl.
  • R 3 and R 4 are each Ci-C 6 alkyl.
  • R 3 and R 4 are each C1-C3 alkyl.
  • R 3 and R 4 are each methyl.
  • LG 1 is selected from the group consisting Cl, Br, and I.
  • LG 1 is Br or I.
  • LG 1 is Br.
  • the palladium-based catalyst comprises (2- Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1 ,1 '-biphenyl)]palladiu m(l I) methanesulfonate (SPhos Pd G3), 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2- (2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate (XPhos Pd G3), Methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-1 ,1 '-biphenyl)(2'-methylamino-1 , 1 '-biphenyl-2- yl)
  • the base comprises dipotassium hydrogenphosphate (K2HPO4), potassium bicarbonate (KHCO 3 ), potassium carbonate (K 2 CO 3 ), potassium dihydrogen phosphate (KH 2 PO 4 ), potassium phosphate (K3PO4), potassium te/Y-butoxide (KOtBu), sodium bicarbonate (NaHCOs), or sodium carbonate (Na 2 CO3).
  • the solvent comprises acetonitrile; 2-methyltetrahydrofuran; tetrahydrofuran (THF); THF-water; THF-water with ethanol; THF-water with 2-propanol; or toluene.
  • the solvent is 2-methyltetrahydrofuran; tetra hydro furan (THF); or THF-water.
  • the solvent is THF-water; THF-water with 10% ethanol; or THF- water with 10% 2-propanol.
  • said reacting step is conducted at a temperature of about 40 °C to about 100 °C.
  • said reacting step is conducted at a temperature of about 50 °C to about 100 °C.
  • said reacting step is conducted at a temperature of about 60 °C to about 100 °C.
  • a compound of Formula (llb-1): aib-i) is prepared by process according to the coupling step.
  • One aspect of the present invention pertains to processes for preparing the intermediate compound of Formula (He) or salt thereof: comprising the step of alkylating a compound of Formula (llb-1):
  • R 2 is selected from 4-6 membered heterocycloalkyl, (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C1-C3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (C1-C3 alkyl), and -O-(Ci-C 3 alkyl); R 2A and R 2B are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, and C 3 - C 6 cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, -
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; and optionally followed by treatment with a mineral acid in presence of an alcoholic solvent to form the salt of the compound of Formula (He).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken togetherwith the nitrogen to which they are attached, form a 3-5 membered heterocycloalkyl ring.
  • R 2A and R 2B taken together with the nitrogen to which they are attached, form a pyrrolidinyl ring optionally substituted with one or more substituents independently selected from -OH, C1-C3 alkyl, and -O-(Ci-C3 alkyl).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B .
  • R 2 is CH 2 -NR 2A R 2B .
  • R 2 is (CH 2 ) 2 -NR 2A R 2B .
  • R 2 is (CH 2 ) 3 -NR 2A R 2B .
  • R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl.
  • R 3 and R 4 are each C1-C3 alkyl.
  • R 3 and R 4 are each methyl.
  • the alkylating step is done in the presence of an alkylating-step base and an alkylating-step solvent.
  • the alkylating step comprises a alkylating-step base comprises calcium carbonate (CaCO 3 ), cesium carbonate (Cs 2 CO 3 ), N,N-diisopropylethylamine (DIPEA), dipotassium hydrogenphosphate (K 2 HPC>4), potassium bicarbonate (KHCO3), potassium carbonate (K 2 CO 3 ), potassium dihydrogen phosphate (KH 2 PO 4 ), potassium phosphate (K3PO4), potassium te/Y-butoxide (KOtBu), sodium bicarbonate (NaHCO 3 ), sodium carbonate (Na 2 CO 3 ), or triethylamine.
  • CaCO 3 calcium carbonate
  • Cs 2 CO 3 cesium carbonate
  • DIPEA N,N-diisopropylethylamine
  • K 2 HPC>4 dipotassium hydrogenphosphate
  • KHCO3 potassium bicarbonate
  • KH 2 CO 3 potassium carbonate
  • KH 2 PO 4 potassium dihydrogen phosphate
  • the alkylating-step solvent comprises acetonitrile, N,N- dimethylacetamide, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), tetra hydrofuran (THF) or mixtures thereof.
  • said alkylating step is conducted at a temperature of about 25 °C to about 100 °C.
  • said alkylating step is conducted at a temperature of about 45 °C to about 100 °C.
  • said alkylating step is conducted at a temperature of about 55 °C to about 100 °C. In some embodiments, said alkylating step is conducted at a temperature of about 65 °C to about 100 °C.
  • alkylating atep is followed by treatment with a mineral acid in presence of an alcoholic solvent to form the salt of the compound of Formula (He).
  • alkylating atep is followed by treatment with HCI in presence of methanol to form the hydrochloride salt of the compound of Formula (He).
  • alkylating atep is followed by treatment with HCI in presence of 2- propanol to form the hydrochloride salt of the compound of Formula (lie).
  • a compound of Formula (llc-1) or a hydrochloride salt thereof: is prepared by process according to the alkylation step.
  • One aspect of the present invention pertains to processes for preparing the intermediate compound of Formula (lid) or salt thereof: wherein R 2 is selected from 4-6 membered heterocycloalkyl, (Ci-C 3 alkylene)-(4- 10 membered heterocycloalkyl), and (Ci-C 3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (Ci-C 3 alkyl), and -O-(Ci-C 3 alkyl);
  • R 2A and R 2B are each independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, and C 3 -C 6 cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, Ci-C 3 alkyl, (Ci-C 3 haloalkyl), and -O-(Ci-C 3 alkyl); and; R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; is prepared by process comprising the step of reducing a compound of Formula (lie) or a salt thereof: wherein R 2 is selected from 4-6 membered heterocycloalkyl, (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl.
  • R 2 is selected from (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-5 membered heterocycloalkyl ring.
  • R 2A and R 2B taken together with the nitrogen to which they are attached, form a pyrrolidinyl ring optionally substituted with one or more substituents independently selected from -OH, C1-C3 alkyl, and -O-(Ci-C 3 alkyl).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B .
  • R 2 is CH 2 -NR 2A R 2B .
  • R 2 is (CH 2 )2-NR 2A R 2B .
  • R 2 is (CH 2 ) 3 -NR 2A R 2B .
  • R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl.
  • R 3 and R 4 are each C1-C3 alkyl.
  • R 3 and R 4 are each methyl.
  • the reducing step is done in the presence of a reducing-step agent and a reducing-step solvent.
  • the reducing step comprises a reducing-step agent is selected from the group consisting of: a) iron (Fe) and ammonium chloride (NH 4 CI); or b) hydrogen and palladium/carbon (Pd/C); or c) sodium dithionite.
  • a reducing-step agent is selected from the group consisting of: a) iron (Fe) and ammonium chloride (NH 4 CI); or b) hydrogen and palladium/carbon (Pd/C); or c) sodium dithionite.
  • the reducing step comprises a reducing-step solvent comprises dimethylsulfoxide (DMSO), ethanol, 2-propanol, water, or mixtures thereof.
  • DMSO dimethylsulfoxide
  • the said reducing is conducted at a temperature of about 15 °C to about 90 °C
  • the said compound of Formula (He) or salt thereof is: wherein R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl; the reducing-step agent comprises hydrogen and palladium/carbon (Pd/C); and the reducing-step solvent is ethanol and water.
  • a compound of Formula (lld-1) or a hydrochloride salt thereof: is prepared by process according to the reduction step.
  • One aspect of the present invention pertains to processes for preparing the intermediate compound of Formula (He) or salt thereof: comprising the step of: coupling the compound of Formula (lid) or a salt thereof: wherein R 2 is selected from 4-6 membered heterocycloalkyl, (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C1-C3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (C1-C3 alkyl), and -O-(Ci-C 3 alkyl); R 2A and R 2B are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, and C 3 - C 6 cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-9 member
  • R 3 and R 4 are each independently selected from H, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; with an acyl chloride of Formula (lld-1) wherein R 1 is selected from R 1 is selected from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 5-9 membered heterocycloalkyl; in the presence of a base and a solvent to form said compound of Formula (He).
  • R 2 is selected from (C1-C3 alkylene)-(4-10 membered heterocycloalkyl), and (C1-C3 alkylene)-NR 2A R 2B , wherein the alkylene and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, (C1-C3 alkyl), and -O-(Ci-C 3 alkyl);
  • R 2A and R 2B are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, and C 3 - C 6 cycloalkyl; or wherein R 2A and R 2B , taken together with the nitrogen to which they are attached, form a 3-7 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from halogen, oxo, -OH, C1-C3 alkyl, (C1-C3 haloalkyl), and -O-(Ci-C 3 alkyl); and; R 3 and R 4 are each independently selected from H and Ci-Ce alkyl.
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B , wherein R 2A and R 2B , taken togetherwith the nitrogen to which they are attached, form a 3-5 membered heterocycloalkyl ring.
  • R 2A and R 2B taken together with the nitrogen to which they are attached, form a pyrrolidinyl ring optionally substituted with one or more substituents independently selected from -OH, C1-C3 alkyl, and -O-(Ci-C 3 alkyl).
  • R 2 is (C1-C3 alkylene)-NR 2A R 2B .
  • R 2 is CH2-NR 2A R 2B .
  • R 2 is (CH 2 )2-NR 2A R 2B .
  • R 2 is (CH 2 )3-NR 2A R 2B .
  • R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl.
  • R 3 and R 4 are each C1-C3 alkyl.
  • R 3 and R 4 are each methyl.
  • R 1 is selected from R 1 is selected from Ci-C 6 alkyl and C 3 -C 6 cycloalkyl.
  • the base is selected from the group consisting of A/,/V- dimethylpyridin-4-amine, 2,6-Dimethylpyridine, /V-ethyl-/V-isopropylpropan-2-amine, potassium carbonate (K 2 CO 3 ), potassium phosphate (K3PO4), potassium hydrogen phosphate (K 2 HPO 4 ), pyridine, and triethylamine.
  • the base is selected from the group consisting of potassium carbonate (K 2 CO 3 ), potassium phosphate (K 3 PO 4 ), potassium hydrogen phosphate (K 2 HPO 4 ), and triethylamine.
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane (DCM), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), 1 ,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran and dichloromethane-water mixture.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethylsulfoxide
  • the said compound of Formula (lid) or salt thereof is: wherein R 3 and R 4 are each independently selected from H and Ci-C 6 alkyl; the base comprises potassium carbonate, potassium phosphate, potassium hydrogen phosphate, or triethylamine; and the solvent comprises dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran or dichloromethane-water mixture.
  • R 3 and R 4 are each methyl.
  • R 1 is cyclopropyl
  • the base is potassium carbonate.
  • the solvent is dichloromethane and water mixture.
  • a compound of Formula (la) or a hydrochloride salt thereof: is prepared by process according to the amide formation step.
  • the compound of Formula (la) is crystalline.
  • 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
  • preparation of compounds 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.
  • the chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, 1999.
  • 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, tetrachloroethylene, trichloroethylene, 1 ,1 ,1- trichloroethane, 1 ,1 ,2-trichloroethane, 1 ,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1 ,2,4-trichlorobenzene, 1 ,2-dichlorobenzene, 1 ,3-dichlorobenzene, 1 ,4-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon te
  • Suitable solvents can include ether solvents, such as: dimethoxymethane, tetra hydro furan, 2-mthyltetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or f-butyl methyl ether.
  • ether solvents such as: dimethoxymethane, tetra hydro furan, 2-mthyltetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tri
  • Suitable solvents can include protic solvents, such as: water, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 -propanol, 2-propanol, 2- methoxyethanol, 1 -butanol, 2-butanol, isobutyl alcohol, f-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • protic solvents such as: water, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 -propanol, 2-propanol, 2- methoxyethanol, 1 -butan
  • Suitable solvents can include aprotic solvents, such as: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, o, m-, or p-xylene, octane, indane, nonane, naphthalene, tetra hydrofuran, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, sulfolane, 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 /7)-pyrimidinone, 1 ,3-dimethyl-2-imidazolidinone,
  • amide refers to the following formula: wherein R, R', and R" may be the same or different.
  • R, R', and R" are each independently selected from H and Ci-C 6 alkyl.
  • R, R', and R" are each independently selected from H and C1-C4 alkyl.
  • R, R', and R" are each independently selected from H and C1-C2 alkyl.
  • Supercritical carbon dioxide can also be used as a solvent.
  • reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).
  • 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 one skilled in the art.
  • preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • Example acids can be inorganic or organic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.
  • Organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butanoic acid, methanesulfonic acid, p- toluene sulfonic acid, benzenesulfonic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.
  • Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.
  • Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and Fbutyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, t- butyl, trimethylsilyl and cyclohexyl substituted amides.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Salts of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • the processes described herein can be stereoselective such that any given reaction starting with one or more chiral reagents enriched in one stereoisomer forms a product that is also enriched in one stereoisomer.
  • the reaction can be conducted such that the product of the reaction substantially retains one or more chiral centers present in the starting materials.
  • the reaction can also be conducted such that the product of the reaction contains a chiral center that is substantially inverted relative to a corresponding chiral center present in the starting materials.
  • An example method includes fractional recrystallization (for example, diastereomeric salt resolution) using a “chiral resolving acid” which is an optically active, saltforming organic acid.
  • 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, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of p-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, /V-methylephedrine, cyclohexylethylamine, 1 ,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds described herein and salts thereof can also include all isotopes of atoms occurring in the intermediates or final compounds or salts thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds described herein and salts thereof can also include tautomeric forms, such as keto-enol tautomers. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products.
  • One aspect of the present disclosure relates to crystalline salts of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline citrate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline fumarate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline hydrochloride salt of A/-(3- (4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline mesylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline phosphate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • One aspect of the present disclosure relates to a crystalline succinate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • Crystalline salts described herein can be identified by their unique solid state signature with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid state methods.
  • DSC differential scanning calorimetry
  • PXRD X-ray powder diffraction
  • thermogravimetric analysis TGA
  • DSC Dynamic Cell Sorting
  • DSC DSC thermograms
  • the temperatures observed will depend upon sample purity, the rate of temperature change, as well as sample preparation technique and the particular instrument employed.
  • the values reported herein relating to DSC thermograms can vary by plus or minus about 4 °C.
  • the values reported herein relating to DSC thermograms can also vary by plus or minus about 20 joules per gram.
  • the DSC thermogram values reported herein relate to desolvation events.
  • the values reported herein are estimates. Scan rate and pan closure can influence DSC values for desolvation events, which can vary by plus or minus about 25 °C. DSC values for desolvation events reported herein were recorded using a sample in an aluminum pan with an uncrimped lid and a scan rate of 10°C/min.
  • the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 26 values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus 0.2 °26 (i.e., ⁇ 0.2).
  • the features reported herein can vary by plus or minus about 5 °C.
  • the TGA features reported herein can also vary by plus or minus about 2% weight change due to, for example, sample variation.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the physical properties of the crystalline form of Compound la are summarized in Table 1 below. Table 1
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide, wherein the crystalline form has an X-ray owder diffraction pattern comprising a peak, in terms of 26, at 5.3° ⁇ 0.2°, and 10.6° ⁇ 0.2°.
  • the crystalline form has an X-ray owder diffraction pattern comprising a peak, in terms of 20, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 12.4° ⁇ 0.2°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 15.9° ⁇ 0.2°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, and 21.1 ° ⁇ 0.2°.
  • the crystalline form has an X- ray powder diffraction pattern comprising peaks, in terms of 20, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, and 21.1 ° ⁇ 0.2°, 22.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 1 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °2O.
  • the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 138.1 °C and about 153.5 °C. In some embodiments, the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 138.1 °C and about 152.5 °C. In some embodiments, the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 139.1 °C and about 152.5 °C. In some embodiments, the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 140.1 °C.
  • the crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 2, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the crystalline form has a thermogravimetric analysis profile showing about 4.0% weight loss below about 240 °C. In some embodiments, the heptane solvate has a thermogravimetric analysis profile showing about 3.8% weight loss below about 240 °C. In some embodiments, the heptane solvate has a thermogravimetric analysis profile showing about 3.6% weight loss below about 240 °C. In some embodiments, the crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 3, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at .3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 138.1 °C and about 153.5 °C; and/or c) a thermogravimetric analysis profile showing about 4.0% weight loss below about 240 °C.
  • One aspect of the present disclosure relates to the crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, and 21 .1 ° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 138.1 °C and about 152.5 °C; and/or c) a thermogravimetric analysis profile showing about 3.8% weight loss below about 240 °C.
  • One aspect of the present disclosure relates to the crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, and 21 .1 ° ⁇ 0.2°, 22.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 139.1 °C and about 152.5 °C; and/or c) a thermogravimetric analysis profile showing about 3.6% weight loss below about 240 °C.
  • One aspect of the present disclosure relates to the crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, and 21 .1 ° ⁇ 0.2°, 22.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 140.1 °C; and/or c) a thermogravimetric analysis profile showing about 3.6% weight loss below about 240 °C.
  • One aspect of the present disclosure relates to the crystalline form having: a) an X-ray powder diffraction pattern substantially as shown in Figure 1 ; b) a differential scanning calorimetry thermogram substantially as shown in Figure 2; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 3.
  • One aspect of the present disclosure relates to crystalline salts of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)).
  • the crystalline salts of Compound la are characterized by PXRD.
  • the physical properties for the crystalline salts as determined by PXRD are summarized below.
  • One aspect of the present disclosure relates to besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the besylate salt is characterized by PXRD.
  • the physical properties for the besylate salt as determined by PXRD are summarized in Table 3 below.
  • Example 5 The physical properties for a besylate salt (Example 5) prepared using procedure from Example 5 are summarized in Table 4 below.
  • One aspect of the present disclosure relates to besylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the besylate salt of Compound la was prepared by procedure from Example 5.
  • One aspect of the present disclosure relates to a besylate salt of A/-(3-(4,6- d imethy I py rimid i n-5-y l)-4-(2-(py rrolid in- 1 -yl)ethoxy)phenyl)cyclopropanecarboxamide, having a powder X-ray diffraction pattern comprising a peak, in terms of 26, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, and 11.6° ⁇ 0.2°.
  • the besylate salt has an X- ray powder diffraction pattern comprising peaks, in terms of 20, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, and 18.0° ⁇ 0.2°.
  • the besylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the besylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11 .3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11 .9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .7° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the besylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11 .3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 1 1.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.3° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the besylate salt has an X-ray powder diffraction pattern substantially as shown in Figure 4, wherein by “substantially” is meant that the reported peaks can vary by
  • the besylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 217.4 °C and about 228.7 °C. In some embodiments, the besylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 217.4 °C and about 227.7 °C. In some embodiments, the besylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 218.4 °C and about 227.7 °C.
  • the besylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 218.4 °C and about 226.7 °C. In some embodiments, the besylate salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 219.4 °C. In some embodiments, the besylate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 5, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the besylate salt has a thermogravimetric analysis profile showing about 2.6% weight loss below about 220 °C. In some embodiments, the besylate salt has a thermogravimetric analysis profile showing about 2.4% weight loss below about 220 °C. In some embodiments, the besylate salt has a thermogravimetric analysis profile showing about 2.2% weight loss below about 220 °C. In some embodiments, the besylate salt has a thermogravimetric analysis profile showing about 2.1 % weight loss below about 220 °C.
  • the besylate salt has a thermogravimetric analysis profile substantially as shown in Figure 6, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 1 1.3° ⁇ 0.2°, 1 1.6° ⁇ 0.2°, 11 .9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, and 18.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 217.4 °C and about 227.7 °C. c) a thermogravimetric analysis profile showing about 2.6% weight loss below about 220 °C.
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 21.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 218.4 °C and about 227.7 °C; and/or c) a thermogravimetric analysis profile showing about 2.4% weight loss below about 220 °C.
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 25.2° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 218.4 °C and about 226.7 °C; and/or c) a thermogravimetric analysis profile showing about 2.2% weight loss below about 220 °C.
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.3° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 26.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 218.4 °C and about 226.7 °C; and/or c) a thermogravi
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 8.8° ⁇ 0.2°, 10.3° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.3° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 26.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 219.4 °C; and/or c) a thermogravimetric analysis profile showing about 2.1
  • One aspect of the present disclosure relates to the besylate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 4; b) a differential scanning calorimetry thermogram substantially as shown in Figure 5; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 6.
  • One aspect of the present disclosure relates to a citrate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the citrate salt of Compound la are characterized by PXRD.
  • the physical properties for the citrate salt as determined by PXRD are summarized in Table 6 below.
  • Example 6 The physical properties for a citrate salt (Example 6) prepared using procedure from Example 6 are summarized in Table 7 below.
  • One aspect of the present disclosure relates to a citrate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to a citrate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 15.8° ⁇ 0.2°.
  • the citrate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the citrate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the citrate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1 ⁇ 0.2°, and 25.9 ⁇ 0.2°.
  • the citrate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.1 ⁇ 0.2°, 27.5 ⁇ 0.2°, and 28.
  • the citrate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.2 °C and about 176.5 °C.
  • the citrate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 170.2 °C and about 176.5 °C.
  • the citrate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.2 °C and about 175.5 °C.
  • the citrate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.2 °C and about 174.5 °C.
  • the citrate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 172.2 °C.
  • the citrate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 8, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the citrate salt has a thermogravimetric analysis profile showing no observable weight loss below about 175 °C.
  • the citrate salt has a thermogravimetric analysis profile substantially as shown in Figure 9, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • citrate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 19.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.2 °C and about 176.5 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 175 °C; and/or
  • citrate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • One aspect of the present disclosure relates to the citrate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1 ⁇ 0.2°, and 25.9 ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with
  • One aspect of the present disclosure relates to the citrate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.1 ⁇ 0.2°, 27.5 ⁇
  • One aspect of the present disclosure relates to the citrate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 9.6° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.5° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 ° ⁇ 0.2°, 19.3° ⁇ 0.2°, 20.1 ° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.1 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.1 ⁇ 0.2°,
  • thermogravimetric analysis profile showing no observable weight loss below about 175 °C
  • citrate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 7; b) a differential scanning calorimetry thermogram substantially as shown in Figure 8; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 9.
  • One aspect of the present disclosure relates to fumarate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the fumarate salt of Compound la are characterized by PXRD.
  • the physical properties for the fumarate salt as determined by PXRD are summarized in Table 9 below.
  • Example 7 The physical properties for a fumarate salt (Example 7) prepared using procedure from Example 7 are summarized in Table 10 below.
  • One aspect of the present disclosure relates to an fumarate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to an fumarate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, and 12.2° ⁇ 0.2°.
  • the fumarate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, and 15.8° ⁇ 0.2°.
  • the fumarate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the fumarate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .6° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the fumarate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .6° ⁇ 0.2°, 22.6° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.1 ° ⁇ 0.2°, 23.5° ⁇ 0.2°, 23.9° ⁇ 0.2°, 26.1 ° ⁇ 0.2°, and 26.9° ⁇ 0.2°
  • the fumarate salt has an X-ray powder
  • the fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 148.3 °C and about 159.1 °C. In some embodiments, the fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 156.1 °C.
  • the fumarate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 11 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the fumarate salt has a thermogravimetric analysis profile showing about 5.5% weight loss below about 200 °C.
  • the fumarate has a thermogravimetric analysis profile showing about 5.3% weight loss below about 200 °C.
  • the fumarate salt has a thermogravimetric analysis profile showing about 5.1 % weight loss below about 200 °C.
  • the fumarate salt has a thermogravimetric analysis profile showing about 4.9% weight loss below about 200 °C.
  • the fumarate salt has a thermogravimetric analysis profile substantially as shown in Figure 12, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, and 15.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 148.3 °C and about 159.1 °C; and/or c) a thermogravimetric analysis profile showing about 5.5% weight loss below about 200 °C.
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 149.3 °C and about 158.1 °C; and/or c) a thermogravimetric analysis profile showing about 5.3% weight loss below about 200 °C.
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 22.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 149.3 °C and about 157.1 °C; and/or c) a thermogravimetric analysis profile showing about
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 22.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 150.3 °C and about 157.1 °C; and/or c) a thermo
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.9° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.1 ° ⁇ 0.2°, 23.5° ⁇ 0.2°, 23.9° ⁇ 0.2°, 26.1 ° ⁇ 0.2°, and 26.9° ⁇ 0.2°; b)
  • One aspect of the present disclosure relates to the fumarate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 10; b) a differential scanning calorimetry thermogram substantially as shown in Figure 11 ; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 12.
  • One aspect of the present disclosure relates to a hydrochloride salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the hydrochloride salt of Compound la are characterized by PXRD.
  • the physical properties for the fumarate salt as determined by PXRD are summarized in Table 12 below.
  • Table 12 The physical properties for a hydrochloride salt (Example 8) prepared using procedure from Example 8 are summarized in Table 13 below.
  • One aspect of the present disclosure relates to an hydrochloride salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to an hydrochloride salt having an X-ray powder diffraction pattern comprising a peak, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, and 13.8° ⁇ 0.2°.
  • the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks, in terms of 29, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks, in terms of 29, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇
  • the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇
  • the hydrochloride salt has an X-ray powder diffraction pattern substantially as shown in Figure 13, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °26.
  • the hydrochloride salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 20.8 °C and about 77.6 °C and between about 185.5 °C and about 196.9 °C..
  • the hydrochloride salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 21 .8 °C and about 76.6 °C and between about 186.5 °C and about 195.9 °C. In some embodiments, the hydrochloride salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 21 .8 °C and about 74.6 °C and between about 186.5 °C and about 194.9 °C.
  • the hydrochloride salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 22.8 °C and about 75.6 °C and between about 187.5 °C and about 194.9 °C.
  • the hydrochloride salt has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 23.8 °C and at about 188.5 °C.
  • the hydrochloride salt has a differential scanning calorimetry thermogram substantially as shown in Figure 14, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the hydrochloride salt has a thermogravimetric analysis profile showing about 5.0% weight loss below about 100 °C.
  • the hydrochloride salt has a thermogravimetric analysis profile showing about 4.8% weight loss below about 100 °C.
  • the hydrochloride salt has a thermogravimetric analysis profile showing about 4.6% weight loss below about 100 °C.
  • the hydrochloride salt has a thermogravimetric analysis profile showing about 4.3% weight loss below about 100 °C.
  • the hydrochloride salt has a thermogravimetric analysis profile substantially as shown in Figure 15, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 16.2° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 20.8 °C and about 77.6 °C and between about 185.5 °C and about 196.9 °C; and/or c) a thermogravimetric analysis profile showing about 5.0% weight loss below about 200 °C.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 23.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 21 .8 °C and about 76.6 °C and between about
  • thermogravimetric analysis profile showing about 4.8% weight loss below about 200 °C.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 24.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 21.8 °C and about 75.6 °C and between about
  • thermogravimetric analysis profile showing about 4.6% weight loss below about 100 °C.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 24.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 22.8 °C and about 75.6 °C and between about
  • thermogravimetric analysis profile showing about 4.3% weight loss or less below about 100 °C.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 12.4° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.8° ⁇ 0.2°, 27.7° ⁇ 0.2°, 27.8° ⁇ 0.2°, and 32.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 23.8 °C and at about 188.5 °C; and/or c) a thermogravimetric analysis profile showing about 4.3% weight loss or less below about 100 °C.
  • hydrochloride salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 13; b) a differential scanning calorimetry thermogram substantially as shown in Figure 14; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 15. 6.
  • Compound 1 Mesylate Salt
  • One aspect of the present disclosure relates to mesylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the mesylate salt of Compound la are characterized by PXRD.
  • the physical properties for the mesylate salt as determined by PXRD are summarized in Table 15 below.
  • One aspect of the present disclosure relates to an mesylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to a mesylate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, and 12.6° ⁇ 0.2°.
  • the mesylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the mesylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.1 ° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the mesylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • the mesylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.3° ⁇ 0.2°, 24.6° ⁇ 0.2°,
  • the mesylate salt has an X-ray powder diffraction pattern substantially as shown in Figure 16, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the mesylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the mesylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the mesylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the mesylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the mesylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 181 .4 °C.
  • the mesylate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 17, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the mesylate salt has a thermogravimetric analysis profile showing about 2.8% weight loss below about 180 °C.
  • the mesylate salt has a thermogravimetric analysis profile showing about 2.6% weight loss below about 180 °C.
  • the mesylate salt has a thermogravimetric analysis profile showing about 2.4% weight loss below about 180 °C.
  • the mesylate salt has a thermogravimetric analysis profile showing about 2.2% weight loss below about 180 °C.
  • the mesylate salt has a thermogravimetric analysis profile substantially as shown in Figure 18, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the mesylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 16.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 178.4 °C and about 192.7 °C; and/or c) a thermogravimetric analysis profile showing about 2.8% weight loss below about
  • One aspect of the present disclosure relates to the mesylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, and 21.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 179.4 °C and about 192.7 °C
  • One aspect of the present disclosure relates to the mesylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 23.5° ⁇ 0.2°; b) a differential scanning ca
  • One aspect of the present disclosure relates to the mesylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 23.5° ⁇ 0.2°; b) a differential scanning ca
  • One aspect of the present disclosure relates to the mesylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.3° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.7° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21 .1 ° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.3° ⁇ 0.2°,
  • mesylate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 16; b) a differential scanning calorimetry thermogram substantially as shown in Figure 17; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 18.
  • One aspect of the present disclosure relates to phosphate salt of A/-(3-(4,6-dimethylpyrimidin-5- yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the phosphate salt of Compound la are characterized by PXRD.
  • the physical properties for the phosphate salt as determined by PXRD are summarized in Table 18 below.
  • Example 10 The physical properties for a phosphate salt (Example 10) prepared using procedure from Example 10 are summarized in Table 19 below.
  • One aspect of the present disclosure relates to an phosphate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to an phosphate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2° and 11.3° ⁇ 0.2°.
  • the phosphate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 18.8° ⁇ 0.2°.
  • the phosphate salt has an X-ray powder diffraction pattern comprising peaks, in terms o 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
  • the phosphate salt has an X-ray powder diffraction pattern comprising peaks, in terms o 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the phosphate salt has an X-ray powder diffraction pattern comprising peaks, in terms o 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.5° ⁇ 0.2°, 27.3° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • the phosphate salt has an X-ray powder diffraction pattern substantially as shown in Figure 19, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the phosphate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the phosphate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the phosphate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the phosphate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the phosphate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 201 .7 °C.
  • the phosphate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 20, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the phosphate salt has a thermogravimetric analysis profile showing about 4.0% weight loss below about 190 °C.
  • the phosphate salt has a thermogravimetric analysis profile showing about 3.8% weight loss below about 190 °C.
  • the phosphate salt has a thermogravimetric analysis profile showing about 3.6% weight loss below about 190 °C.
  • the phosphate salt has a thermogravimetric analysis profile showing about 3.4% weight loss below about 190 °C.
  • the phosphate salt has a thermogravimetric analysis profile substantially as shown in Figure 21 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 1 1 .3° ⁇ 0.2°, 1 1 .7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 18.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 198.7 °C and about 220.9 °C; and/or c) a thermogravimetric analysis profile showing about 4.0%
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 1 1 .3° ⁇ 0.2°, 1 1 .7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 20.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 199.7 °
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 1 1 .3° ⁇ 0.2°, 1 1 .7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning ca
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 1 1 .3° ⁇ 0.2°, 1 1 .7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning ca
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 9.2° ⁇ 0.2°, 9.9° ⁇ 0.2°, 1 1 .3° ⁇ 0.2°, 1 1 .7° ⁇ 0.2°, 12.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.1 ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.0° ⁇ 0.2°,
  • One aspect of the present disclosure relates to the phosphate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 19; b) a differential scanning calorimetry thermogram substantially as shown in Figure 20; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 21 .
  • One aspect of the present disclosure relates to a succinate salt of A/-(3-(4,6-dimethylpyrimidin-5- yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the succinate salt of Compound la are characterized by PXRD.
  • the physical properties for the succinate salt as determined by PXRD are summarized in Table 21 below.
  • Example 11 The physical properties for a succinate salt (Example 11) prepared using procedure from Example 11 are summarized in Table 22 below.
  • One aspect of the present disclosure relates to a succinate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to a succinate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 7.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.8° ⁇ 0.2°, and 13.1 ° ⁇ 0.2°.
  • the succinate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1 ° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1 ° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 17.5° ⁇ 0.2°.
  • the succinate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1 ° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1 ° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the succinate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1 ° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1 ° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • the succinate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1 ° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1 ° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 23.8° ⁇ 0.2°, 26.8° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • the succinate salt has an X-ray powder diffraction pattern substantially as shown in Figure 22, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °26>.
  • the succinate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the succinate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the succinate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the succinate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the succinate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 1 16.3 °C.
  • the succinate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 23, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the succinate salt has a thermogravimetric analysis profile showing about 25.4% weight loss below about 275 °C.
  • the succinate salt has a thermogravimetric analysis profile showing about 25.2% weight loss below about 275 °C.
  • the succinate salt has a thermogravimetric analysis profile showing about 25.0% weight loss or less below about 275 °C.
  • the succinate salt has a thermogravimetric analysis profile showing about 24.8% weight loss or less below about 275 °C.
  • the succinate salt has a thermogravimetric analysis profile substantially as shown in Figure 24, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • the succinate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 17.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 113.3 °C and about 122.8 °C; and/or c) a thermogravimetric analysis profile showing about 25.4% weight loss below about 275 °C.
  • the succinate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, and 21.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 114.3 °C and about 122.8 °C; and/or c) a thermogravimetric analysis profile showing about 25.2% weight loss below about 275 °C.
  • the succinate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 23.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 114.3 °C and about 121.8 °C; and/or c) a thermogravimetric analysis profile showing about 25.0% weight loss or less below about 275 °C.
  • the succinate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, and 23.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 115.3 °C and about 120.8 °C; and/or c) a thermogravimetric analysis profile showing about 25.0% weight loss or less below about 275 °C.
  • the succinate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 23.8° ⁇ 0.2°, 26.8° ⁇ 0.2°, and 27.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 116.3 °C; and/or c) a thermogravimetric
  • One aspect of the present disclosure relates to the succinate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 22; b) a differential scanning calorimetry thermogram substantially as shown in Figure 23; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 24.
  • One aspect of the present disclosure relates to a tosylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la).
  • the tosylate salt of Compound la are characterized by PXRD.
  • the physical properties for the tosylate salt as determined by PXRD are summarized in Table 30 below.
  • Example 12 The physical properties for a tosylate salt (Example 12) prepared using procedure from Example 12, Method 2, are summarized in Table 31 below.
  • One aspect of the present disclosure relates to a tosylate salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide.
  • One aspect of the present disclosure relates to a tosylate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 13.0° ⁇ 0.2°.
  • the tosylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
  • the tosylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
  • the tosylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.08° ⁇ 0.2°, and 23.1 ° ⁇ 0.2°.
  • the tosylate salt has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .3° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.08° ⁇ 0.2°, 23.1 ° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the tosylate salt has an X-ray powder diffraction pattern substantially as shown in Figure 25, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °26>.
  • the tosylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the tosylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the tosylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the tosylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about
  • the tosylate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 151 .3 °C.
  • the tosylate salt has a differential scanning calorimetry thermogram substantially as shown in Figure 26, wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 4 °C and that the reported DSC features can vary by about ⁇ 20 joules per gram.
  • the tosylate salt has a thermogravimetric analysis profile showing about 2.1 % weight loss below about 180 °C.
  • the tosylate salt has a thermogravimetric analysis profile showing about 1 .9% weight loss below about 180 °C.
  • the tosylate salt has a thermogravimetric analysis profile showing about 1 .7% weight loss below about 180 °C.
  • the tosylate salt has a thermogravimetric analysis profile showing about 1 .5% weight loss below about 180 °C.
  • the tosylate salt has a thermogravimetric analysis profile substantially as shown in Figure 27, wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5 °C, and that that the reported TGA features can vary by about ⁇ 2% weight change.
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 18.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 148.3 °C and about 173.1 °C; and/or c) a thermogravimetric analysis profile showing about 2.1 % weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 20.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 149.3 °C and about 173.1 °C; and/or c) a thermogravimetric analysis profile showing about 1 .9% weight loss below about
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .3° ⁇ 0.2°, 21 .5° ⁇ 0.2°, 22.08° ⁇ 0.2°, and 23.1 ° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .3° ⁇ 0.2°, 21 .5° ⁇ 0.2°, 22.08° ⁇ 0.2°, and 23.1 ° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 5.2° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.4° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.9° ⁇ 0.2°, 21 .3° ⁇ 0.2°, 21 .5° ⁇ 0.2°, 22.08° ⁇ 0.2°, 23.1 ° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.0° ⁇ 0.2°, 24.2° ⁇ 0.2°,
  • One aspect of the present disclosure relates to the tosylate salt having: a) an X-ray powder diffraction pattern substantially as shown in Figure 25; b) a differential scanning calorimetry thermogram substantially as shown in Figure 26; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 27.
  • the crystalline forms described herein can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments the crystalline forms described herein are prepared according to the Examples. In some embodiments, the crystalline forms described herein can be prepared by heating crystalline forms other than the crystalline forms described herein. In some embodiments, the crystalline forms described herein can be prepared by recrystallizing crystalline forms other than the crystalline forms described herein.
  • Compounds of Formula (He) of the present disclosure may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]).
  • the present disclosure embraces each enantiomer and mixtures thereof. Separation of the individual isomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • the compounds disclosed herein are useful in the treatment of several additional diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, these include the following:
  • the compounds of Formula (He), and pharmaceutically acceptable salts thereof are useful as 5-HT 2 A serotonin receptor modulators for the treatment of disorders associated with 5- HT 2 A serotonin receptor expression and/or activity, such as cardiovascular disorders (for example, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, platelet aggregation, and blood clot formation or symptoms thereof.
  • cardiovascular disorders for example, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, platelet aggregation, and blood clot formation or symptoms thereof.
  • the modulators of 5-HT 2 A receptor activity disclosed herein are believed to be useful in the treatment of several diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, some of them include the following:Antiplatelet agents (antiplatelets) are prescribed for a variety of conditions. For example, in coronary artery disease they are used to help prevent myocardial infarction or stroke in patients who are at risk of developing obstructive blood clots (e.g., coronary thrombosis).
  • heart attack In a myocardial infarction (heart attack), the heart muscle does not receive enough oxygen-rich blood as a result of a blockage in the coronary blood vessels. If taken while an attack is in progress or immediately afterward (preferably within 30 minutes), antiplatelets can reduce the damage to the heart.
  • TIA transient ischemic attack
  • mini-stroke A transient ischemic attack
  • Antiplatelet drugs have been found to be effective in preventing TIAs.
  • Angina is a temporary and often recurring chest pain, pressure or discomfort caused by inadequate oxygen-rich blood flow (ischemia) to some parts of the heart.
  • ischemia oxygen-rich blood flow
  • antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.
  • Stroke is an event in which the brain does not receive enough oxygen-rich blood, usually due to blockage of a cerebral blood vessel by a blood clot. In high-risk patients, taking antiplatelets regularly has been found to prevent the formation blood clots that cause first or second strokes.
  • Angioplasty is a catheter-based technique used to open arteries obstructed by a blood clot. Whether or not stenting is performed immediately after this procedure to keep the artery open, antiplatelets can reduce the risk of forming additional blood clots following the procedure(s).
  • Coronary bypass surgery is a surgical procedure in which an artery or vein is taken from elsewhere in the body and grafted to a blocked coronary artery, rerouting blood around the blockage and through the newly attached vessel. After the procedure, antiplatelets can reduce the risk of secondary blood clots.
  • Atrial fibrillation is the most common type of sustained irregular heart rhythm (arrythmia). Atrial fibrillation affects about two million Americans every year. In atrial fibrillation, the atria (the heart's upper chambers) rapidly fire electrical signals that cause them to quiver rather than contract normally. The result is an abnormally fast and highly irregular heartbeat. When given after an episode of atrial fibrillation, antiplatelets can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism).
  • 5-HT 2 A receptors are expressed on smooth muscle of blood vessels and 5-HT secreted by activated platelets causes vasoconstriction as well as activation of additional platelets during clotting.
  • 5-HT 2A inverse agonist will inhibit platelet aggregation and thus be a potential treatment as an antiplatelet therapy (see Satimura, K, et al., Clin Cardiol 2002 Jan. 25 (1):28-32; and Wilson, H.C et al., Thromb Haemost 1991 Sep 2;66(3):355-60).
  • the 5-HT 2 A inverse agonists disclosed herein provide beneficial improvement in microcirculation to patients in need of antiplatelet therapy by antagonizing the vasoconstrictive products of the aggregating platelets in, for example and not limitation, the indications described above. Accordingly, in some embodiments, the present invention provides methods for reducing platelet aggregation in a patient in need thereof comprising administering to said patient a composition comprising a 5-HT 2 A inverse agonist disclosed herein.
  • the present invention provides methods for treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or a symptom of any of the foregoing in a patient in need of said treatment, comprising administering to said patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • the present invention provides methods for reducing risk of blood clot formation in an angioplasty or coronary bypass surgery patient, or a patient suffering from atrial fibrillation, comprising administering to a said patient a composition comprising a 5-HT 2A inverse agonist disclosed herein at a time where such risk exists.
  • the present invention provides methods for reducing risk of, or treating the effects of, PCI, comprising administering to a patient a composition comprising a 5- HT 2A inverse agonist disclosed herein at a time where such risk exists.
  • the present invention provides methods for the prevention or treatment of Raynaud’s, comprising administering to a patient a composition comprising a 5-HT 2A inverse agonist disclosed herein.
  • the reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive 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 by the skilled artisan. Reactions 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), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LC-MS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified
  • Scheme A provides general guidance in connection with preparing the compounds of the invention.
  • the compound of Formula (He) can be prepared as shown in Scheme A.
  • the present disclosure includes polymorphs and pseudopolymorphs of the compound of Formula (la) of the present disclosure.
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • crystalline phases can contain an API host and either solvent or water molecules, respectively, as guests.
  • Crystalline phases that share the same API host, but differ with respect to the guests, can be referred to as pseudopolymorphs of one another.
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
  • Stahly published a polymorph screen of 245 compounds consisting of a “wide variety of structural types” that revealed about 90% of them exhibited multiple solid forms. Overall, approximately half of the compounds were polymorphic, often having one to three forms. About one-third of the compounds formed hydrates, and about one-third formed solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026).
  • One aspect of the present disclosure relates to methods for the treatment of a 5HT 2A - related disorder disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a crystalline form of 5HT 2 -related disorder as described herein, for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present disclosure relates to a crystalline form of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, for use in a method of treatment of a 5HT 2 -related disorder.
  • One aspect of the present disclosure relates to methods for the treatment of 5HT 2 -related disorder in an individual, wherein the 5HT 2 -related disorder is selected from a condition associated with platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, or symptoms thereof, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods forthe treatment of 5HT 2 A-related disorder in an individual, wherein the 5HT 2 -related disorder is an effect of PCI selected from microvascular obstruction (MVO), myocardial injury, reduced cardiac function, or a major adverse cardiac event (MACE), comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • MVO microvascular obstruction
  • MACE major adverse cardiac event
  • One aspect of the present disclosure relates to methods forthe treatment of 5HT 2 -related disorder in an individual, wherein the 5HT 2 A-related disorder is Raynaud’s, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for treating a condition associated with platelet aggregation in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of a 5HT 2A - related disorder disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a crystalline salt of 5HT 2 A-related disorder as described herein, for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present disclosure relates to a crystalline salt of A/-(3-(4,6- dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, for use in a method of treatment of a 5HT 2A -related disorder.
  • One aspect of the present disclosure relates to methods forthe treatment of 5HT 2A -related disorder in an individual, wherein the 5HT 2 A-related disorder is selected from a condition associated with platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, or symptoms thereof, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods forthe treatment of 5HT 2A -related disorder in an individual, wherein the 5HT 2A -related disorder is an effect of PCI selected from microvascular obstruction (MVO), myocardial injury, reduced cardiac function, or a major adverse cardiac event (MACE), comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • MVO microvascular obstruction
  • MACE major adverse cardiac event
  • One aspect of the present disclosure relates to methods forthe treatment of 5HT 2A -related disorder in an individual, wherein the 5HT 2A -related disorder is Raynaud’s, comprising administering to the individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for treating a condition associated with platelet aggregation in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to a method for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof, a therapeutically effective amount of a crystalline salt as described herein or a pharmaceutical composition thereof.
  • a further aspect of the present disclosure pertains to pharmaceutical compositions comprising the compounds of Formula (He), or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition comprises a compound of Formula (He), and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a salt of the compound of Formula (lie), and a pharmaceutically acceptable carrier.
  • Some embodiments of the present disclosure include a method of producing a pharmaceutical composition comprising admixing the compound of Formula (lie), or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Some embodiments of the present disclosure include a method of producing a pharmaceutical composition comprising admixing a salt of the compound of Formula (lie), as disclosed herein and a pharmaceutically acceptable carrier.
  • compositions comprising a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein.
  • compositions comprising a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Formula (la)) as described herein, and a pharmaceutically acceptable carrier.
  • Some embodiments of the present disclosure include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
  • One aspect of the present disclosure relates to process of making a composition
  • a composition comprising mixing a crystalline form of A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide, with a pharmaceutically acceptable carrier.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations may 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 may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the disclosure in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present disclosure can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.)
  • a compound of the disclosure may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the disclosure may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient is defined in the context of a “pharmaceutical composition” and refers to a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the compounds of the present disclosure can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present disclosure.
  • Representative doses of the present disclosure include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient, or an active salt or derivative thereof, 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.
  • a model system typically an animal model
  • these extrapolations may 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. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this disclosure.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present disclosure can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the disclosure or a pharmaceutically acceptable salt, solvate or hydrate of a compound of the disclosure.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • the term “preparation” includes the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component 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.
  • 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 may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may 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 may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds according to the present disclosure may thus be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multidose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may 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 active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations which can be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the compounds according to the disclosure may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may 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.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds of the present disclosure or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • 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.
  • solutions or dispersions of the compounds of the present disclosure in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like.
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound In formulations for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • 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.
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds according to the disclosure may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p- toluenesulfonic and the like.
  • Certain compounds of the present disclosure which contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cations and cations derived from organic bases.
  • Representative metals include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. In some embodiments the pharmaceutically acceptable metal is sodium.
  • Organic bases include, but are not limited to, benzathine (A/ 1 ,/V 2 -dibenzylethane-1 ,2-diamine), chloroprocaine (2-(diethylamino)ethyl 4- (chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4/?,5S)- 6-(methylamino)hexane-1 ,2,3,4, 5-pentaol), procaine (2-(diethylamino)ethyl 4-aminobenzoate), and the like.
  • Certain pharmaceutically acceptable salts are listed in Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this disclosure may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs can be converted to “pro-drugs.”
  • the term “prodrugs” refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the disclosure containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound.
  • Some embodiments of the present disclosure include a method of producing a pharmaceutical composition for “combination-therapy” comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • Another object of the present disclosure relates to radio-labeled compounds of the present disclosure that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating 5-HT2A receptors in tissue samples, including human, and for identifying 5-HT 2 A receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this disclosure to develop novel 5-HT 2 A receptor assays of which comprise such radio- labeled compounds.
  • Isotopically-labeled crystalline forms of the present disclosure embraces isotopically-labeled crystalline forms of the present disclosure.
  • Isotopically or radio-labeled compounds are those which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • Suitable radionuclides that may be incorporated in compounds of the present disclosure include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 CI, 75 Br, 76 Br, 77 Br, 82 Br, 123
  • a “radio-labeled ” or “labeled compound” is a crystalline form of Compound la that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3 H, 14 C, 125 l , 35 S and 82 Br.
  • isotopically-labeled crystalline forms of the present disclosure are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or 14 C isotopes are useful in these studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled crystalline forms of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the disclosure and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as follows:
  • Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • Synthetic methods for incorporating activity levels of 125 l into target molecules include:
  • Aryl and heteroaryl bromide exchange with 125 l This method is generally a two step process.
  • the first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [/.e., Pd(Ph 3 P) 4 ] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ],
  • Some embodiments of the present disclosure include a method of producing a pharmaceutical composition for “combination therapy” comprising admixing the compound of Formula (He) or any other Formula herein, such as Formula (la), or pharmaceutically acceptable salt thereof together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • 5-HT2A receptor modulators when utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other nonhuman mammals as well. Indeed, advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as 5-HT 2 A receptor modulators, for the treatment of a 5-HT 2 A mediated diseases or disorders in domestic animals (e.g., cats and dogs) and in other domestic animals (e.g., such as cows, chickens, and fish). Those of ordinary skill in the art will understand the utility of such compounds in such settings.
  • Tetrahydrofuran (THF) 37.20 kg was added to a solution of potassium phosphate tribasic (10.24 kg) in purified water (24.32 kg), and the mixture was heated to 20-30 °C.
  • 5-Bromo-4,6- dimethylpyrimidine (3.00 kg, 16.0 mol) and 2-Fluoro-5-nitrophenylboronic acid (3.26, 17.6 mol) were added, and the reactor interior was rinsed down with purified water (6.00 kg).
  • the mixture was sparged with nitrogen, and a nitrogen atmosphere was maintained for the duration of the reaction.
  • SPhos Pd G3 (0.50 kg) was added, and the reaction mixture was heated to 40-45 °C for 1 h.
  • the mixture was heated to 55-65 °C and stirred at this temperature for 4 h, when HPLC analysis showed ⁇ 1 % of 5-bromo-4,6-dimethylpyrimidine remained.
  • the reaction was cooled to 25-35 °C, celite (0.46 kg) was added, and the mixture was stirred for 1 h. Solids were filtered and washed with THF (3.80 kg), and the washing was combined with the filtrate. The filtrate was heated to 25-35 °C, stirring was stopped, and the mixture was allowed to settle. The bottom aqueous layer was back-extracted with methyl tert- butyl ether (MTBE) (11.18 kg), and the organic layers were combined. Celite (0.3 kg) was added, and the mixture was stirred for 1 h. Solids were filtered and washed with MTBE (3.00 kg), and the washing was combined with the filtrate.
  • MTBE methyl tert- butyl ether
  • the filtrate was concentrated at atmospheric pressure and temperature ⁇ 65°C to a target volume of 15.00 L.
  • Heptane 21 .00 kg was added, and the mixture was concentrated at atmospheric pressure and temperature ⁇ 65°C to a target volume of 18.00 L.
  • the mixture was cooled to ⁇ 50°C, Isopropyl Alcohol (IPA) (0.6 kg) was added, and the resulting mixture was cooled to 20-30°C and stirred for 2 h.
  • the mixture was filtered, and the filter cake was washed with Heptane/IPA (95:5 v/v, 10.35 kg).
  • MTBE (50.55 kg) was added, and the mixture was stirred for 30 min at 20-30 °C. Layers were allowed to settle, and the bottom aqueous layer was back- extracted with MTBE (50.65 kg). The organic layers were combined, washed with 5% sodium chloride aqueous solution (2 x 16.80 kg), and concentrated under vacuum at ⁇ 55°C to a target volume of 16.80 L. MTBE (80.30 kg) was added, and the mixture was filtered to remove solids. The solids were washed with MTBE (6.8 kg), and the wash was combined with the filtrate.
  • the product was dissolved in ethanol (45.50 kg) at 50-60 °C and recrystallized by addition of MTBE (22.20 kg), cooling to 15-25 °C, and stirring at this temperature for at least 8 h.
  • the recrystallized product was filtered and washed with MTBE/Ethanol (3:1 v/v, 11 kg) and MTBE (8.60 kg), and dried under vacuum (> 26 inches Hg) and nitrogen purge at 15-25 °C for at least 12 h to give 2.25 kg (5.94 mol, 44% yield) of 4,6-dimethyl-5-(5-nitro-2-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyrimidine hydrochloride (llc-1).
  • the hydrogen pressure was released through a scrubber, and the reactor was purged with nitrogen three times and maintained under nitrogen for the duration of the workup.
  • the mixture was filtered, washed with purified water (5.62 kg), and the wash was combined with the filtrate.
  • the filtrate was stirred with SiliaMetS Thiourea (0.30 kg) at 15-25°C for 24 h to scavenge residual Pd.
  • the solids were filtered, washed with purified water (5.50 kg), and the wash was combined with the filtrate.
  • the filtrate was concentrated under vacuum at temperature ⁇ 45°C to a volume of 15 L.
  • Residual water was removed through azeotropic distillation with Ethanol (10 x 18 kg) to a final volume of ⁇ 20 L until Karl Fischer analysis showed ⁇ 1% water remained. The mixture was cooled to 0-10°C and stirred at this temperature for 5 h.
  • the material was characterized by PXRD ( Figure 1), and DSC/TGA ( Figures 2 and 3 respectively).
  • DSC analysis showed a broad endothermic melt with onset at 140.1 °C and peak at 151 .5 °C.
  • TGA analysis displayed a 3.6 wt. % loss up to 240 °C (theoretically 0.8 eq. water).
  • Example 5 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Besylate Salt).
  • Benzenesulfonic acid (0.416 g, 2.63 mmol) was dissolved in 4 mL ethyl acetate and this solution was added dropwise over 5 minutes to the A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)cyclopropanecarboxamide solution at 40 °C and was stirred at this temperature for a further two hours.
  • the benzenesulfonate (besylate) salt precipitated and was collected by filtration using a Buchner funnel and dried at 40 °C for 16 hours.
  • Example 6 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Citrate Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (2.00 g, 5.26 mmol) was added to a 250 mL round bottom flask and dissolved in ethanol (40 mL).
  • Citric acid monohydrate (1 .105 g, 5.26 mmol) was added to a 100 mL Erlenmeyer flask and dissolved in ethanol (10 mL).
  • the citric acid solution was added to the A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide solution in 0.5 mL portions over 10 minutes while stirring the reaction.
  • the citrate salt began to slowly precipitate form solution after a few minutes and the reaction was stirred for 24 h.
  • the salt was isolated by Buchner filtration and subsequently dried in the oven at 40 °C for 5 hours.
  • Example 7 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Fumarate Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (20 mg) was dissolved in 0.2 ml ethyl acetate and an equimolar amount of fumaric acid was also dissolved in 0.2 mL ethyl acetate.
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide solution was added to the fumaric acid solution while stirring at 40 °C and then stirred at 40 °C40 °C for one hour. Then it was cooled to 20 °C with stirring for additional 72 hours. The precipitated salt was isolated by centrifugation.
  • the resulting crystalline material, fumarate salt, was characterized by PXRD ( Figure 10), and DSC/TGA ( Figures 11 and 12 respectively).
  • DSC analysis showed a endothermic melt with onset at 151.3 °C and peak at 156.1 °C.
  • TGA analysis displayed a 4.9 wt. % loss up to 200 °C (theoretically 2.5 eq. water).
  • Example 8 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Hydrochloride Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (100 mg) was dissolved in 2 mL isopropyl acetate and heated to 40 °C and an equimolar amount of aqueous 3.3M HCI solution (79.6 mL) was added and stirred for one hour at 40 °C. The reaction was stirred overnight during which it cooled down to 20 °C. The reaction mixture was evaporated at room temperature and then the resulting solid was dried in a vacuum oven at 40 °C for 48 hours.
  • the resulting crystalline material, hydrochloride salt, was characterized by PXRD ( Figure 13), and DSC/TGA ( Figures 14 and 15 respectively).
  • DSC analysis showed a broad endothermic event (onset: 23.8 °C; peak: 74.6 °C) associated with solvent loss and a second endothermic event (onset: 188.5 °C; peak: 193.9 °C) associated with melting.
  • TGA analysis displayed a 4.3 wt. % loss up to 200 °C (theoretically 1 .03 eq. water).
  • Example 9 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Mesylate Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (20 mg) was dissolved in 0.4 mL ethyl acetate and heated to 40 °C with rapid stirring and 1.0 equivalent of methanesulfonic acid (3.3M in ethyl acetate) solution was added and continued stirring at 40 °C for one hour and then stirred overnight during which it cooled down to 20 °C. The reaction mixture was evaporated at room temperature and then the resulting solid was dried in a vacuum oven at 40 °C for 24 hours.
  • the resulting crystalline material, mesylate salt, was characterized by PXRD (Figure 16), and DSC/TGA ( Figures 17 and 18 respectively).
  • DSC analysis showed one endothermic event (onset: 181 .4 °C; peak: 189.7 °C) associated with melting.
  • TGA analysis displayed a 2.2 wt. % loss up to 180 °C (theoretically 0.6 eq. water).
  • Example 10 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Phosphate Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (100 mg) was dissolved in 2.0 mL acetonitrile and heated to 40 °C with rapid stirring and 1.0 equivalent of phosphoric acid (79 mL, 3.3M) solution was added and continued stirring at 40 °C for one hour and then it was cooled down to 20 °C. The reaction mixture was decanted and the collected solids dried in a vacuum oven at 40 °C for 3 hours.
  • the resulting crystalline material, phosphate salt was characterized by PXRD (Figure 19), and DSC/TGA ( Figures 20 and 21 respectively).
  • DSC analysis showed one endothermic event (onset: 201.7 °C; peak: 217.9 °C) associated with melting.
  • TGA analysis displayed a 3.4 wt. % loss up to 180 °C (theoretically 0.9 eq. water).
  • Example 11 Preparation of /V-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (Compound la; Succinate Salt).
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (175 mg) was dissolved in 3.5 mL ethyl acetate and heated to 40 °C with rapid stirring and 1 .0 equivalent of succinic acid solution (in ethyl acetate) was added and continued stirring at 40 °C for one hour and then it was cooled down to 20 °C overnight. The precipitated solids were collected by filtration and the collected solids dried in a vacuum oven at 40 °C.
  • A/-(3-(4,6-dimethylpyrimidin-5-yl)-4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl)cyclopropanecarboxamide (175 mg) was dissolved in 3.5 mL ethyl acetate and heated to 40 °C with rapid stirring and 1.0 equivalent of p-toluenesulfonic acid solution (in ethyl acetate) was added and continued stirring at 40 °C for one hour and then it was cooled down to 20 °C overnight. The precipitated solids were collected by filtration and the collected solids dried in a vacuum oven at 40 °C.
  • the resulting crystalline material, tosylate salt, was characterized by PXRD (Figure 25), and DSC/TGA ( Figures 26 and 27 respectively).
  • DSC analysis showed one endothermic event (onset: 151 .3 °C; peak: 170.1 °C) associated with melting.
  • TGA analysis displayed a 1 .5 wt. % loss up to 168 °C (theoretically 0.47 eq. water).
  • Example 12 Powder X-ray Diffraction.
  • PXRD analysis was carried out on a PANalytical X’pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35° 20.
  • the material was gently ground (where required) to release any agglomerates and loaded onto a multi-well plate with Kapton or Mylar polymer film to support the sample.
  • Example 13 Differential Scanning Calorimetry (DSC).

Abstract

La présente divulgation concerne une forme cristalline et des sels cristallins de N-(3-(4,6-diméthylpyrimidin-5-yl)-4-(2-(pyrrolidin-1-yl)éthoxy)phényl)cyclopropanecarboxamide (composé Ia) et des compositions pharmaceutiques de celui-ci qui modulent l'activité du récepteur 5 HT2A. La présente divulgation concerne en outre des processus utiles dans la préparation de la forme cristalline et des sels du composé Ia et des compositions pharmaceutiques de celui-ci.
PCT/IB2022/060059 2021-10-22 2022-10-19 Formes cristallines et processus pour la préparation de dérivés de pyrimidine utiles en tant que modulateurs du récepteur 5-ht2a de la sérotonine WO2023067520A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1264820A1 (fr) * 2000-03-14 2002-12-11 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amides
WO2007136703A1 (fr) * 2006-05-18 2007-11-29 Arena Pharmaceuticals, Inc. Amines primaires et dérivés de celles-ci utilisés en tant que modulateurs du récepteur de la sérotonine 5-ht2a utiles pour traiter des troubles associés à ce récepteur
WO2022093849A1 (fr) * 2020-10-27 2022-05-05 Arena Pharmaceuticals, Inc. Dérivés de pyrimidine en tant que modulateurs du récepteur 5-ht2a de la sérotonine utiles pour le traitement de troubles associés à celui-ci

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Publication number Priority date Publication date Assignee Title
EP1264820A1 (fr) * 2000-03-14 2002-12-11 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amides
WO2007136703A1 (fr) * 2006-05-18 2007-11-29 Arena Pharmaceuticals, Inc. Amines primaires et dérivés de celles-ci utilisés en tant que modulateurs du récepteur de la sérotonine 5-ht2a utiles pour traiter des troubles associés à ce récepteur
WO2022093849A1 (fr) * 2020-10-27 2022-05-05 Arena Pharmaceuticals, Inc. Dérivés de pyrimidine en tant que modulateurs du récepteur 5-ht2a de la sérotonine utiles pour le traitement de troubles associés à celui-ci

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COLLIER, T. L., J. LABELLED COMPD. RADIOPHARM., vol. 42, 1999, pages S264 - S266
G. P. STAHLY, CRYSTAL GROWTH & DESIGN, vol. 7, no. 6, 2007, pages 1007 - 1026
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