WO2023059610A1 - Formes cristallines et processus de préparation de modulateurs des récepteurs cannabinoïdes - Google Patents

Formes cristallines et processus de préparation de modulateurs des récepteurs cannabinoïdes Download PDF

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WO2023059610A1
WO2023059610A1 PCT/US2022/045638 US2022045638W WO2023059610A1 WO 2023059610 A1 WO2023059610 A1 WO 2023059610A1 US 2022045638 W US2022045638 W US 2022045638W WO 2023059610 A1 WO2023059610 A1 WO 2023059610A1
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solvate
crystalline form
ray powder
powder diffraction
diffraction pattern
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PCT/US2022/045638
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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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Publication of WO2023059610A1 publication Critical patent/WO2023059610A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to crystalline forms of 3-((4a5,5aS)-3-((l,l,l-trifluoro-2- methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH-cyclopropa[4,5]cyclopenta[ 1,2- c]pyrazol-l-yl)pyrazine 1 -oxide (Compound 1) and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB2 receptor.
  • Compound 1 and pharmaceutical compositions thereof are useful in the treatment of central nervous system (CNS) inflammation, for example CNS inflammation associated with a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis (ALS); and undesired immune cell activity; CNS tumors; Alzheimer's disease; stroke; stroke -induced damage; dementia; ALS; and Parkinson's disease.
  • CNS inflammation associated with a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis (ALS); and undesired immune cell activity
  • CNS tumors Alzheimer's disease
  • stroke stroke
  • stroke -induced damage dementia
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis (ALS); and undesired immune cell activity
  • the present invention further relates to processes useful in the preparation of crystalline forms and solvates of Compound 1 and pharmaceutical compositions thereof.
  • Cannabinoids are a group of extracellular signaling molecules that are found in both plants and animals. Signals from these molecules are mediated in animals by two G-protein coupled receptors, cannabinoid receptor 1 (CBi) and cannabinoid receptor 2 (CB2). CBi is expressed most abundantly in the neurons of the CNS, but is also present at lower concentrations in a variety of peripheral tissues and cells. In contrast, CB2 is expressed predominantly, although not exclusively, in non-neural tissues (e.g., in hematopoietic cells, endothelial cells, osteoblasts, osteoclasts, the endocrine pancreas, and cancerous cell lines). As such, CBi is believed to be primarily responsible for mediating the psychotropic effects of cannabinoids on the body, whereas CB2 is believed to be primarily responsible for most of their non-neural effects.
  • CBi cannabinoid receptor 1
  • CB2 cannabinoid receptor 2
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1):
  • One aspect of the present disclosure relates to processes for preparing an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • One aspect of the present disclosure relates to processes for preparing a crystalline form of
  • crystallising solvent is selected from a group consisting of tetrahydrofuran (THF), heptane, acetone, ethyl acetate, methanol, ethanol, 2-propanol, tert-butyl methyl ether (TBME), methyl isobutyl ketone (MIBK), and dimethyl sulfoxide (DMSO), and combinations thereof.
  • THF tetrahydrofuran
  • heptane heptane
  • acetone ethyl acetate
  • methanol ethanol
  • 2-propanol tert-butyl methyl ether
  • MIBK methyl isobutyl ketone
  • DMSO dimethyl sulfoxide
  • One aspect of the present disclosure relates to processes wherein the crystallising solvent is ethyl acetate.
  • One aspect of the present disclosure relates to processes for preparing an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • l,2-c]pyrazol-l-yl)pyrazine 1-oxide comprising the step of: a) isolating the crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan- 2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1 H-cyclopropa[ 4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1-oxide from a crystallizing mixture to obtain the anhydrous crystalline form of 3-(
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide prepared by a process as described herein.
  • compositions comprising an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • compositions comprising an anhydrous crystalline form of 3-((4aS'.5a.S')-3-(( l . l . l -trifliioro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a- tetrahydro- lH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide 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 an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2- methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH-cyclopropa[4,5]cyclopenta[ 1,2- c]pyrazol-l-yl)pyrazine 1-oxide as described herein, with a phamaceutically acceptable carrier.
  • One aspect of the present disclosure relates to methods for the treatment of a cannabinoid receptor-mediated disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form of 3-((4a.S'.5aS')-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of a CB2 receptor- mediated disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form of 3-((4aS'.5a.S')-3-(( l . l . l-trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide as described herein, in the manufacture of a medicament for the treatment of a cannabinoid receptor-mediated disorder.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form of 3-((4aS'.5a.S')-3-(( l . l . l-trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide as described herein, in the manufacture of a medicament for the treatment of a CB2 receptor-mediated disorder.
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide 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 an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide as described herein, for use in a method of treatment of a cannabinoid receptor-mediated disorder.
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide as described herein, for use in a method of treatment of a CB2 receptor-mediated disorder.
  • One aspect of the present disclosure relates to non-selective solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • THF tetrahydrofuran
  • One aspect of the present disclosure relates to heptane solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to acetone solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to ethyl acetate solvates of 3-((4a.S'.5aS')-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to methanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to ethanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to isopropanol solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • TBME tert-butyl methyl ether
  • MIBK methyl isobutyl ketone
  • One aspect of the present disclosure relates to dimethyl sulfoxide (DMSO) solvates of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • DMSO dimethyl sulfoxide
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern for a sample containing an anhydrous crystalline form of Compound 1.
  • Figure 2 shows a differential scanning calorimetry (DSC) thermogram for a sample containing anhydrous crystalline form of Compound 1.
  • FIG 3 shows a thermogravimetric analysis (TGA) thermogram of a sample containing anhydrous crystalline form of Compound 1.
  • Figure 4 shows a 1 H-NMR of Compound 1 (Anhydrous Form).
  • Figure 5 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (THF Solvate).
  • Figure 6 shows the asymmetric unit for the hemi-THF solvate of Compound 1 based on single-crystal X-ray diffraction (SCXRD) analysis.
  • FIG. 7 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (THF Solvate).
  • FIG 8 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (THF Solvate).
  • Figure 9 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (Heptane Solvate).
  • Figure 10 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (Heptane Solvate).
  • FIG 11 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (Heptane Solvate).
  • Figure 12 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (Acetone Solvate).
  • PXRD powder X-ray diffraction
  • Figure 13 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (Acetone Solvate).
  • FIG 14 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (Acetone Solvate).
  • Figure 15 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (Ethyl Acetate Solvate).
  • Figure 16 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (Ethyl Acetate Solvate).
  • FIG 17 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (Ethyl Acetate Solvate).
  • Figure 18 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (Methanol Solvate).
  • Figure 19 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (Methanol Solvate).
  • FIG 20 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (Methanol Solvate).
  • Figure 21 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (Ethanol Solvate).
  • Figure 22 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (Ethanol Solvate).
  • FIG 23 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (Ethanol Solvate).
  • Figure 24 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (2-Propanol Solvate).
  • Figure 25 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (2 -Propanol Solvate).
  • FIG 26 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (2 -Propanol Solvate).
  • Figure 27 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (TBME Solvate).
  • Figure 28 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (TBME Solvate).
  • FIG 29 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (TBME Solvate).
  • Figure 30 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (MIBK Solvate).
  • Figure 31 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (MIBK Solvate).
  • FIG 32 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (MIBK Solvate).
  • Figure 33 shows a powder X-ray diffraction (PXRD) pattern for a sample containing a crystalline form of Compound 1 (DMSO Solvate).
  • Figure 34 shows a differential scanning calorimetry (DSC) thermogram for a sample containing a crystalline form of Compound 1 (DMSO Solvate).
  • FIG. 35 shows a thermogravimetric analysis (TGA) thermogram of a sample containing a crystalline form of Compound 1 (DMSO Solvate).
  • agonist refers to a moiety that interacts with and activates a G-protein-coupled receptor, for instance a cannabinoid receptor, and can thereby initiate a physiological or pharmacological response characteristic of that receptor.
  • a G-protein-coupled receptor for instance a cannabinoid receptor
  • an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding to a membrane.
  • in need of treatment and the term “in need thereof when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., physician, nurse, nurse practitioner, etc.) that an individual 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 is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds described herein. Accordingly, the compounds described herein can be used in a protective or preventive manner; or compounds described herein can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • the term “individual” refers to a human.
  • modulate or modulating refers to an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • composition refers to a composition comprising at least one active ingredient of the present disclosure, whereby the composition is amenable to investigation for a specified, efficacious outcome.
  • active ingredient e.g., a pharmaceutically acceptable salt, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt.
  • 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.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue or system that is being sought by a researcher, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology);
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the present disclosure is directed to, inter alia, processes useful in the preparation of an anhydrous crystalline form of 3-((4aS',5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro- 1 H-cyclopropa[ 4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide, a modulator of the cannabinoid CB2 receptor.
  • One aspect of the present disclosure relates to processes for preparing a crystalline form of 3-((4aS,5aS)-3-(( 1,1, l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide comprising the steps of: a) crystallizing 3 -((4aS,5 S)-3 -((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-lH-cyclopropa[4,5]cyclopenta[ l,2-c]pyrazol-l-yl)pyrazine 1-oxide from a crystallizing mixture to obtain a crystalline form of 3-((4a.S'.5a.S')-3-(
  • One aspect of the present disclosure relates to processes for preparing a crystalline form of
  • One aspect of the present disclosure relates to processes for preparing a crystalline form of 3-((4aS'.5a.S')-3-(( l . l . l-trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine, wherein the crystallizing solvent is selected from a group consisting of tetrahydrofuran (THF), heptane, acetone, ethyl acetate, methanol, ethanol, 2-propanol, tert-butyl methyl ether (TBME), methyl isobutyl ketone (MIBK), water, and dimethyl sulfoxide (DMSO) and combinations thereof.
  • THF tetrahydrofuran
  • TBME tert-buty
  • One aspect of the present disclosure relates to processes for preparing a crystalline form of 3-((4aS,5aS)-3-(( 1,1, l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine, wherein the crystallizing solvent is ethyl acetate.
  • One aspect of the present disclosure relates to processes for preparing an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • crystallizing is conducted at a temperature of about -10 °C to about 45 °C. In some embodiments, crystallizing is conducted at a temperature of about -10 °C to about
  • crystallizing is conducted at a temperature of about -10 °C to about
  • crystallizing is conducted at a temperature of about -10 °C to about
  • crystallizing is conducted at a temperature of about -5 °C to about 5
  • the crystallizing solvent is ethyl acetate and the crystallizing mixture is prepared by the steps of: a) dissolving 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-lH-cyclopropa[4,5]cyclopenta[ l,2-c]pyrazol-l-yl)pyrazine 1-oxide in a first amount of ethyl acetate to form a first mixture; and b) adding a second amount of ethyl acetate to the first mixture to obtain the crystallizing mixture.
  • dissolving is conducted at a temperature of about 25 °C to about 85 °C. In some embodiments, dissolving is conducted at a temperature of about 30 °C to about 80 °C. In some embodiments, dissolving is conducted at a temperature of about 45 °C to about 75 °C. In some embodiments, dissolving is conducted at a temperature of about 50 °C to about 70 °C. In some embodiments, dissolving is conducted at a temperature of about 55 °C to about 65 °C. In some embodiments, dissolving is conducted at a temperature of about 55 °C to about 60 °C. In some embodiments, dissolving is conducted at a temperature of about 60 °C.
  • isolating comprises filtering the crystalline form of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide from the crystallizing mixture.
  • isolating comprises removing the crystalline form of 3-((4a.S'.5aS')- 3 -(( 1 , 1 , 1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5 ,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide from the crystallizing mixture.
  • One aspect of the present disclosure relates to processes for preparing an anhydrous crystalline form wherein the processes further comprises the step of drying the crystalline form of 3-((4aS,5aS)-3-(( 1,1, l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide to obtain the anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- IH-cyclopropa
  • drying is conducted at a temperature of about 15 °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 45 °C to about 85 °C. In some embodiments, drying is conducted at a temperature of about 65 °C to about 85 °C. In some embodiments, drying is conducted at a temperature of about 85 °C. In some embodiments, drying is conducted at a pressure of less than 760 mm Hg and a temperature of about 80 °C to about 85 °C. In some embodiments, drying is conducted at a pressure of less than 760 mm Hg and a temperature of about 85 °C.
  • the anhydrous crystalline form of 3-((4a.S'.5aS')-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide has a chemical purity of about 95% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide has a chemical purity of about 98% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide has a chemical purity of about 99% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide has an enantiomeric excess of about 95% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide has an enantiomeric excess of about 98% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide has an enantiomeric excess of about 99% or greater.
  • the anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide has a chemical purity of about 99% or greater and an enantiomeric excess of about 99% or greater.
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide 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 an anhydrous crystalline form of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2- methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH-cyclopropa[4,5]cyclopenta[ 1,2- c]pyrazol-l-yl)pyrazine 1-oxide as described herein with a phamaceutically 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.
  • One aspect of the present disclosure relates to anhydrous and solvate forms of 3-((4aS,5aS)- 3 -(( 1 , 1 , 1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5 ,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to an anhydrous form of3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to non-selective solvates of 3-((4aS,5 S)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to THF solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to heptane solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to acetone solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to ethyl acetate solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to methanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to ethanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to 2-propanol solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to tert-butyl methyl ether solvates of 3- ((4a.S'.5aS')-3-(( 1, l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to methyl isobutyl ketone solvates of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • One aspect of the present disclosure relates to DMSO solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • Crystalline forms of the solvates and anhydrous forms 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 2 //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 an anhydrous form of3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the physical properties of the crystalline form of Compound 1 anhydrous form are summarized in Table 1 below.
  • Table 2 One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to an anhydrous crystalline form of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide, wherein the anhydrous crystalline form has an X-ray owder diffraction pattern comprising a peak, in terms of 2ft at 7.8° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 10.5° ⁇ 0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 14.2° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 14.6° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 18.0° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 18.8° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the anhydrous 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 °2ft
  • the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.6 °C and about 180.6 °C.
  • the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 170.6 °C and about 178.6 °C.
  • the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.6 °C and about 176.6 °C. In some embodiments, the anhydrous crystalline form has having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.6 °C and about 175.6 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 173.6 °C.
  • the anhydrous 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 anhydrous crystalline form has a thermogravimetric analysis profde 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 anhydrous crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.6 °C and about 180.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 10.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 170.6 °C and about 178.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 14.6'° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.6 °C and about 176.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 18.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.6 °C and about 175.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 21.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.6 °C and about 175.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.6 °C and about 175.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 173.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous crystalline form having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 28.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 164.6 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 263 °C.
  • One aspect of the present disclosure relates to the anhydrous 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 profde substantially as shown in Figure 3.
  • One aspect of the present disclosure relates to non-selective solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • Non-selective solvates refer to solvates that have substantially the same crystalline form as determined by PXRD, and depending on the purity, after de-solvation will have similar extrapolated onset temperature (+/- 4.0 °C) as determined by DSC regardless what solvent or solvents were used to prepare the solvate. It is understood that the TGA trace will vary from one non-selective solvate to another and is primarily determined by the solvent used in the preparation, the solvate formed, and the amount of the solvent present in the solvate.
  • the non-selective solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the non-selective solvates as determined by PXRD are summarized in tables below.
  • THF solvates One aspect of the present disclosure relates to THF solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the THF solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the THF solvates as determined by PXRD are summarized in Table 3 below.
  • THF solvates can vary, and be up to about 8.0% by weight.
  • the amount of THF can readily be determined by TGA.
  • the physical properties for a THF solvate (Example 4) prepared using procedure from Example 3, Method 4, are summarized in Table 4 below.
  • One aspect of the present disclosure relates to THF solvate of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the THF solvate of compound 1 was prepared by procedure from Example 3, Method 4.
  • THF solvate of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide, having a powder X-ray diffraction pattern comprising a peak, in terms of 20, at 6.5° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, and 7.3° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°. In some embodiments, the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3 ⁇ 0.2°, 7.8° ⁇ 0.2°, and 10.6° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.8° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 14.3° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 15.9° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the THF solvate has an X-ray powder diffraction pattern substantially as shown in Figure 5, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the THF solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 142.1 °C and about
  • the THF solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 143.1 °C and about 151.1 °C and between about 169.9 °C and about 175.9 °C. In some embodiments, the THF solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144.1 °C and about 150.1 °C and between about 170.9 °C and about 174.9 °C.
  • the THF solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144.1 °C and about 149.1 °C and between about 171.9 °C and about 173.9 °C. In some embodiments, the THF solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about
  • the THF solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 7, 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 THF solvate has a thermogravimetric analysis profde showing about 6.0% weight loss below about 180 °C. In some embodiments, the THF solvate has a thermogravimetric analysis profde showing about 5.5% weight loss below about 180 °C. In some embodiments, the THF solvate has a thermogravimetric analysis profde showing about 5.0% weight loss below about 180 °C. In some embodiments, the THF solvate has a thermogravimetric analysis profde showing about 4.5% weight loss below about 180 °C. In some embodiments, the THF solvate has a thermogravimetric analysis profde showing about 4.0% weight loss below about 180 °C.
  • the THF solvate has a thermogravimetric analysis profde substantially as shown in Figure 8, 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.
  • THF solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 142.1 °C and about 152.1 °C and between about
  • THF solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 143.1 °C and about 151.1 °C and between about
  • THF solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, and 14.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144.1 °C and about 150.1 °C and between about
  • THF solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 21.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144.1 °C and about 149.1 °C and between about
  • thermogravimetric analysis profde showing showing about 6.0% weight loss below about 180 °C.
  • THF solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 145.1 °C and at about 172.9 °C; and/or c) a thermogravimetric analysis profde showing showing about 6.0% weight loss below about 180 °C.
  • THF solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 145.1 °C and at about 172.9 °C; and/or c) a thermogravimetric analysis profde showing showing about 5.5% weight loss below about 180 °C.
  • THF solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 145.1 °C and at about 172.9 °C; and/or c) a thermogravimetric analysis profde showing showing about 5.0% weight loss below about 180 °C.
  • THF solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 145.1 °C and at about 172.9 °C; and/or c) a thermogravimetric analysis profde showing showing about 4.5% weight loss below about 180 °C.
  • THF solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 5; b) a differential scanning calorimetry thermogram substantially as shown in Figure 7; and/or c) a thermogravimetric analysis profde substantially as shown in Figure 8.
  • One aspect of the present disclosure relates to heptane solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the heptane solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the heptane solvates as determined by PXRD are summarized in Table 6 below.
  • One aspect of the present disclosure relates to an heptane solvate of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide.
  • One aspect of the present disclosure relates to an heptane solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.4° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20. at 6.4° ⁇ 0.2° and 7.3° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, and 14.3° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2° and 21.3° ⁇ 0.2°.
  • the heptane solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26.
  • the heptane solvate has an X-ray powder diffraction pattern substantially as shown in Figure 9, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °26.
  • the heptane solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 75 °C and about 105 °C and between about 170 °C and about 180 °C.
  • the heptane solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 102 °C and between about 172 °C and about 178 °C.
  • the heptane solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 85 °C and about 101 °C and between about 173 °C and about 176 °C.
  • the heptane solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 95 °C and about 101 °C and between about 174 °C and about 176 °C.
  • the heptane solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 78.6 °C and at about 173.3 °C.
  • the heptane solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 10, 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 heptane solvate has a thermogravimetric analysis profile showing about 2.7% weight loss below about 180 °C.
  • the heptane solvate has a thermogravimetric analysis profile showing about 2.3% weight loss below about 180 °C.
  • the heptane solvate has a thermogravimetric analysis profile showing about 2.0% weight loss below about 180 °C.
  • the heptane solvate has a thermogravimetric analysis profile showing about 1.5% weight loss below about 180 °C.
  • the heptane solvate has a thermogravimetric analysis profile showing about 1.0% weight loss below about 180 °C.
  • the heptane solvate has a thermogravimetric analysis profile substantially as shown in Figure 11, 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 heptane solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 75 °C and about 105 °C and between about 170 °C and about 180 °C; and/or
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, and 14.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 85 °C and about 101 °C and between about 173 °C and about 176 °C; and/or
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 15.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 95 °C and about 101 °C and between about 174 °C and about 176 °C; and/or
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, and 18.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 102 °C and between about 172 °C and about 178 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.7% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3 ⁇ 0.2°, 14.7° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 78.6 °C and at about 173.3 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.7% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 78.6 °C and at about 173.3 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.3% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3 ⁇ 0.2°, 14.7° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 78.6 °C and at about 173.3 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2°, 14.3 ⁇ 0.2°, 14.7° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 78.6 °C and at about 173.3 °C; and/or c) a thermogravimetric analysis profde showing showing about 1.5% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the heptane solvate having: a) an X-ray powder diffraction patern substantially as shown in Figure 9; b) a differential scanning calorimetry thermogram substantially as shown in Figure 10; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 11.
  • One aspect of the present disclosure relates to acetone solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the Acetone solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the acetone solvates as determined by PXRD are summarized in Table 9 below.
  • acetone solvate (Example 6) prepared using procedure from Example 3, Method 4, are summarized in Table 10 below.
  • One aspect ofthe present disclosure relates to an acetone solvate of3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to an acetone solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.4° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2° and 7.3° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 13.7° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at .4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the acetone solvate has an X-ray powder diffraction pattern substantially as shown in Figure 12, wherein by “substantially” is meant that the reported peaks can vary by about
  • the acetone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 120 °C and about 130 °C and between about 170 °C and about 180 °C.
  • the acetone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 122 °C and about 128 °C and between about 171 °C and about 178 °C.
  • the acetone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 123 °C and about 126 °C and between about 172 °C and about 176 °C.
  • the acetone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 123 °C and about 125 °C and between about 172 °C and about 174 °C.
  • the acetone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 124.5 °C and at about 173.2 °C.
  • the acetone solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 13, 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 acetone solvate has a thermogravimetric analysis profde substantially as shown in Figure 14, 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 acetone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 120 °C and about 130 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 225 °C.
  • One aspect of the present disclosure relates to the acetone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 11.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 122 °C and about 128 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 225 °C.
  • One aspect of the present disclosure relates to the acetone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 13.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 123 °C and about 126 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 225 °C.
  • One aspect of the present disclosure relates to the acetone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 15.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 123 °C and about 125 °C and between about 172 °C and about 174 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 225 °C.
  • One aspect of the present disclosure relates to the acetone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 23.6° ⁇ 0.2; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 124.5 °C and at about 173.2 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 225 °C
  • One aspect of the present disclosure relates to the acetone solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 12; b) a differential scanning calorimetry thermogram substantially as shown in Figure 13; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 14.
  • One aspect of the present disclosure relates to ethyl acetate solvates of 3-((4a.S'.5aS')-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1 -oxide (Compound a).
  • the Ethyl acetate solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the ethyl acetate solvates as determined by PXRD are summarized in Table 12 below.
  • Example 7 The amount of ethyl acetate present in these solvates can vary and can readily be determined by TGA.
  • the physical properties for a ethyl acetate solvate (Example 7) prepared using procedure from Example 3, Method 4, are summarized in Table 13 below.
  • One aspect of the present disclosure relates to an ethyl acetate solvate of 3-((4a.S'.5aS')-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to an ethyl acetate solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2ft at 6.4° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.7° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.7° ⁇ 0.2°, and 23.7° ⁇ 0.2°.
  • the ethyl acetate solvate has an X-ray powder diffraction pattern substantially as shown in Figure 15, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 85 °C and about 115 °C and between about 170 °C and about 180 °C.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 90 °C and about 110 °C and between about 171 °C and about 178 °C.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 95 °C and about 105 °C and between about 172 °C and about 176 °C.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 100 °C and about 105 °C and between about 172 °C and about 174 °C.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 88.4 °C and at about 173.3 °C.
  • the ethyl acetate solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 16, 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 ethyl acetate solvate has a thermogravimetric analysis profile showing about 2.7% weight loss below about 180 °C.
  • the ethyl acetate solvate has a thermogravimetric analysis profile showing about 2.3% weight loss below about 180 °C.
  • the ethyl acetate solvate has a thermogravimetric analysis profile showing about 2.0% weight loss below about 180 °C.
  • the ethyl acetate solvate has a thermogravimetric analysis profile showing about 1.5% weight loss below about 180 °C.
  • the ethyl acetate solvate has a thermogravimetric analysis profile showing about 1.0% weight loss below about 180 °C. In some embodiments, the ethyl acetate solvate has a thermogravimetric analysis profile substantially as shown in Figure 17, 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 ethyl acetate solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 85 °C and about 115 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profile showing showing about 1.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the ethyl acetate solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 13.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 90 °C and about 110 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profile showing showing about 1.5% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the ethyl acetate solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 95 °C and about 105 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profile showing showing about 2.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the ethyl acetate solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, and 18.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 100 °C and about 105 °C and between about 172 °C and about 174 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.3% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the ethyl acetate solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.7° ⁇ 0.2°, and 23.7° ⁇ 0.2; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 88.4 °C and at about 173.3 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.7% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the ethyl acetate solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 15; b) a differential scanning calorimetry thermogram substantially as shown in Figure 16; and/or c) a thermogravimetric analysis profde substantially as shown in Figure 17.
  • One aspect of the present disclosure relates to methanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the Methanol solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the methanol solvates as determined by PXRD are summarized in Table 15 below.
  • Example 8 The amount of methanol present in these solvates can vary and can readily be determined by TGA.
  • Table 16 The physical properties for a methanol solvate (Example 8) prepared using procedure from Example 1, Method 2, are summarized in Table 16 below. Table 16
  • One aspect of the present disclosure relates to an methanol solvate of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to a methanol solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.7° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 14.2° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 15.6° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, and 18.0° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the methanol solvate has an X-ray powder diffraction pattern substantially as shown in Figure 18, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the methanol solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.4 °C and about 180.4 °C.
  • the methanol solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 170.4 °C and about 178.4 °C.
  • the methanol solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.4 °C and about 176.4 °C.
  • the methanol solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.4 °C and about 175.4 °C.
  • the methanol solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 173.4 °C.
  • the methanol solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 19, 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 methanol solvate has a thermogravimetric analysis profile substantially as shown in Figure 20, 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 methanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 169.4 °C and about 180.4 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the methanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 14.2° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 170.4 °C and about 178.4 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the methanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, and 18.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 171.4 °C and about 176.4 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the methanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 21.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 172.4 °C and about 175.4 °C; and/or c) a thermogravimetric analysis profile showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the methanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 26.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 173.4 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the methanol solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 18; b) a differential scanning calorimetry thermogram substantially as shown in Figure 19; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 20.
  • One aspect of the present disclosure relates to ethanol solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the Ethanol solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the ethanol solvates as determined by PXRD are summarized in Table 18 below.
  • One aspect of the present disclosure relates to an ethanol solvate of 3-((4aS,5aS)-3-(( 1,1,1 - trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro-lH- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide.
  • One aspect of the present disclosure relates to an ethanol solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°and 10.5° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 14.6° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.4° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.6° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the ethanol solvate has an X-ray powder diffraction pattern substantially as shown in Figure 21, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the ethanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 140 °C and about 150 °C and between about 170 °C and about 180 °C.
  • the ethanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 142 °C and about 149 °C and between about 171 °C and about 178 °C.
  • the ethanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 143 °C and about 148 °C and between about 172 °C and about 176 °C.
  • the ethanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144 °C and about 147 °C and between about 172 °C and about 175 °C. In some embodiments, the ethanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 145.7 °C and at about 173.9 °C.
  • the ethanol solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 22, 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 ethanol solvate has a thermogravimetric analysis profde substantially as shown in Figure 23, 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 ethanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 140 °C and about 150 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the ethanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, and 14.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 142 °C and about 149 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profde showing no observable weight loss below about 212.5 °C.
  • One aspect of the present disclosure relates to the ethanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 22.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 143 °C and about 148 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profile showing showing about 2.0% weight
  • One aspect of the present disclosure relates to the ethanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.4° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 25.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 144 °C and about 147
  • One aspect of the present disclosure relates to the ethanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.4° ⁇
  • One aspect of the present disclosure relates to the ethanol solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 21; b) a differential scanning calorimetry thermogram substantially as shown in Figure 22; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 23.
  • One aspect of the present disclosure relates to 2-Propanol solvates of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the 2-Propanol solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the 2-propanol solvates as determined by PXRD are summarized in Table 21 below.
  • Table 23 One aspect of the present disclosure relates to a 2-propanol solvate of 3-((4aS,5aS)-3- ((1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to a 2-propanol solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2ft, at 6.5° ⁇ 0.2°.
  • the 2- propanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 2ft. at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the 2-propanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, and 12.9° ⁇ 0.2°.
  • the 2-propanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.3° ⁇ 0.2°.
  • the 2-propanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the 2-propanol solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, and 23.7° ⁇ 0.2°.
  • the 2-propanol solvate has an X-ray powder diffraction pattern substantially as shown in Figure 24, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °2ft.
  • the 2-propanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 150 °C and about 160 °C and between about 170 °C and about 180 °C.
  • the 2-propanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 151 °C and about 158 °C and between about 171 °C and about 178 °C.
  • the 2-propanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 151 °C and about 156 °C and between about 172 °C and about 176 °C. In some embodiments, the 2-propanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 152 °C and about 154 °C and between about 172 °C and about 174 °C.
  • the 2-propanol solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 152.8 °C and at about 173.5 °C.
  • the 2-propanol solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 25, 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 2-propanol solvate has a thermogravimetric analysis profde showing about 1.1% weight loss below about 180 °C.
  • the 2-propanol solvate has a thermogravimetric analysis profde showing about 0.8% weight loss below about 180 °C.
  • the 2-propanol solvate has a thermogravimetric analysis profde showing about 0.6% weight loss below about 180 °C.
  • the 2-propanol solvate has a thermogravimetric analysis profde showing about 0.5% weight loss below about 180 °C.
  • the 2-propanol solvate has a thermogravimetric analysis profde showing about 0.3% weight loss below about 180 °C.
  • the 2-propanol solvate has a thermogravimetric analysis profde substantially as shown in Figure 26, 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 2-propanol solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 150 °C and about 160 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profde showing showing about 0.3% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the 2-propanol solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 151 °C and about 158 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profde showing showing about 0.5% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the 2-propanol solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.4° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 151 °C and about 156 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profde showing showing about 0.6% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the 2-propanol solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 21.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 152 °C and about 154 °C and between about 172 °C and about 174 °C; and/or c) a thermogravimetric analysis profde showing showing about 0.8% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the 2-propanol solvate having: a) an X-ray powder diffraction patern comprising peaks, in terms of 10, at 6.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 21.7° ⁇ 0.2°, and 23.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 152.8 °C and at about 173.5 °C; and/or c) a thermogravimetric analysis profde showing showing about 1.1% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the 2-propanol solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 24; b) a differential scanning calorimetry thermogram substantially as shown in Figure 25; and/or c) a thermogravimetric analysis profile substantially as shown in Figure 26.
  • One aspect of the present disclosure relates to 'e /- Butyl Methyl Ether solvates of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the Tert-Butyl Methyl Ether solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the /ert-butyl methyl ether solvates as determined by PXRD are summarized in Table 24 below.
  • One aspect of the present disclosure relates to a tert-butyl methyl ether solvate of 3- ((4a.S'.5aS')-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to a tert-butyl methyl ether solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.3° ⁇ 0.2°.
  • the Tert-Butyl Methyl Ether solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • the / -butyl methyl ether solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, and 13.4° ⁇ 0.2°.
  • the / -butyl methyl ether solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 15.5° ⁇ 0.2°.
  • the / -butyl methyl ether solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the tert-butyl methyl ethersolvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the tert-butyl methyl ether solvate has an X-ray powder diffraction pattern substantially as shown in Figure 27, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 60 °C and about 110 °C and between about 170 °C and about 180 °C.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 65 °C and about 100 °C and between about 171 °C and about 178 °C.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 68 °C and about 90 °C and between about 172 °C and about 176 °C.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 70 °C and about 85 °C and between about 172 °C and about 175 °C.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 71.7 °C and at about 174.1 °C.
  • the tert-butyl methyl ether solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 28, 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 tert-butyl methyl ether solvate has a thermogravimetric analysis profde showing about 2.4% weight loss below about 180 °C.
  • the tert-butyl methyl ether solvate has a thermogravimetric analysis profde showing about 2.0% weight loss below about 180 °C.
  • the tert-butyl methyl ether solvate has a thermogravimetric analysis profde showing about 1.5% weight loss below about 180 °C.
  • the tert-butyl methyl ether solvate has a thermogravimetric analysis profde showing about 1.0% weight loss below about 180 °C.
  • the tert-butyl methyl ether solvate has a thermogravimetric analysis profde showing about 0.5% weight loss below about 180 °C. In some embodiments, the tert-butyl methyl ether solvate has a thermogravimetric analysis profile substantially as shown in Figure 29, 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 tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, and 7.8° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 60 °C and about 110 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profile showing showing about 0.5% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, and 13.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 65 °C and about 100 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profile showing showing about 1.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 15.5° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 68 °C and about 90 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profile showing showing about 1.5% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 21.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 70 °C and about 85 °C and between about 172 °C and about 175 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.0% weight loss
  • One aspect of the present disclosure relates to the tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.5° ⁇ 0.2°, 13.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 28.7° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 71.7 °C and at about 174.1 °C; and/or c) a thermogravimetric analysis profde
  • One aspect of the present disclosure relates to the tert-butyl methyl ether solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 27; b) a differential scanning calorimetry thermogram substantially as shown in Figure 28; and/or c) a thermogravimetric analysis profde substantially as shown in Figure 29.
  • One aspect of the present disclosure relates to methyl isobutyl ketone solvates of 3- ((4aS,5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the Methyl isobutyl ketone solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the tert-butyl methyl ether solvates as determined by PXRD are summarized in Table 27 below.
  • Table 27 The amount of methyl isobutyl ketone present in these solvates can vary and can readily be determined by TGA.
  • the physical properties for a methyl isobutyl ketone solvate (Example 12) prepared using procedure from Example 1, Method 2, are summarized in Table 28 below.
  • One aspect of the present disclosure relates to a methyl isobutyl ketone solvate of 3- ((4a.S'.5aS)-3-(( 1,1,1 -trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a-tetrahydro- 1H- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to a methyl isobutyl ketone solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 6.3° ⁇ 0.2°.
  • the Methyl isobutyl ketone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 10.9° ⁇ 0.2°.
  • the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, and 13.4° ⁇ 0.2°.
  • the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
  • the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 21.0° ⁇ 0.2°.
  • the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 21.0° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 27.3° ⁇ 0.2°.
  • the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern substantially as shown in Figure 30, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 120 °C and between about 170 °C and about 180 °C.
  • the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 116 °C and between about 171 °C and about 178 °C.
  • the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 112 °C and between about 172 °C and about 176 °C.
  • the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 110 °C and between about 172 °C and about 175 °C. In some embodiments, the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 83.8 °C and at about 173.5 °C.
  • the methyl isobutyl ketone solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 31, 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 methyl isobutyl ketone solvate has a thermogravimetric analysis profde showing about 7.2% weight loss below about 180 °C.
  • the methyl isobutyl ketone solvate has a thermogravimetric analysis profde showing about 6.2% weight loss below about 180 °C.
  • the methyl isobutyl ketone solvate has a thermogravimetric analysis profde showing about 5.2% weight loss below about 180 °C.
  • the methyl isobutyl ketone solvate has a thermogravimetric analysis profde showing about 4.2% weight loss below about 180 °C.
  • the methyl isobutyl ketone solvate has a thermogravimetric analysis profde showing about 2.0% weight loss below about 180 °C.
  • the methyl isobutyl ketone solvate has a thermogravimetric analysis profde substantially as shown in Figure 32, 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 methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 10.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 120 °C and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profde showing showing about 2.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, and 13.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 116 °C and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profde showing showing about 4.2% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 18.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 112 °C and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profde showing showing about 5.2% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 21.0° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 80 °C and about 110 °C and between about 172 °C and about 175 °C; and/or c) a thermogravimetric analysis profde showing showing about 6.2% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 10.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 21.0° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 27.3° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 83.8 °C and at about 173.5 °C; and/or c) a thermogravimetric analysis profde showing showing about 7.2% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the methyl isobutyl ketone solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 30; b) a differential scanning calorimetry thermogram substantially as shown in Figure
  • thermogravimetric analysis profile substantially as shown in Figure 32.
  • One aspect of the present disclosure relates to DMSO solvates of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1).
  • the DMSO solvates of Compound 1 are characterized by PXRD.
  • the physical properties for the tert-butyl methyl ether solvates as determined by PXRD are summarized in Table 30 below.
  • DMSO solvate (Example 13) prepared using procedure from Example 1, Method 2, are summarized in Table 31 below.
  • One aspect of the present disclosure relates to a DMSO solvate of 3-((4aS,5aS)-3-((l,l,l- trifluoro-2-mcthylpropan-2-yl)carbamoyl)-4.4a.5.5a-tctrahydro- l//- cyclopropa[4,5 ]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)pyrazine 1 -oxide .
  • One aspect of the present disclosure relates to a DMSO solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2ft at 6.4° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 2ft at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 11.1° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.6° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 19.4° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, and 27.2° ⁇ 0.2°.
  • the DMSO solvate has an X-ray powder diffraction pattern substantially as shown in Figure 33, wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2 °20.
  • the DMSO solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 30 °C and about 70 °C, between about 100 °C and about 135 °C, between about 150 °C and about 160 °C, and between about 170 °C and about 180 °C.
  • the DMSO solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 32 °C and about 68 °C, between about 101 °C and about 125 °C, between about 151 °C and about 158 °C, and between about 171 °C and about 178 °C.
  • the DMSO solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 34 °C and about 66 °C, between about 102 °C and about 115 °C, between about 153 °C and about 157 °C, and between about 172 °C and about 176 °C.
  • the DMSO solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 36 °C and about 60 °C, between about 103 °C and about 105 °C, between about 154 °C and about 156 °C, and between about 172 °C and about 175 °C.
  • the DMSO solvate has a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 37.1 °C, at about 104.0 °C, at about 155.0 °C, and at about 173.3 °C.
  • the DMSO solvate has a differential scanning calorimetry thermogram substantially as shown in Figure 34, 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 DMSO solvate has a thermogravimetric analysis profile showing about 8.3% weight loss below about 180 °C.
  • the DMSO solvate has a thermogravimetric analysis profile showing about 6.3% weight loss below about 180 °C.
  • the DMSO solvate has a thermogravimetric analysis profile showing about 4.3% weight loss below about 180 °C.
  • the DMSO solvate has a thermogravimetric analysis profile showing about 2.3% weight loss below about 180 °C. In some embodiments, the DMSO solvate has a thermogravimetric analysis profile showing about 1.0% weight loss below about 180 °C.
  • the DMSO solvate has a thermogravimetric analysis profile substantially as shown in Figure 35, 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 DMSO solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20. at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 11.1° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 30 °C and about 70 °C, between about 100 °C and about 135 °C, between about 150 °C and about 160 °C, and between about 170 °C and about 180 °C; and/or c) a thermogravimetric analysis profile showing showing about 1.0% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the DMSO solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 14.6° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 32 °C and about 68 °C, between about 101 °C and about 125 °C, between about 151 °C and about 158 °C, and between about 171 °C and about 178 °C; and/or c) a thermogravimetric analysis profile showing showing about 2.3% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the DMSO solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 19.4° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 34 °C and about 66 °C, between about 102 °C and about 115 °C, between about 153 °C and about 157 °C, and between about 172 °C and about 176 °C; and/or c) a thermogravimetric analysis profile showing showing about 4.3% weight loss below about 180 °C.
  • One aspect of the present disclosure relates to the DMSO solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 25.9° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature between about 36 °C and about 60 °C, between about 103 °C and about 105 °C, between about 154 °C and about 156 °C, and between about 172
  • One aspect of the present disclosure relates to the DMSO solvate having: a) an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 6.4° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, and 27.2° ⁇ 0.2°; b) a differential scanning calorimetry thermogram comprising endotherms with an extrapolated onset temperature at about 37.1 °C, at about 104.0 °C, at about 155.0 °C, and at about 173.3
  • One aspect of the present disclosure relates to the DMSO solvate having: a) an X-ray powder diffraction pattern substantially as shown in Figure 33; b) a differential scanning calorimetry thermogram substantially as shown in Figure 34; and/or c) a thermogravimetric analysis profde substantially as shown in Figure 35.
  • 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.
  • Compound 1 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:
  • Cannabinoid receptor agonists have been demonstrated to attenuate aberrant immune responses in autoimmune disorders, and in some cases, to provide protection to the tissue that is being inappropriately targeted by the immune system.
  • MS Multiple Sclerosis
  • EAE Experimental Autoimmune Encephalomyelitis
  • CBi-selective agonist WIN 55212-2 provides significant neuroprotection in the experimental allergic uveitis (EAU) model in mice, whereas CB2-selective agonist HU-308 markedly reduces the recruitment of immature myeloid cells and T cells, microglial and infiltrating myeloid cell proliferation, and axonal loss in the EAE model.
  • the CB1/CB2 agonist WIN 55212-2 significantly inhibits leukocyte rolling and adhesion in the brain in the EAE mouse model, an effect that is blocked by the CB2-selective antagonist SR144528 but not the CBi-selective antagonist SR141716A.
  • CB2-selective agonists and/or CB1/CB2 agonists find use in the treatment and/or prophylaxis of Multiple Sclerosis and related autoimmune demyelinating diseases, e.g., Guillan-Barre syndrome, polyradiculoneuropathy and chronic inflammatory demyelination.
  • autoimmune demyelinating diseases e.g., Guillan-Barre syndrome, polyradiculoneuropathy and chronic inflammatory demyelination.
  • CB2 agonists have been demonstrated to attenuate inflammation in the CNS. For example, administration of CB2 agonists prevents the activation of microglia in rodent models of Alzheimer’s Disease. Likewise, administration of CB2 agonists reduces the volume of infarcts by 30% in a rodent occlusion model of stroke. Thus, CB2 agonists find use in the treatment and/or prophylaxis of neuropathologies associated with CNS inflammation, e.g., Alzheimer's, stroke-induced damage, dementia, and ALS.
  • Agonists of CB2 modulate the expansion of the progenitor pool of neurons in the CNS.
  • CB2 antagonists inhibit the proliferation of cultured neural stem cells and the proliferation of progenitor cells in the SVZ of young animals, whereas CB2-selective agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals.
  • agonists of CB2 are useful in regenerative medicine, for example to promote the expansion of progenitor cells for the replacement of neurons lost during injury or disease, such as Alzheimer's Disease, stroke- induced damage, dementia, amyotrophic lateral sclerosis (ALS) and Parkinson’s Disease.
  • One aspect of the present disclosure relates to methods for the treatment of a cannabinoid receptor-mediated disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of a CB2 receptor- mediated disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of pain in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of CNS inflammation in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of CNS inflammation associated with a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of Alzheimer's disease in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of stroke-induced damage in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of dementia in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of amyotrophic lateral sclerosis in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to methods for the treatment of Parkinson's disease in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of an anhydrous crystalline form as described herein or a pharmaceutical composition thereof.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of a cannabinoid receptor- mediated disorder.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of a CB2 receptor-mediated disorder.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of CNS inflammation.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of CNS inflammation associated with a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of Alzheimer's disease.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of stroke-induced damage.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of dementia.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of amyotrophic lateral sclerosis.
  • One aspect of the present disclosure relates to the use of an anhydrous crystalline form as described herein, in the manufacture of a medicament for the treatment of Parkinson's disease.
  • One aspect of the present disclosure relates to an anhydrous crystalline form 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 an anhydrous crystalline form as described herein, for use in a method of treatment of a cannabinoid receptor-mediated disorder.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of a CB2 receptor-mediated disorder.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of pain.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of CNS inflammation.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of CNS inflammation associated with a disorder selected from: Alzheimer's disease, stroke, dementia, and amyotrophic lateral sclerosis.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of Alzheimer's disease.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of stroke-induced damage.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of dementia.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of amyotrophic lateral sclerosis.
  • One aspect of the present disclosure relates to an anhydrous crystalline form as described herein, for use in a method of treatment of Parkinson's disease.
  • compositions comprising an anhydrous crystalline form of 3-((4a5,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • compositions comprising an anhydrous crystalline form of 3-((4a5,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)-4,4a,5,5a- tctrahydro- IH-cyclopropa
  • compositions comprising a solvate as described herein.
  • 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.
  • 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, com starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as com 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.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions 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 multi -dose 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, benzene sulfonic, benzoic, camphorsulfonic, citric, ethene sulfonic, 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.
  • Representative organic bases include, but are not limited to, benzathine ( ' l , ' 2 -dibcnzylcthanc- l .2-diaminc).
  • chloroprocaine (2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2/?.3/?.4/?.5.S')-6-(mcthylamino)hcxanc- l .2.3.4.5-pcntaol).
  • procaine (2-(diethylamino)ethyl 4-aminobenzoate), and the like.
  • 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.
  • the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate or hydrate thereof.
  • various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. England, Vol.
  • one aspect of the present disclosure pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-mass spectroscopy
  • TGA-Infrared spectroscopy TGA-Infrared spectroscopy
  • XRPD powder X-ray diffraction
  • Karl Fisher titration Karl Fisher titration
  • high resolution X-ray diffraction and the like.
  • 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 cannabinoid receptors in tissue samples, including human and for identifying cannabinoid receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this disclosure to develop novel cannabinoid 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), n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 C1, 75 Br, 76 Br, 77 Br, 82 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • a “radio-labeled ” or “labeled compound” is a crystalline form of Compound 1 that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3 H, and 14 C.
  • 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 I into target molecules include:
  • Aryl and heteroaryl bromide exchange with 125 I This method is generally a two step process.
  • the first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using for example, a Pd catalyzed reaction ⁇ i.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 ],
  • a radiolabeled cannabinoid receptor compound can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • test compound can be evaluated for its ability to reduce binding of the “radio-labeled Compound 1” to a cannabinoid receptor. Accordingly, the ability of a test compound to compete with the “radio-labeled Compound 1” for the binding to a cannabinoid receptor directly correlates to its binding affinity.
  • Certain labeled compounds of the present disclosure bind to certain cannabinoid receptors.
  • the labeled compound has an IC50 less than about 500 pM, in another embodiment the labeled compound has an IC50 less than about 100 pM, in yet another embodiment the labeled compound has an IC50 less than about 10 pM, in yet another embodiment the labeled compound has an IC50 less than about 1 pM and in still yet another embodiment the labeled inhibitor has an IC50 less than about 0.1 pM.
  • Example 1 Preparation of 3-((4aA,5aA)-3-((l,l,l-trifluoro-2-methylpropan-2- yl)carbamoyl)-4,4a,5,5a-tetrahydro-LH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l- yl)pyrazine 1-oxide (Compound 1).
  • the reaction was then charged with deionized water (28 mL) and stirred vigorously for an hour at 20-25 °C followed by a second addition of deionized water (84 mL) and then stirred vigorously for an hour at 20-25 °C.
  • the reaction was then warmed up to 50-55 °C and the resulting clear solution was filtered through a Whatman filter paper.
  • the reaction vessel was washed with acetonitrile (14 mL) and deionized water (14 mL) and the combined filtrates were concentrated under vacuum.
  • the resulting concentrate was charged with deionized water (140 mL) and stirred for 3 hours at 20-25 °C which resulted in formation of as thick slurry.
  • the filtrate was concentrated to 120-135 mL volume by atmospheric distillation. The solution was then refluxed for 20-30 minutes and gradually cooled down to 0-5 °C over 5-6 hours. The resulting slurry was maintained at 0-5 °C for 3-4 hours and then the precipitated solid was collected by filtration. The filter cake was washed at 0-5 °C with ethyl acetate (3 x 15 mL) and the collected solid was dried under nitrogen flow followed by drying in a vacuum oven at 80-85 °C to provide Compound 1 as the anhydrous form. The material was characterized by PXRD (Figure 1), and DSC/TGA ( Figures 2 and 3 respectively).
  • Example 3 General Methods: Preparation of Non-Selective Solvates (Compound 1, Non- Selective Solvates).
  • the compound formed a solution at 25 °C and was subjected to antisolvent treatment until turbid, followed seeding with the starting crystalline Compound 1 and allowed to mature at room temperature in a platform shaker incubator for 48 hours.
  • the precipitated solid material was filtered and allowed to dry overnight under ambient conditions before analysis by PXRD.
  • the compound remained as suspension at 25 °C, in 400 pL volume of solvent, was then held for 2 minutes at 40 °C and then allowed to maturate isothermally for 7 days at 40°C, 500 rpm.
  • the precipitated solid material was isolated by pressure filtration at room temperature. The collected solid was allowed to dry overnight under ambient conditions before analysis by PXRD.
  • Example 4 Preparation of 3-((4a5,5a5)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, THF Solvate).
  • the THF Solvate of Compound 1 was prepared from a slurry of Compound 1 in THF and the crystal structure of this material was solved, see Figure 6.
  • the PXRD pattern was characterized. See Figure 5. This material showed a loss of weight by TGA of about 6.0%, a DSC that shows a shallow endotherm at about 145 °C and a subsequent melting onset endotherm temperature at about 173 °C. See Figures 8 and 7.
  • Example 5 Preparation of 3-((4a5,5a5)-3-((l,l,l-ti’ifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-LH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, Heptane Solvate).
  • the Heptane Solvate of Compound 1 was prepared from a slurry of Compound 1 in heptane.
  • the PXRD pattern was characterized. See Figure 9. This material showed a loss of weight by TGA of about 2.7%, a DSC that shows a shallow endotherm at about 79 °C and subsequent melting onset endotherm temperate at about 173 °C. See Figure 11 and 10.
  • Example 6 Preparation of 3-((4a5,5a5)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, Acetone Solvate).
  • the Acetone Solvate of Compound 1 was prepared from a slurry of Compound 1 in acetone.
  • the PXRD pattern was characterized. See Figure 12. This material showed a TGA, a shallow endotherm began at about 124.5 °C and subsequent melting onset endotherm temperate at about 173.2 °C, a DSC that shows a shallow endotherm at about 124 °C and subsequent melting onset endotherm temperate at about 173 °C. See Figure 14 and 13.
  • Example 7 Preparation of 3-((4a5,5a5)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, Ethyl Acetate Solvate).
  • the Ethyl acetate Solvate of Compound 1 was prepared from a slurry of Compound 1 in ethyl acetate.
  • the PXRD pattern was characterized. See Figure 15. This material showed a loss of weight by TGA of about 2.7%, a DSC that shows a shallow endotherm at about 103 °C and a subsequent melting onset endotherm temperature at about 173 °C. See Figures 17 and 16.
  • Example 8 Preparation of 3-((4a5,5a5)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, Methanol Solvate).
  • the Methanol acetate Solvate of Compound 1 was prepared from a slurry of Compound 1 in methanol.
  • the PXRD pattern was characterized. See Figure 18. This material showed no observable weight loss a loss by TGA analysis, a DSC that shows a sharp melting onset endotherm temperature at about 173 °C. See Figures 20 and 19.
  • Example 9 Preparation of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2-yl)carbamoyl)- 4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l-yl)pyrazine 1-oxide (Compound 1, Ethanol Solvate).
  • the Ethanol Solvate of Compound 1 was prepared from a slurry of Compound 1 in ethanol.
  • the PXRD pattern was characterized. See Figure 21. This material showed no observable weight loss a loss by TGA analysis, a DSC that shows a shallow endotherm at about 146.5 °C and a subsequent melting onset endotherm temperature at about 173.9 °C. See Figures 23 and 22.
  • Example 10 Preparation of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2- yl)carbamoyl)-4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l- yl)pyrazine 1-oxide (Compound 1, 2-Propanol Solvate).
  • the 2-Propanol Solvate of Compound 1 was prepared from a slurry of Compound 1 in 2- propanol.
  • the PXRD pattern was characterized. See Figure 24. This material showed a loss of weight by TGA of about 1.1%, a DSC that shows a shallow endotherm at about 152.8 °C and a subsequent melting onset endotherm temperature at about 174.8 °C. See Figures 26 and 25.
  • Example 11 Preparation of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2- yl)carbamoyl)-4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l- yl)pyrazine 1-oxide (Compound 1, Tert-Butyl Methyl Ether Solvate).
  • the Tert-Butyl methyl ether Solvate of Compound 1 was prepared from a slurry of Compound 1 in tert-butyl methyl ether.
  • the PXRD pattern was characterized. See Figure 27. This material showed a loss of weight by TGA of about 2.4%, a DSC that shows a shallow endotherm at about 83.3 °C and a subsequent melting onset endotherm temperature at about 175.1 °C. See Figures 29 and 28.
  • Example 12 Preparation of 3-((4aS,5aS)-3-((l,l,l-trifluoro-2-methylpropan-2- yl)carbamoyl)-4,4a,5,5a-tetrahydro-TH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l- yl)pyrazine 1-oxide (Compound 1, Methyl Isobutyl Ketone Solvate).
  • the Methyl isobutyl ketone Solvate of Compound 1 was prepared from a slurry of Compound 1 in methyl isobutyl ketone.
  • the PXRD pattern was characterized. See Figure 30. This material showed a loss of weight by TGA of about 7.2%, a DSC that shows a shallow endotherm at about 109.4 °C and a subsequent melting onset endotherm temperature at about 174.9 °C. See Figures 32 and 31.
  • Example 13 Preparation of 3-((4aA,5aA)-3-((l,l,l-trifluoro-2-methylpropan-2- yl)carbamoyl)-4,4a,5,5a-tetrahydro-LH-cyclopropa[4,5]cyclopenta[l,2-c]pyrazol-l- yl)pyrazine 1-oxide (Compound 1, DMSO Solvate).
  • the DMSO Solvate of Compound 1 was prepared from a slurry of Compound 1 in DMSO.
  • the PXRD pattern was characterized. See Figure 33. This material showed a loss of weight by TGA of about 8.3%, a DSC that shows shallow endotherms at about 61.2 °C, at about 112.2 °C, and at about 155.3 °C, and a subsequent melting onset endotherm temperature at about 174.7 °C. See Figures 35 and 34.
  • Example 14 Powder X-ray Diffraction.
  • PXRD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry.
  • a 0.5° slit, 4 mm mask and 0.04 rad Seller slits with a focusing mirror were used on the incident beam.
  • the software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analysed and presented using Diffrac Plus EVA or HighScore Plus.
  • Samples were prepared and analysed in either a metal or Millipore 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal wellplate and powders (approximately 1-2 mg) were used as received.
  • the Millipore plate was used to isolate and analyse solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
  • the scan mode for the metal plate used the gonio scan axis, whereas a 20 scan was utilised for the Millipore plate.
  • Powder X-ray Diffraction (PXRD) data were collected on an X’Pert PRO MPD powder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kV and 40 mA, Cu(Ka) radiation and an X'Celerator detector. Samples were added to the sample holder and smoothed flat with a spatula and weigh paper. With the samples spinning, X-ray diffractograms were obtained by a 12-min scan over the 2-theta range 5-40 °20. Diffraction data were viewed and analyzed with the X'Pert Data Viewer Software, version 1.0a and X’Pert HighScore Software, version 1.0b.
  • Example 15 Single Crystal X-ray Diffraction (SCXRD).
  • Example 16 Differential Scanning Calorimetry (DSC).
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 205 °C. A purge of dry nitrogen at 50 mlmL/min was maintained over the sample.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS.
  • TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto sampler. Typically, 1-5 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 mlmL/min was maintained over the sample.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS.

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Abstract

La présente divulgation concerne des formes cristallines de 3-((4aS,5aS)-3-((1,1,1-trifluoro-2-méthylpropan-2-yl)carbamoyl)-4,4a,5,5a-tétrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)pyrazine1-oxide (composé1) et des compositions pharmaceutiques de celles-ci qui modulent l'activité du récepteur cannabinoïde CB2 et sont utiles dans le traitement d'une inflammation du SNC, par exemple une inflammation du SNC associée à un trouble choisi parmi : la maladie d'Alzheimer, un accident vasculaire cérébral, la démence et la sclérose latérale amyotrophique ; une activité des cellules immunitaires indésirables ; des tumeurs du SNC ; la maladie d'Alzheimer ; un accident vasculaire cérébral, des lésions provoquées par les accidents vasculaires cérébraux ; la démence ; la sclérose latérale amyotrophique et la maladie de Parkinson. La présente divulgation concerne en outre des procédés utiles dans la préparation de formes cristallines et de solvates du composé 1 et des compositions pharmaceutiques associées.
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