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WO2022076717A1 - Formes solvatées d'un inhibiteur pan-jak - Google Patents

Formes solvatées d'un inhibiteur pan-jak Download PDF

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Publication number
WO2022076717A1
WO2022076717A1 PCT/US2021/054016 US2021054016W WO2022076717A1 WO 2022076717 A1 WO2022076717 A1 WO 2022076717A1 US 2021054016 W US2021054016 W US 2021054016W WO 2022076717 A1 WO2022076717 A1 WO 2022076717A1
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Prior art keywords
crystalline form
peaks
compound
xrpd
xrpd pattern
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English (en)
Inventor
Christopher DE DOBBELAERE
Alain Collas
Richard Edwards
Bjorn GIELEN
Robert Michael Geertman
Kate ASHURST
Claire WOMBWELL
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Janssen Biotech Inc
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Janssen Biotech Inc
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Publication of WO2022076717A1 publication Critical patent/WO2022076717A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • the present invention relates to novel crystalline forms of (3-((U?,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile), and the pharmaceutical formulations, and therapeutic uses thereof.
  • IBDs ulcerative colitis
  • CD Crohn’s disease
  • JAK inhibitors may be useful in the treatment of UC and other inflammatory diseases such as CD, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).
  • UC and other inflammatory diseases such as CD, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • JAK inhibitors due to the modulating effect of the JAK/STAT pathway on the immune system, systemic exposure to JAK inhibitors may have an adverse systemic immunosuppressive effect. Therefore, it would be desirable to provide new JAK inhibitors that are locally acting at the site of action without significant systemic effects.
  • gastrointestinal inflammatory diseases such as UC and CD
  • it would be desirable to provide new JAK inhibitors which can be administered orally and achieve therapeutically relevant exposure in the gastrointestinal tract with minimal systemic exposure.
  • Form I of Compound I was previously identified in U.S. Patent Nos. 9,725,470 and 10,072,026.
  • Form I is characterized by a powder X- ray diffraction (XRPD) pattern having significant diffraction peaks, among other peaks, at 20 values of 7.87 ⁇ 0.20, 12.78 ⁇ 0.20, 15.78 ⁇ 0.20, and 20.41 ⁇ 0.20.
  • XRPD powder X- ray diffraction
  • the present invention is directed to novel forms of Compound I.
  • novel forms may be useful, for example, for treating human patients suffering from an inflammatory bowel disease (IBD) such as UC or other inflammatory diseases such as CD, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • the novel crystalline forms disclosed herein may also be useful, for example, for preparing a medicament for treating an IBD or other inflammatory diseases (e.g., CD, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD)).
  • CD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • novel forms of the present invention may also be useful, for example, for inhibiting the Janus kinase (“JAK”) family of enzymes in vitro, and can be used, therefore, in biological assays as a control compound for identifying other JAK inhibitors.
  • the present invention is directed to novel forms of (3- ((17?,3s,5S)-3-((7-((5-methyl-17/-pyrazol-3-yl)arr no)-l,6-naphthyridin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile).
  • the present invention is directed to novel crystalline solvate forms of (3-((17?,3s,5S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5- yl)amino)-8-azabicyclo[3.2. l]octan-8-yl)propanenitrile).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) 3 -methyl- 1 -butanol (Compound 1 Form 6).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) 3 -methyl- 1 -butanol (Compound 1 Form 11).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) isopropanol (Compound 1 Form 12).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) 1-propanol (Compound 1 Form 14).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) dimethylsulfoxide hydrate (Compound 1 Form 22).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) l,3-dimethyl-2-imidazolidinone hydrate (Compound 1 Form 24).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2. l]octan-8- yl)propanenitrile) /V-methylpyrrolidinone (Compound 1 Form 34).
  • the present invention is directed to (3-((lR,3s,5S)-3-((7-((5- methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8- yl)propanenitrile) /V,JV-dimethylacetamide (Compound 1 Form 35).
  • the present invention is directed to a method of treating a gastrointestinal inflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline forms of Compound I of the present invention, or the pharmaceutical composition of the present invention.
  • the present invention is directed to a crystalline Form of Compound I of the present invention, or the pharmaceutical composition of the present invention, for use in a method of treating a gastrointestinal inflammatory disorder.
  • the present invention is directed to use of a crystalline Form of Compound I of the present invention, or the pharmaceutical composition of the present invention, in the manufacture of a medicament for treating a gastrointestinal inflammatory disorder.
  • the present invention is directed to a crystalline Form of Compound I of the present invention, or the pharmaceutical composition of the present invention, for use in medical therapy.
  • FIG. 1 shows the XRPD pattern for Compound I Form 6.
  • FIG. 2 shows the XRPD peaks for Compound I Form 6.
  • FIG. 3 shows the DSC for Compound I Form 6.
  • FIG. 4 shows the TGA for Compound I Form 6.
  • FIG. 5 shows the XRPD pattern for Compound I Form 9.
  • FIG. 6 shows the XRPD peaks for Compound I Form 9.
  • FIG. 7 shows the DSC thermogram for Compound I Form 9.
  • FIG. 8 shows the TGA thermogram for Compound I Form 9.
  • FIG. 9 shows the XRPD pattern for Compound I Form 10.
  • FIG. 10 shows the XRPD peaks for Compound I Form 10.
  • FIG. 11 shows the DSC thermogram for Compound I Form 10.
  • FIG. 12 shows the TGA thermogram for Compound I Form 10.
  • FIG. 13 shows the XRPD pattern for Compound I Form 11.
  • FIG. 14 shows the XRPD peaks for Compound I Form 11.
  • FIG. 15 shows the DSC thermogram for Compound I Form 11.
  • FIG. 16 shows the TGA thermogram for Compound I Form 11.
  • FIG. 17 shows the XRPD pattern for Compound I Form 12.
  • FIG. 18 shows the XRPD peaks for Compound I Form 12.
  • FIG. 19 shows the DSC thermogram for Compound I Form 12.
  • FIG. 20 shows the TGA thermogram for Compound I Form 12.
  • FIG. 21 shows the XRPD pattern for Compound I Form 14.
  • FIG. 22 shows the XRPD peaks for Compound I Form 14.
  • FIG. 23 shows the DSC thermogram for Compound I Form 14.
  • FIG. 24 shows the TGA thermogram for Compound I Form 14.
  • FIG. 25 shows the XRPD pattern for Compound I Form 22.
  • FIG. 26 shows the XRPD peaks for Compound I Form 22.
  • FIG. 27 shows the DSC thermogram for Compound I Form 22.
  • FIG. 28 shows the TGA thermogram for Compound I Form 22.
  • FIG. 29 shows the XRPD pattern for Compound I Form 24.
  • FIG. 30 shows the XRPD peaks for Compound I Form 24.
  • FIG. 31 shows the XRPD pattern for Compound I Form 34.
  • FIG. 32 shows the XRPD peaks for Compound I Form 34.
  • FIG. 33 shows the XRPD pattern for Compound I Form 35.
  • FIG. 34 shows the XRPD peaks for Compound I Form 35.
  • FIG. 35 shows the DSC thermogram for Compound I Form 35.
  • FIG. 36 shows the TGA thermogram for Compound I Form 35.
  • FIG. 37 shows the XRPD pattern for amorphous Compound I.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 6, a solvate of 3-methyl-l -butanol, crystalline Compound I Form 11, a solvate of 3 -methyl- 1 -butanol, crystalline Compound I Form 12, a solvate of 2-propanol, crystalline Compound I Form 14, a solvate of 1 -propanol, crystalline Compound I Form 22, a dimethylsulfoxide hydrate, crystalline Compound I Form 24, a dimethyl-2-imidazolidinone hydrate, crystalline Compound I Form 34, a solvate of N-methylpyrrolidinone. and crystalline Compound I Form 35, a solvate of N.N-dimethylacetamide.
  • Compound I can form a mixture of two or more crystalline forms, or form a single crystalline form substantially free of other crystalline forms.
  • Colon refers to the portion of the intestinal tract following the small intestine, and includes the ascending colon, transverse colon, descending colon, and the sigmoid colon.
  • “Gastrointestinal inflammatory disease”, “inflammatory bowel disease” and “IBD” are used interchangeably to describe inflammatory diseases of the colon and small intestine. These inflammatory diseases include ulcerative colitis (including proctosigmoiditis, ulcerative proctitis, left-sided colitis, pancolitis, extensive colitis), Crohn’s disease, collagenous colitis, lymphocytic colitis, diversion colitis, Behcet’s disease, celiac disease, checkpoint cancer treatment-induced colitis, (e.g. CTLA-4 inhibitor-induced colitis), ileitis, graft versus host disease-related colitis, infectious colitis and other gastrointestinal diseases characterized by inflammation of the intestine and colon.
  • ulcerative colitis including proctosigmoiditis, ulcerative proctitis, left-sided colitis, pancolitis, extensive colitis
  • Crohn’s disease collagenous colitis
  • lymphocytic colitis diversion colitis
  • Behcet’s disease celiac disease
  • “Hydrate” refers to a complex formed by the combining of Compound I and water. The term includes stoichiometric as well as non-stoichiometric hydrates.
  • Solvate refers to a complex formed by the combining of Compound I and a solvent.
  • the term includes stoichiometric as well as non-stoichiometric solvates.
  • Subject refers to any animal, such as a mammal, including a human.
  • mammal as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, nonhuman primates (NHPs) such as monkeys or apes, humans, etc., including a human.
  • mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, nonhuman primates (NHPs) such as monkeys or apes, humans, etc., including a human.
  • NHPs nonhuman primates
  • “Substantially as shown in” refers to any crystal or amorphous solid form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile (Compound I) characterized by the graphical data in the identified figure, optionally having one or more of small variations, e.g., one or more variations described below or known to one of skill in the art.
  • Such data may include, without limitation, powder X-ray diffractograms, differential scanning calorimetry curves, and thermogravimetric analysis curves, among others.
  • graphical data may provide additional technical information to further define the crystal polymorph, amorphous solid form, or other composition.
  • such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity.
  • “Substantially free of’ refers to a crystalline or amorphous solid form of Compound I containing no significant amount of such other crystalline or amorphous solid forms of Compound I.
  • a first crystalline form can be substantially free of a second crystalline form when the first crystalline form constitutes at least about 95% by weight of the crystalline Compound I present, or at least about 96%, 97%, 98%, 99%, or at least about 99.5% by weight of the crystalline Compound I present.
  • “Therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any coadministered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • Treat”, “treating” and “treatment” as used herein means the treatment of a disease, disorder, or medical condition (such as a gastrointestinal inflammatory disease), in a patient, such as a mammal (particularly a human) which includes one or more of the following: (a) preventing the disease, disorder, or medical condition from occurring, i.e., preventing the reoccurrence of the disease or medical condition or prophylactic treatment of a patient that is pre-disposed to the disease or medical condition; (b) ameliorating the disease, disorder, or medical condition, i.e., eliminating or causing regression of the disease, disorder, or medical condition in a patient, including counteracting the effects of other therapeutic agents; (c) suppressing the disease, disorder, or medical condition, i.e., slowing or arresting the development of the disease, disorder, or medical condition in a patient; or (d) alleviating the symptoms of the disease, disorder, or medical condition in a patient.
  • a disease, disorder, or medical condition such as a gastrointestinal inflammatory disease
  • the present invention results from the surprising discoveries of new solid forms of 3- ((17?,3s,5S)-3-((7-((5-methyl-17/-pyrazol-3-yl)arruno)-l,6-naphthyridin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile (Compound I; see U.S. Patent No. 9,725,470), including crystalline forms such as crystalline solvate and solvate/hydrate forms thereof.
  • the present invention provides a crystalline form of Compound I having the structure: and solvates and solvate/hydrates thereof.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 6, a solvate of 3-methyl-l -butanol, crystalline Compound I Form 11, a solvate of 3-methyl-l -butanol, crystalline Compound I Form 12, a solvate of 2- propanol, crystalline Compound I Form 14, a solvate of 1-propanol, crystalline Compound I Form 22, a dimethylsulfoxide hydrate, crystalline Compound I Form 24, a dimethyl-2- imidazolidinone hydrate, crystalline Compound I Form 34, a solvate of N- methylpyrrolidinone, and crystalline Compound I Form 35, a solvate of N,N- dimethylacetamide.
  • Compound I can form a mixture of two or more crystalline forms, or form a single crystalline hydrate form substantially free of other crystalline forms of Compound I.
  • the present invention provides a crystalline form of the compound 3-((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5- yl)amino)-8-azabicyclo[3.2. l]octan-8-yl)propanenitrile (Compound I).
  • U.S. Patent No. 9,725,470 describes the crystalline form of the compound 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile (Compound I Form 1).
  • the crystalline Compound I Form 1 is anhydrous.
  • the Compound I Form 1 is characterized by an X-ray powder diffraction (PXRD) pattern comprising peaks at 7.87°, 12.78°, 15.78° and 20.41° 20 ⁇ 0.2° 20.
  • the Compound I Form 1 may be further characterized by an X-ray powder diffraction (PXRD) pattern comprising peaks at 7.87°, 10.80°, 12.78°, 13.47°, 13.64°, 14.66°, 15.11°, 15.54°, 15.78°, 17.75°, 20.41°, 21.00°, 22.22°, 22.93°, and 23.65° 20 ⁇ 0.2° 20.
  • the structure of crystalline Compound I Form 1 has been further characterized by single crystal x-ray diffraction analysis.
  • the crystals belong to a monoclinic crystal system and P21/n space group.
  • the calculated density is 1.317 g/cm 3 .
  • the crystals contain four molecules per unit cell. The structure confirms that the crystals do not contain water or other solvent molecules.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 6, a solvate of 3-methyl-l -butanol.
  • the compound 3-methyl-l- butanol can also be referred to as isoamyl alcohol or isopentyl alcohol, and is identified by Chemical Abstracts No. 123-51-3.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile 3-methyl-l -butanol: characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 4.2°, 6.2°, 9.7°, 11.5° or 17.1° 20 ⁇ 0.2° 20, Compound I 3-methyl-l -butanol, Form 6.
  • XRPD X-ray powder diffraction
  • the Compound I Form 6 is characterized by an XRPD pattern comprising four or more peaks at 4.2°, 6.2°, 9.7°, 11.5° or 17.1° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern comprising peaks at 4.2°, 6.2°, 9.7°, 11.5° and 17.1° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern comprising peaks at 4.2°, 6.2°, 9.7°, 11.5°, 17.1°, 19.1° and 19.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern further comprising one or more peaks at 13.2°, 16.4°, 17.8° or 22.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern further comprising two or more peaks at 13.2°, 16.4°, 17.8° or 22.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern further comprising three or more peaks at 13.2°, 16.4°, 17.8° or 22.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern comprising three or more peaks at 6.2°, 17.1°, 17.8°, 19.1° or 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern comprising four or more peaks at 6.2°, 17.1°, 17.8°, 19.1° or 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern comprising peaks at 6.2°, 17.1°, 17.8°, 19.1° and 19.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern further comprising one or more peaks at 4.2°, 9.7°, 11.5°, 19.4° or 22.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern further comprising two or more peaks at 4.2°, 9.7°, 11.5°, 19.4° or 22.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern further comprising three or more peaks at 4.2°, 9.7°, 11.5°, 19.4° or 22.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern further comprising four or more peaks at 4.2°, 9.7°, 11.5°, 19.4° or 22.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 6 is characterized by an XRPD pattern comprising peaks at 4.2°, 6.2°, 9.7°, 11.5°, 17.1°, 17.8°, 19.1°, 19.4°, 19.7° and 22.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern comprising peaks at 4.2°, 6.2°, 9.7°, 11.5°, 13.2°, 16.4°, 17.1°, 17.8°, 19.1°, 19.7° and 22.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 6 is characterized by an XRPD pattern substantially as shown in FIG. 1.
  • the Compound I Form 6 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 108.1 °C or about 225.1 °C. In some embodiments, the Compound I Form 6 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 108 °C or about 225 °C. In some embodiments, the Compound I Form 6 is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 108 °C and about 225 °C. In some embodiments, the Compound I Form 6 is characterized by a DSC thermogram substantially as shown in FIG. 3.
  • DSC differential scanning calorimetry
  • the Compound I Form 6 is characterized by: (a) an XRPD pattern comprising peaks at 4.2°, 6.2°, 9.7°, 11.5°, 13.2°, 16.4°, 17.1°, 17.8°, 19.1°, 19.7° and 22.9° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 108 °C and about 225 °C.
  • the Compound I Form 6 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 1; and (b) a DSC thermogram substantially as shown in FIG. 3.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 11, a solvate of 3 -methyl- 1 -butanol.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabicyclo[3.2. l]octan-8-yl)propanenitrile 3-methyl-l -butanol: characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7° or 19.7° 20 ⁇ 0.2° 20, Compound I 3-methyl-l-butanol, Form 11.
  • XRPD X-ray powder diffraction
  • the Compound I Form 11 is characterized by an XRPD pattern comprising four or more peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7° or 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern comprising five or more peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7° or 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern comprising peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7° and 19.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern further comprising one or more peaks at 16.7°, 17.0°, 20.2°, 21.8°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern further comprising two or more peaks at 16.7°, 17.0°, 20.2°, 21.8°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern further comprising three or more peaks at 16.7°, 17.0°, 20.2°, 21.8°, 22.5° or 25.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern further comprising four or more peaks at 16.7°, 17.0°, 20.2°, 21.8°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern further comprising five or more peaks at 16.7°, 17.0°, 20.2°, 21.8°, 22.5° or 25.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern comprising peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7°, 16.7°, 17.0°, 19.7°, 20.2°, 21.8°, 22.5° and 25.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern comprising three or more peaks at 9.0°, 16.7°, 17.0°, 19.7° or 21.8° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern comprising four or more peaks at 9.0°, 16.7°, 17.0°, 19.7° or 21.8° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern comprising peaks at 9.0°, 16.7°, 17.0°, 19.7° and 21.8° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern further comprising one or more peaks at 11.3°, 14.7°, 20.2°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern further comprising two or more peaks at 11.3°, 14.7°, 20.2°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern further comprising three or more peaks at 11.3°, 14.7°, 20.2°, 22.5° or 25.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern further comprising four or more peaks at 11.3°, 14.7°, 20.2°, 22.5° or 25.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 11 is characterized by an XRPD pattern comprising peaks at 9.0°, 11.3°, 14.7°, 16.7°, 17.0°, 19.7°, 20.2°, 21.8°, 22.5° and 25.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern comprising peaks at 7.7°, 9.0°, 9.4°, 11.3°, 13.1°, 14.7°, 15.2°, 15.6°, 16.7°, 17.0°, 17.3°, 17.9°, 18.7°, 19.7°, 20.2°, 20.8°, 21.1°, 21.8°, 22.1°, 22.5°, 23.4°, 24.2°, 25.2°, 25.9°, 26.3°, 26.7°, 27.3°, 28.0°, 29.0°, 29.7° and 31.6° 20 ⁇ 0.2° 20.
  • the Compound I Form 11 is characterized by an XRPD pattern substantially as shown in FIG. 13.
  • the Compound I Form 11 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 116.4 °C, about 137.9 °C, or about 232.9 °C. In some embodiments, the Compound I Form 11 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 116 °C, about 137 °C, or about 232 °C. In some embodiments, the Compound I Form 11 is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 116°C, about 137°C, and about 232°C. In some embodiments, the Compound I Form 11 is characterized by a DSC thermogram substantially as shown in FIG. 15.
  • the Compound I Form 11 is characterized by: (a) an XRPD pattern comprising peaks at 7.7°, 9.0°, 11.3°, 13.1°, 14.7°, 16.7°, 17.0°, 19.7°, 20.2°, 21.8°, 22.5° and 25.9° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 116 °C, about 137 °C, and about 232 °C.
  • the Compound I Form 11 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 13; and (b) a DSC thermogram substantially as shown in FIG. 15.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 12, a solvate of 2-propanol.
  • the compound 2-propanol can also be referred to as isopropanol or isopropyl alcohol, and is identified by Chemical Abstracts No. 67-63-0.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile isopropanol: characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 6.6°, 10.1°, 11.1°, 17.1° or 19.7° 20 ⁇ 0.2° 20, Compound I isopropanol, Form 12.
  • XRPD X-ray powder diffraction
  • the Compound I Form 12 is characterized by an XRPD pattern comprising four or more peaks at 6.6°, 10.1°, 11.1°, 17.1° or 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern comprising peaks at 6.6°, 10.1°, 11.1°, 17.1° and 19.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern further comprising one or more peaks at 17.7°, 19.2°, 19.9°, 20.9°, 21.9° or 23.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern further comprising two or more peaks at 17.7°, 19.2°, 19.9°, 20.9°, 21.9° or 23.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern further comprising three or more peaks at 17.7°, 19.2°, 19.9°, 20.9°, 21.9° or 23.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern further comprising four or more peaks at 17.7°, 19.2°, 19.9°, 20.9°, 21.9° or 23.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern comprising peaks at 6.6°, 10.1°, 11.1°, 17.1°, 17.7°, 19.2°, 19.7°, 19.9°, 20.9°, 21.9° and 23.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern comprising three or more peaks at 6.6°, 17.1°, 19.7°, 19.9° or 20.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern comprising four or more peaks at 6.6°, 17.1°, 19.7°, 19.9° or 20.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern comprising peaks at 6.6°, 17.1°, 19.7°, 19.9° and 20.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern further comprising one or more peaks at 11. 1°, 17.7°, 19.2°, 21.9° or 23.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern further comprising two or more peaks at 11.1°, 17.7°, 19.2°, 21.9° or 23.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern further comprising three or more peaks at 11. 1°, 17.7°, 19.2°, 21.9° or 23.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern further comprising four or more peaks at 11. 1°, 17.7°, 19.2°, 21.9° or 23.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 12 is characterized by an XRPD pattern comprising peaks at 6.6°, 11.1°, 17.1°, 17.7°, 19.2°, 19.7°, 19.9°, 20.9°, 21.9° and 23.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern comprising peaks at 6.6°, 8.5°, 10.1°, 11.1°, 12.7°, 13.3°, 13.8°, 14.0°, 14.8°, 16.3°, 16.6°, 17.1°, 17.7°, 17.9°, 19.2°, 19.7°, 19.9°, 20.9°, 21.9°, 22.5°, 23.5°, 24.1°, 24.4°, 26.1° and 30.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 12 is characterized by an XRPD pattern substantially as shown in FIG. 17.
  • the Compound I Form 12 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 128.5 °C, about 147.9 °C, or about 230.2 °C. In some embodiments, the Compound I Form 12 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 128 °C, about 147 °C, or about 230 °C. In some embodiments, the Compound I Form 12 is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 128 °C, about 147 °C, and about 230 °C. In some embodiments, the Compound I Form 12 is characterized by a DSC thermogram substantially as shown in FIG. 19.
  • the Compound I Form 12 is characterized by: (a) an XRPD pattern comprising peaks at 6.3°, 7.7°, 9.3°, 12.6°, 12.9°, 15.5°, 19.5°, 20.2°, 20.8°, 22.7° and 25.7° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 128°C, about 147°C, and about 230°C.
  • the Compound I Form 12 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 17; and (b) a DSC thermogram substantially as shown in FIG. 19.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 14, a solvate of 1 -propanol.
  • the compound 1 -propanol can also be referred to as propyl alcohol, and is identified by Chemical Abstracts No. 71-23-8.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile 1-propanol: characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.9°, 10.0°, 15.0°, and 17.0° 20 ⁇ 0.2° 20, Compound I 1-propanol, Form 14.
  • XRPD X-ray powder diffraction
  • the Compound I Form 14 is characterized by an XRPD pattern further comprising one or more peaks at 18.9°, 19.6°, 19.8°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern further comprising two or more peaks at 18.9°, 19.6°, 19.8°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern further comprising three or more peaks at 18.9°, 19.6°, 19.8°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern further comprising four or more peaks at 18.9°, 19.6°, 19.8°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern further comprising five or more peaks at 18.9°, 19.6°, 19.8°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern comprising peaks at 6.9°, 10.0°, 15.0°, 17.0°, 18.9°, 19.6°, 19.8°, 20.1°, 21.4° and 22.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern comprising three or more peaks at 6.9°, 17.0°, 18.9°, 19.6° or 19.8° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern comprising four or more peaks at 6.9°, 17.0°, 18.9°, 19.6° or 19.8° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern comprising peaks at 6.9°, 17.0°, 18.9°, 19.6° and 19.8° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern further comprising one or more peaks at 10.0°, 15.0°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern further comprising two or more peaks at 10.0°, 15.0°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern further comprising three or more peaks at 10.0°, 15.0°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern further comprising four or more peaks at 10.0°, 15.0°, 20.1°, 21.4° or 22.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 14 is characterized by an XRPD pattern comprising peaks at 6.9°, 10.0°, 15.0°, 17.0°, 18.9°, 19.6°, 19.8°, 20.1°, 21.4° and 22.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern comprising peaks at 5.9°, 6.9°, 10.0°, 11.6°, 12.0°, 15.0°, 15.7°, 17.0°, 18.9°, 19.6°, 19.8°, 20.1°, 20.7°, 21.1°, 21.4°, 22.0°, 22.7°, 23.4°, 24.2°, 28.6°, 29.5°, 30.4°, 30.7° and 31.3° 20 ⁇ 0.2° 20.
  • the Compound I Form 14 is characterized by an XRPD pattern substantially as shown in FIG. 21.
  • the Compound I Form 14 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 105.9 °C or about 230.1 °C. In some embodiments, the Compound I Form 14 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 105 °C or about 230 °C. In some embodiments, the Compound I Form 14 is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 109 °C and about 230 °C. In some embodiments, the Compound I Form 14 is characterized by a DSC thermogram substantially as shown in FIG. 23.
  • the Compound I Form 14 is characterized by: (a) an XRPD pattern comprising peaks at 6.9°, 10.0°, 15.0°, 17.0°, 18.9°, 19.6°, 19.8°, 20.1°, 21.4° and 22.0° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 109°C and about 230°C.
  • the Compound I Form 14 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 21; and (b) a DSC thermogram substantially as shown in FIG. 23.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 22, a dimethylsulfoxide hydrate.
  • the compound dimethylsulfoxide is also referred to as DMSO, and is identified by Chemical Abstracts No. 67-68-5.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile dimethylsulfoxide hydrate: characterized by an X-ray powder diffraction (XRPD) patern comprising three or more peaks at 6.3°, 7.7°, 9.3°, 12.9° or 15.5° 20 ⁇ 0.2° 20, Compound I dimethylsulfoxide hydrate, Form 22.
  • XRPD X-ray powder diffraction
  • the Compound I Form 22 is characterized by an XRPD patern comprising four or more peaks at 6.3°, 7.7°, 9.3°, 12.9° or 15.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern comprising peaks at 6.3°, 7.7°, 9.3°, 12.9° and 15.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD patern further comprising one or more peaks at 12.6°, 19.5°, 20.2°, 20.8°, 22.7° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern further comprising two or more peaks at 12.6°, 19.5°, 20.2°, 20.8°, 22.7° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern further comprising three or more peaks at 12.6°, 19.5°, 20.2°, 20.8°, 22.7° or 25.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD pattern further comprising four or more peaks at 12.6°, 19.5°, 20.2°, 20.8°, 22.7° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern further comprising five or more peaks at 12.6°, 19.5°, 20.2°, 20.8°, 22.7° or 25.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD pattern comprising peaks at 6.3°, 7.7°, 9.3°, 12.6°, 12.9°, 15.5°, 19.5°, 20.2°, 20.8°, 22.7° and 25.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD patern comprising three or more peaks at 12.9°, 15.5°, 19.5°, 20.2° or 22.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern comprising four or more peaks at 12.9°, 15.5°, 19.5°, 20.2° or 22.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD patern comprising peaks at 12.9°, 15.5°, 19.5°, 20.2° and 22.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD patern further comprising one or more peaks at 12.6°, 17.2°, 20.8°, 23.5° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD patern further comprising two or more peaks at 12.6°, 17.2°, 20.8°, 23.5° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD patern further comprising three or more peaks at 12.6°, 17.2°, 20.8°, 23.5° or 25.7° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD pattern further comprising four or more peaks at 12.6°, 17.2°, 20.8°, 23.5° or 25.7° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 22 is characterized by an XRPD pattern comprising peaks at 12.6°, 12.9°, 15.5°, 17.2°, 19.5°, 20.2°, 20.8°, 22.7°, 23.5° and 25.7° 20 ⁇ 0.2° 20
  • the Compound I Form 22 is characterized by an XRPD pattern comprising peaks at 6.3°, 7.7°, 9.3°, 11.7°, 12.6°, 12.9°, 13.8°, 14.0°, 14.3°, 14.7°, 15.1°, 15.5°, 16.5°, 16.7°, 17.2°, 18.0°, 18.6°, 18.9°, 19.5°, 20.2°, 20.5°, 20.8°, 21.0°, 21.7°, 21.9°, 22.7°, 23.5°, 23.8°, 24.3°, 25.1°, 25.7°, 26.1°, 26.4°, 27.3°, 28.1° and 29.6° 20 ⁇ 0.2° 20.
  • the Compound I Form 22 is characterized by an XRPD pattern substantially as shown in FIG. 25.
  • the Compound I Form 22 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 43.8 °C or about 235.2 °C. In some embodiments, the Compound I Form 22 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 43 °C or about 235 °C. In some embodiments, the Compound I Form 22 is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 43°C and about 235°C. In some embodiments, the Compound I Form 22 is characterized by a DSC thermogram substantially as shown in FIG. 27.
  • the Compound I Form 22 is characterized by: (a) an XRPD pattern comprising peaks at 6.3°, 7.7°, 9.3°, 12.6°, 12.9°, 15.5°, 19.5°, 20.2°, 20.8°, 22.7° and 25.7° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having endotherms with an onset of about 43°C and about 235°C.
  • the Compound I Form 22 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 25; and (b) a DSC thermogram substantially as shown in FIG. 27.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 24, a dimethyl-2-imidazolidinone hydrate.
  • the compound dimethyl-2-imidazolidinone can also be referred to as dimethyl ethylene urea, DMI, DMEU or l,3-dimethyl-2-imidazolidinone, and is identified by Chemical Abstracts No. 80-73-9.
  • the present invention provides a crystalline form of 3- ((17?,3s,5S)-3-((7-((5-methyl-17/-pyrazol-3-yl)arr no)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2.
  • the Compound I Form 24 is characterized by an XRPD pattern comprising four or more peaks at 7.7°, 8.1°, 10.1°, 14.9° or 18.9° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern comprising peaks at 7.7°, 8.1°, 10.1°, 14.9° and 18.9° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern further comprising one or more peaks at 15.2°, 16.0°, 17.4°, 20.7°, 22.2° or 25.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern further comprising two or more peaks at 15.2°, 16.0°, 17.4°, 20.7°, 22.2° or 25.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern further comprising three or more peaks at 15.2°, 16.0°, 17.4°, 20.7°, 22.2° or 25.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern further comprising four or more peaks at 15.2°, 16.0°, 17.4°, 20.7°, 22.2° or 25.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern further comprising five or more peaks at 15.2°, 16.0°, 17.4°, 20.7°, 22.2° or 25.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern comprising peaks at 7.7°, 8.1°, 10.1°, 14.9°, 15.2°, 16.0°, 17.4°, 18.9°, 20.7°, 22.2° and 25.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern comprising three or more peaks at 7.7°, 14.9°, 18.9°, 20.7° or 25.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern comprising four or more peaks at 7.7°, 14.9°, 18.9°, 20.7° or 25.5° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern comprising peaks at 7.7°, 14.9°, 18.9°, 20.7° and 25.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern further comprising one or more peaks at 8.1°, 15.2°, 16.0°, 17.4° or 22.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern further comprising two or more peaks at 8.1°, 15.2°, 16.0°, 17.4° or 22.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern further comprising three or more peaks at 8.1°, 15.2°, 16.0°, 17.4° or 22.2° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern further comprising four or more peaks at 8.1°, 15.2°, 16.0°, 17.4° or 22.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 24 is characterized by an XRPD pattern comprising peaks at 7.7°, 8.1°, 14.9°, 15.2°, 16.0°, 17.4°, 18.9°, 20.7°, 22.2° and 25.5° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern comprising peaks at 7.7°, 8.1°, 9.6°, 10.1°, 10.6°, 12.6°, 13.0°, 13.4°, 14.9°, 15.2°, 15.5°, 16.0°, 16.2°, 16.6°, 17.4°, 17.5°, 18.9°, 19.5°, 19.8°, 20.4°, 20.7°, 21.1°, 21.5°, 22.2°, 23.0°, 23.6°, 24.2°, 24.6°, 25.5°, 26.4°, 26.8°, 27.1°, 27.7°, 28.1°, 28.9°, 29.6° and 30.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 24 is characterized by an XRPD pattern substantially as shown in FIG. 29.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 34, a solvate of N-methylpyrrolidinone.
  • the compound N- methylpyrrolidinone can also be referred to as l-methyl-2-pyrrolidinone or NMP, and is identified by Chemical Abstracts No. 872-50-4.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile N-methylpyrrolidinone: characterized by an X-ray powder diffraction (XRPD) patern comprising peaks at 3.5°, 6.3°, 13.3° and 23.5° 20 ⁇ 0.2° 20, Compound I N-methylpyrrolidinone, Form 34.
  • the Compound I Form 34 is characterized by an XRPD pattern comprising peaks at 3.5°, 6.3°, 12.2°, 13.3°, 23.5°, 25.0° and 25.4° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD patern further comprising one or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD patern further comprising two or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD pattern further comprising three or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD pattern further comprising four or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD pattern comprising peaks at 3.5°, 6.3°, 11.6°, 12.2°, 13.3°, 13.9°, 23.5°, 24.0°, 24.7°, 25.0°, 25.4° and 27.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD patern comprising three or more peaks at 12.2°, 13.3°, 23.5°, 25.0° or 25.4° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD pattern comprising four or more peaks at 12.2°, 13.3°, 23.5°, 25.0° or 25.4° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD patern comprising peaks at 12.2°, 13.3°, 23.5°, 25.0° and 25.4° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD patern further comprising one or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD patern further comprising two or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD patern further comprising three or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD pattern further comprising four or more peaks at 11.6°, 13.9°, 24.0°, 24.7° or 27.0° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 34 is characterized by an XRPD pattern comprising peaks at 11.6°, 12.2°, 13.3°, 13.9°, 23.5°, 24.0°, 24.7°, 25.0°, 25.4° and 27.0° 20 ⁇ 0.2° 20.
  • the Compound I Form 34 is characterized by an XRPD pattern comprising peaks at 3.5°, 5.3°, 6.3°, 7.1°, 10.7°, 11.6°, 11.8°, 12.2°, 12.5°, 12.7°, 13.0°, 13.3°, 13.7°, 13.9°, 14.3°, 15.1°, 15.5°, 15.7°, 15.9°, 16.2°, 16.4°, 16.6°, 17.0°, 17.5°, 17.9°,
  • the Compound I Form 34 is characterized by an XRPD pattern substantially as shown in FIG. 31.
  • Compound I can adopt a variety of crystalline forms, including, but not limited to, crystalline Compound I Form 35, a solvate of N.A i methyl acetamide.
  • the compound dimethylacetamide can also be referred to as A A i methyl acetamide or DMA, and is identified by Chemical Abstracts No. 127-19-5.
  • the present invention provides a crystalline form of 3- ((17?,35,5 ⁇ S)-3-((7-((5-methyl-17/-pyrazol-3-yl)amino)-l,6-naphthyridin-5-yl)amino)-8- azabi cyclo [3.2. l]octan-8-yl)propanenitrile N.N-dimethylacetamide: characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 7.4°, 10.9°, 17.6°, 19.6° or 20.2° 20 ⁇ 0.2° 20, Compound I A/A imethylacetamide.
  • XRPD X-ray powder diffraction
  • the Compound I Form 35 is characterized by an XRPD pattern comprising four or more peaks at 7.4°, 10.9°, 17.6°, 19.6° or 20.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 35 is characterized by an XRPD pattern comprising peaks at 7.4°, 10.9°, 17.6°, 19.6° and 20.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 35 is characterized by an XRPD pattern further comprising one or more peaks at 15.5°, 21.8°, 22. 1°, 25.4° or 26.2° 20 ⁇ 0.2° 20.
  • the Compound I Form 35 is characterized by an XRPD pattern further comprising two or more peaks at 15.5°, 21.8°, 22.1°, 25.4° or 26.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 35 is characterized by an XRPD pattern further comprising three or more peaks at 15.5°, 21.8°, 22.1°, 25.4° or 26.2° 20 ⁇ 0.2° 20. In some embodiments, the Compound I Form 35 is characterized by an XRPD pattern further comprising four or more peaks at 15.5°, 21.8°, 22.1°, 25.4° or 26.2° 20 ⁇ 0.2° 20.
  • the Compound I Form 35 is characterized by an XRPD pattern comprising peaks at 7.4°, 10.9°, 15.5°, 17.6°, 19.6°, 20.2°, 21.8°, 22.1°, 25.4° and 26.2° 20 ⁇ 0.2° 20.
  • the Compound I Form 35 is characterized by an XRPD pattern comprising peaks at 7.4°, 9.4°, 10.5°, 10.9°, 11.4°, 11.9°, 14.5°, 14.9°, 15.2°, 15.5°, 17.0°, 17.6°, 17.9°, 18.9°, 19.3°, 19.6°, 20.2°, 20.6°, 21.1°, 21.8°, 22.1°, 22.6°, 23.0°, 23.6°, 24.1°, 24.4°, 25.0°, 25.4°, 26.0°, 26.2°, 26.8°, 28.9°, 29.4°, 29.8°, 30.2°, 30.4°, 31.0° and 31.4° 20 ⁇ 0.2° 20.
  • the Compound I Form 35 is characterized by an XRPD pattern substantially as shown in FIG. 33.
  • the Compound I Form 35 is characterized by a differential scanning calorimetry (DSC) thermogram having at least one endotherm with an onset of about 95.7°C. In some embodiments, the Compound I Form 35 is characterized by a differential scanning calorimetry (DSC) thermogram having one endotherm with an onset of about 95°C. In some embodiments, the Compound I Form 35 is characterized by a DSC thermogram substantially as shown in FIG. 35.
  • DSC differential scanning calorimetry
  • the Compound I Form 35 is characterized by: (a) an XRPD pattern comprising peaks at 7.4°, 10.9°, 15.5°, 17.6°, 19.6°, 20.2°, 21.8°, 22.1°, 25.4° and 26.2° 20 ⁇ 0.2° 20; and (b) a differential scanning calorimetry (DSC) thermogram having one endotherm with an onset of about 95°C.
  • the Compound I Form 35 is characterized by: (a) an XRPD pattern substantially as shown in FIG. 33; and (b) a DSC thermogram substantially as shown in FIG. 35.
  • Compound I can be prepared by a variety of methods. For example, Compound I can be dissolved in a single solvent system and allowed to crystallize. Alternatively, Compound I can be crystallized from a two-solvent system by dissolving Compound I in a solvent (a good solvent), and then adding an anti-solvent (a bad solvent, i.e., a solvent in which Compound I is substantially insoluble) to the mixture causing Compound I to crystallize.
  • a solvent a good solvent
  • an anti-solvent a bad solvent, i.e., a solvent in which Compound I is substantially insoluble
  • the solvent can be any solvent suitable to form a solution.
  • the solvent can be a polar solvent, which in some embodiments is a protic solvent.
  • suitable solvents include non-polar solvents.
  • Suitable solvents include, but are not limited to, water, alkanes such as heptanes, hexanes, and cyclohexane, petroleum ether, C1-C3 alcohols (methanol, ethanol, propanol, isopropanol), ethylene glycol and polyethylene glycol such as PEG400, alkanoates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, acetonitrile, alkanones such as acetone, butanone, methyl ethyl ketone (MEK), methyl propyl ketone (MPK) and methyl iso-butyl ketone (MIBK), ethers such as diethyl ether, methyl
  • Suitable solvents also include, but are not limited to halogenated C1-C3 alcohols (trifluoromethanol, trifluoroethanol (TFE), hexafluoroisopropanol (HFIPA)).
  • the solvent can be a polar aprotic solvent such as dichloromethane, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dimethylformamide (DMF), acetonitrile (AcCN), dimethyl sulfoxide (DMSO), among others.
  • the solvent can also be a polar protic solvent such as t-butanol, n-propanol, isopropanol, ethanol, methanol, acetic acid, water, among others.
  • the solvent can also be a non-polar solvent, such as hexane, pentanes, petroleum ether, benzene, toluene, diethyl ether, methyl-t-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1,2-dimethoxy ethane and 1,4-di oxane, chloroform, and carbon tetrachloride.
  • Two or more solvents can be used in a solvent mixture in any suitable ratio.
  • the ratio of a first solvent and a second solvent can be from 10: 1 to about 1: 10 (volume/volume or weight/weight), or about 10:1 to 1:5, or 10:1 to 1:1, or 10:1 to 5:1, or 5:1 to 1:5, or 5:1 to 1: 1, or 4:1 to 1:1, or 3:1 to 1: 1, or 2:1 to 1:1.
  • Other solvent ratios include about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4: 1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or about 1:10 (volume/ volume or weight/weight).
  • the methods of preparing solid forms of Compound I can be performed under any suitable reaction conditions.
  • the methods of preparing the crystalline forms of Compound I can be performed at any suitable temperature, such as, but not limited to, below room temperature, at room temperature, or above room temperature.
  • the temperature can be from about -78 °C to about 100 °C, or from about 0 °C to about 50 °C, or from about 10 °C to about 30 °C.
  • the reaction mixture be at a temperature of about 20 °C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 °C.
  • the reaction mixture can also be at a temperature of about 20 °C, 15, 10, 5, 0, -5, -10, -20, -30, - 40, -50, -60, -70 or about -78 °C.
  • the temperature can be the reflux temperature of the particular solvent used in the method.
  • crystalline forms of Compound I can be heated above about 100 °C such that one crystalline Form of Compound I forms a second crystalline Form of Compound I.
  • the methods of preparing solid forms of Compound I can include a variety of other steps.
  • the solvent can be evaporated, a seed crystal can be added to the mixture, the mixture can be heated and cooled a single time or repeatedly, etc.
  • the methods can include heating the reaction mixture to a temperature of about 20 °C, or 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 °C.
  • the methods can also include cooling the reaction mixture to a temperature of about 20 °C, 15, 10, 5, 0, -5, -10, -20, -30, -40, -50, -60, -70 or about -78 °C.
  • the temperature of the reaction mixture can be changed at any suitable rate.
  • the rate of temperature change can be from about 0.1 °C/min to about 10 °C/min.
  • the methods of preparing crystalline forms of Compound I can be performed for any suitable time.
  • the time can be for minutes, hours or days. In some embodiments, the time can be several hours, such as overnight.
  • the methods of preparing crystalline forms of Compound I can be also be performed at any suitable pressure.
  • the pressure can be below atmospheric pressure, at about atmospheric pressure, or above atmospheric pressure.
  • Crystallization can be induced by methods known in the art, for example by mechanical means such as scratching or rubbing the contact surface of the reaction vessel with e.g. a glass rod.
  • the saturated or supersaturated solution may be inoculated with seed crystals.
  • the method preparing solid forms of Compound I can also include a seed crystal of crystalline Compound I.
  • Isolation of the desired crystalline form can be accomplished by removing the solvent from the crystals. Generally this is carried out by known methods, such as, filtration, suction filtration, decantation or centrifugation. Further isolation can be achieved by removing any excess of the solvent(s) from the crystalline form by methods known to the one skilled in the art as for example application of a vacuum, and/or by heating.
  • compositions typically used in the form of a pharmaceutical composition or formulation.
  • Such pharmaceutical compositions may be administered to a patient by any acceptable route of administration including, but not limited to, oral, rectal, nasal, inhaled, topical (including transdermal) and parenteral modes of administration.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or excipient and a crystalline form of Compound I.
  • such pharmaceutical compositions may contain other therapeutic and/or formulating agents if desired.
  • compositions may contain other therapeutic and/or formulating agents if desired.
  • active agent the crystalline forms of Compound I may also be referred to as the “active agent”.
  • compositions of the invention typically contain a therapeutically effective amount of a crystalline form of Compound I of the present invention.
  • a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.
  • such pharmaceutical compositions will contain from about 0.1 to about 95% by weight of the active agent; including from about 5 to about 70% by weight; such as from about 10 to about 60% by weight of the active agent.
  • any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.
  • the choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts.
  • the carriers or excipients used in the pharmaceutical compositions of this invention are commercially-available.
  • conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Md. (1999).
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose (e.g., lactose monohydrate), glucose and sucrose; starches, such as com starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and
  • compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically-acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills and the like using conventional procedures and equipment.
  • the pharmaceutical compositions of the invention may be packaged in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units.
  • unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration.
  • the pharmaceutical compositions of the invention are suitable for oral administration.
  • Suitable pharmaceutical compositions for oral administration may be in the Form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water- in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of Compound I as an active ingredient.
  • compositions of the invention When intended for oral administration in a solid dosage form (i.e., as capsules, tablets, pills and the like), the pharmaceutical compositions of the invention will typically comprise the active agent and one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate.
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate.
  • such solid dosage forms may also comprise: fillers or extenders, such as starches, microcrystalline cellulose, lactose, lactose monohydrate, dicalcium phosphate, sucrose, glucose, mannitol, and/or silicic acid; binders, such as carboxymethylcellulose, hydroxypropylmethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as crosscarmellose sodium, crospovidone, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and/or glycerol monostearate; absorbents, such as kaolin and/or bentonite clay;
  • antioxidants can also be present in the pharmaceutical compositions of the invention.
  • pharmaceutically-acceptable antioxidants include: water- soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, and the like; and metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid, phosphoric acid, and the like.
  • Coating agents for tablets, capsules, pills and like include those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid, methacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like.
  • enteric coatings such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid, methacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like.
  • compositions of the invention may also be formulated to provide slow or controlled release of the active agent using, by way of example, hydroxypropyl methyl cellulose in varying proportions; or other polymer matrices, liposomes and/or microspheres.
  • the pharmaceutical compositions of the invention may optionally contain opacifying agents and may be formulated so that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active agent can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Suitable liquid dosage forms for oral administration include, by way of illustration, pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Liquid dosage forms typically comprise the active agent and an inert diluent, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (esp., cottonseed, groundnut, com, germ, olive, castor and sesame oils), oleic acid, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • certain liquid formulations can be converted, for example, by spray drying, to a powder, which is
  • Suspensions in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • the crystalline forms of Compound I of this invention can also be administered parenterally (e.g. by intravenous, subcutaneous, intramuscular or intraperitoneal injection).
  • parenteral administration the active agent is typically admixed with a suitable vehicle for parenteral administration including, by way of example, sterile aqueous solutions, saline, low molecular weight alcohols such as propylene glycol, polyethylene glycol, vegetable oils, gelatin, fatty acid esters such as ethyl oleate, and the like.
  • Parenteral formulations may also contain one or more anti-oxidants, solubilizers, stabilizers, preservatives, wetting agents, emulsifiers, buffering agents, or dispersing agents. These formulations may be rendered sterile by use of a sterile injectable medium, a sterilizing agent, filtration, irradiation, or heat.
  • compositions of the invention are formulated for administration by inhalation.
  • Suitable pharmaceutical compositions for administration by inhalation will typically be in the form of an aerosol or a powder.
  • Such compositions are generally administered using well-known delivery devices, such as a metered-dose inhaler, a dry powder inhaler, a nebulizer or a similar delivery device.
  • the pharmaceutical compositions of the invention When administered by inhalation using a pressurized container, the pharmaceutical compositions of the invention will typically comprise the active ingredient and a suitable propellant, such as dichlorodifluoromethane, tri chlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Additionally, the pharmaceutical composition may be in the Form of a capsule or cartridge (made, for example, from gelatin) comprising a compound of the invention and a powder suitable for use in a powder inhaler. Suitable powder bases include, by way of example, lactose or starch.
  • the crystalline forms of Compound I of the invention can also be administered transdermally using known transdermal delivery systems and excipients.
  • the active agent can be admixed with permeation enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a patch or similar delivery system.
  • permeation enhancers such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like
  • Additional excipients including gelling agents, emulsifiers and buffers, may be used in such transdermal compositions if desired.
  • crystalline forms of Compound I of the invention may be administered in the form of suppositories.
  • a typical suppository formulation will generally consist of active agent with a binding and/or lubricating agent such as a gelatin or cocoa butter or other low melting vegetable or synthetic wax or fat.
  • the crystalline form of Compound I is dry blended with microcrystalline cellulose, polyvinyl pyrrolidone, and/or croscarmellose sodium in a ratio of 4:5: 1 : 1 and compressed into tablets to provide a unit dosage of, for example, 5 mg, 20 mg, 40 mg, 80 mg, 200 mg or 270 mg active agent per tablet.
  • the tablet comprising the crystalline form of Compound I further comprises a coating.
  • the tablet coating is an aqueous film coating (e.g., Opadry II blue).
  • the crystalline form of Compound I thereof is combined with microcrystalline cellulose, polyvinyl pyrrolidone, and/or crosscarmellose sodium in a ratio of 4: 5 : 1 : 1 by wet granulation and loaded into gelatin or hydroxypropyl methylcellulose capsules to provide a unit dosage of, for example, 1 mg to about 400 mg of active agent per capsule, including from about 5 mg to about 300 mg and from about 20 mg to about 270 mg.
  • the crystalline form of Compound I is combined with microcrystalline cellulose to provide a unit dosage of, for example, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 200 mg, or 270 mg active agent per capsule.
  • the crystalline form of Compound I is dry or wet granulated with excipients such as microcrystalline cellulose, lactose (e.g., lactose monohydrate), and/or magnesium stearate.
  • the dry or wet granulated blends are compressed into tablets to provide a unit dosage of, for example, 1 mg to about 400 mg of active agent per tablet, including from about 5 mg to about 300 mg and from about 20 mg to about 270 mg.
  • the crystalline form of Compound I is combined with microcrystalline cellulose to provide a unit dosage of, for example, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 200 mg, or 270 mg active agent per tablet.
  • the tablet comprising the crystalline form of Compound I further comprises a coating.
  • the tablet coating is an aqueous film coating (e.g., Opadry II blue).
  • a liquid formulation comprising Compound I (0.1%), water (98.9%) and ascorbic acid (1.0%) is formed by adding a crystalline form of Compound I of the invention to a mixture of water and ascorbic acid.
  • Enteric Coated Oral Dosage Form The crystalline form of Compound I is dissolved in an aqueous solution containing polyvinyl pyrrolidone and spray coated onto microcrystalline cellulose or sugar beads in a ratio of 1:5 w/w Compound I: beads and then an approximately 5% weight gain of an enteric coating comprising an acrylic copolymer, for example a combination of acrylic copolymers available under the trade names Eudragit-L® and Eudragit-S®, or hydroxypropyl methylcellulose acetate succinate is applied.
  • the enteric coated beads are loaded into gelatin or hydroxypropyl methylcellulose capsules to provide a unit dosage of, for example, 30 mg of Compound I per capsule.
  • An enteric coating comprising a combination of Eudragit-L® and Eudragit-S®, or hydroxypropyl methylcellulose acetate succinate is applied to a tablet oral dosage Form or a capsule oral dosage Form described above.
  • the crystalline forms of Compound I of the invention have been shown to be potent inhibitors of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2. Inhibition of the family of JAK enzymes could inhibit signaling of many key pro-inflammatory cytokines.
  • the JAK inhibitors of the invention are expected to be useful in the treatment of inflammatory diseases (including gastrointestinal inflammatory diseases) such as ulcerative colitis, Crohn's disease, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).
  • inflammatory diseases including gastrointestinal inflammatory diseases
  • COPD chronic obstructive pulmonary disease
  • Compound I has been found to have minimal systemic exposure when administered to the gastrointestinal tract. As described previously in U.S. Patent No. 9,725,470, the absorption and distribution of Compound I has been extensively profiled in preclinical assays. Compound I tested in cannulated rats showed low absorption into plasma at the portal vein. In addition, Compound I is designed to have its effect at the site of action in the gastrointestinal tract. Compound I exhibited a ratio of exposure in the colon to exposure in plasma in rat greater than about 450. In particular, Compound I has demonstrated significantly higher exposure throughout the gastrointestinal tract than exposure in plasma upon oral dosing in preclinical species. Furthermore, Compound I has been evaluated in healthy human subjects and was found to exhibit high drug concentration in stool samples suggesting significant exposure in the gastrointestinal tract.
  • Oxazol one-induced colitis is an experimental model that has a histological resemblance to human ulcerative colitis.
  • Compound I demonstrated activity in the oxazolone- induced colitis model in mice. Further, when tested in an immunosuppression model in mice, which probes systemic functional activity, the compound demonstrated minimal effect of immunosuppression at the same dose required to demonstrate efficacy in the oxazolone model. Thus Compound I demonstrated anti-colitic activity without exhibiting systemic effects in preclinical models.
  • Compound I is useful for a variety of gastrointestinal inflammatory indications that include, but are not limited to, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn's disease, collagenous colitis, lymphocytic colitis, Behcet's disease, celiac disease, checkpoint cancer treatment-induced colitis, (e.g. CTLA-4 inhibitor-induced colitis), ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis.
  • ulcerative colitis proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis
  • Crohn's disease collagenous colitis
  • lymphocytic colitis Behcet's disease
  • celiac disease celiac disease
  • checkpoint cancer treatment-induced colitis e.g. CTLA-4 inhibitor-induced colitis
  • ileitis eosinophilic e
  • the crystalline forms of Compound I of the invention are expected to be useful for the induction and maintenance of remission of ulcerative colitis, and for the treatment of Crohn's disease, CTLA-4 inhibitor-induced colitis, and the gastrointestinal adverse effects in graft versus host disease.
  • the invention provides a method of treating a gastrointestinal inflammatory disease in a mammal (e.g., a human), the method comprising administering to the mammal a therapeutically-effective amount of a crystalline form of Compound I of the invention or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a crystalline form of Compound I of the invention.
  • a mammal e.g., a human
  • the method comprising administering to the mammal a therapeutically-effective amount of a crystalline form of Compound I of the invention or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a crystalline form of Compound I of the invention.
  • the invention further provides a method of treating ulcerative colitis in a mammal, the method comprising administering to the mammal a therapeutically-effective amount of a crystalline form of Compound I of the invention or of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a crystalline form of Compound I of the invention.
  • Compound I of the invention will typically be administered orally in a single daily dose or in multiple doses per day, although other forms of administration may be used.
  • the amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • Suitable doses for treating ulcerative colitis and other gastrointestinal inflammatory disorders are expected to range from about 1 to about 400 mg/day of active agent, including from about 5 to about 300 mg/day and from about 20 to about 70 mg per day of active agent for an average 70 kg human. Suitable doses include at least about 0.1 mg/kg, or 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/kg.
  • the subject is administered a crystalline form of Compound I of the invention, at a dose of at least about 0.1 mg/kg.
  • the subject is administered a crystalline form of Compound I of the invention at a dose of at least about 1 mg/kg.
  • the subject is administered a crystalline form of Compound I of the invention, at a dose of about 10 mg/kg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of from about 0.1 mg/kg to about 10 mg/kg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of from about 1 mg/kg to about 10 mg/kg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of from about 0.1 mg/kg to about 1 mg/kg.
  • the subject is administered a crystalline form of Compound I of the invention, at a dose of 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 200 mg, or 270 mg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of 20 mg, 80 mg, or 200 mg. In some embodiments, the subject is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of 20 mg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of 80 mg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of 200 mg. In some embodiments, the subject is administered a crystalline form of Compound I of the invention, at a dose of 270 mg. Combination Therapy
  • Crystalline and amorphous solid forms of Compound I of the invention may also be used in combination with one or more agents which act by the same mechanism or by different mechanisms to effect treatment of gastrointestinal inflammatory disorders.
  • agents for combination therapy include, but are not limited to, aminosalicylates, steroids, systemic immunosuppressants, anti-TNFa antibodies, anti-VLA-4 antibodies, anti- integrin a4p7 antibodies, anti-bacterial agents, and anti-diarrheal medicines.
  • the method further comprises administering one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are aminosalicylates, steroids, systemic immunosuppressants, anti-TNFa antibodies, anti-VLA-4 antibodies, anti-integrin a4137 antibodies, anti-bacterial agents, or anti-diarrheal medicines.
  • Aminosalicylates that may be used in combination with the crystalline forms of Compound I include, but are not limited to, mesalamine, osalazine and sulfasalazine.
  • steroids examples include, but are not limited to, prednisone, prednisolone, hydrocortisone, budesonide, beclomethasone, and fluticasone.
  • Systemic immunosuppressants useful for treatment of inflammatory disorders include, but are not limited to cyclosporine, azathioprine, methotrexate, 6-mercaptopurine, and tacrolimus.
  • anti-TNFa antibodies which include, but are not limited to, infliximab, adalimumab, golimumab, and certolizumab
  • Useful compounds acting by other mechanisms include anti-VLA-4 antibodies, such as natalizumab, anti-integrin a4p7 antibodies, such as vedolizumab, anti-bacterial agents, such as rifaximin, and anti-diarrheal medicines, such as loperamide.
  • the invention provides a therapeutic combination for use in the treatment of gastrointestinal inflammatory disorders, the combination comprising a crystalline form of Compound I of the invention and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders.
  • the invention provides a combination comprising a crystalline form of Compound I of the invention and one or more agents selected from aminosalicylates, steroids, systemic immunosuppressants, anti-TNFa antibodies, anti-VLA-4 antibodies, anti-integrin a4p7 antibodies, anti-bacterial agents, and anti-diarrheal medicines.
  • Secondary agent(s), when included, are present in a therapeutically effective amount, i.e. in any amount that produces a therapeutically beneficial effect when co-administered with a crystalline form of Compound I of the invention.
  • composition comprising a crystalline form of Compound I of the invention and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders.
  • the invention provides a method of treating gastrointestinal inflammatory disorders, the method comprising administering to the mammal a crystalline form of Compound I of the invention and one or more other therapeutic agents useful for treating gastrointestinal inflammatory disorders.
  • the agents When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, as disclosed above, or the agents may be provided in separate compositions that are administered simultaneously or at separate times, by the same or by different routes of administration. When administered separately, the agents are administered sufficiently close in time so as to provide a desired therapeutic effect.
  • compositions can be packaged separately or may be packaged together as a kit.
  • the two or more therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration.
  • Compound I has been demonstrated to be potent inhibitors of the JAK1, JAK2, JAK3, and TYK2 enzymes in enzyme binding assays and to have potent functional activity without cytotoxicity in cellular assays.
  • XRPD X-ray Powder Diffraction
  • the incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge.
  • the diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector.
  • the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
  • the software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analyzed 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 well-plate and powders (approximately 1 to 2 mg) were used as received.
  • the Millipore plate was used to isolate and analyze 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 utilized for the Millipore plate.
  • DSC Differential Scanning Calorimetry
  • DSC data were also collected on a TA Instruments Discovery DSC equipped with a 50-position auto-sampler. Typically, 0.5 to 3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
  • TGA Thermo-Gravimetric Analysis
  • TGA data were also collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, 5 to 10 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C/min from ambient to 350 °C. A nitrogen purge at 25 ml/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
  • sample was placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm was performed as outlined below (2 scans per complete cycle).
  • the standard isotherm was performed at 25 °C at 10 %RH intervals over a 0 - 90 %RH range.
  • a double cycle (4 scans) was carried out.
  • Data analysis was carried out within Microsoft Excel using the DVS Analysis Suite.
  • the sample was recovered after completion of the isotherm and re-analysed by XRPD.
  • SCXRD Single Crystal X-Ray Diffraction
  • Data were collected on a Rigaku Oxford Diffraction Supernova Dual Source, Cu at Zero, Atlas CCD diffractometer equipped with an Oxford Cryosystems Cobra cooling device. The data were collected using Cu Ka or Mo Ka radiation as stated in the experimental tables. Structures were solved and refined using the Bruker AXS SHELXTL suite or the OLEX2 crystallographic software. Full details can be found in the CIF. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter. A reference diffractogram for the crystal structure was generated using Mercury (1).
  • Method 2 A small scale experiment was performed using Compound I Form 1 (100 mg) placed in a grinding jar with a metal ball bearing and milled twice for 30 min at 30 Hz on a Retsch mill. The material was mixed with a spatula between runs for consistency of milling. Aliquots were analyzed by XRPD.
  • Method 3 A large-scale ball milling experiment was performed using Compound I Form 1 (1.0 g each) placed into two 25 ml grinding jars with a metal ball bearing and milled for 60 min at 30 Hz on a Retsch mill. An aliquot of the solid was taken from inside the lid and at the base after each run and analyzed by XRPD. The jars were allowed to cool naturally at RT for an hour as some heat is generated during the milling process. The milling process was then repeated until a uniformly amorphous material was obtained with no discernible peaks related to the starting material. In total, the material in each jar was milled for 4 hours.
  • Amorphous Compound I (30 mg) was weighed into an HPLC vial and a stirrer bar added. The sample was treated with 3-methyl-l-butanol (10 vol, 300 pl) while stirring at 5 °C, 600 rpm and visual assessments made after 10 minutes. Additional solvent was added if the sample remained as a suspension, either until the solids dissolved or up to a maximum of 50 vol was added. Solutions obtained were allowed to evaporate at RT with vial caps removed. Suspensions were matured at 5 °C for 3 days, and subsequently filtered into a Millipore 96-well plate for XRPD analysis. The solids were analyzed after brief vacuumdrying and air-drying so that the sample remained damp. XRPD analysis was collected on the damp sample and then on the dry sample, after vacuum drying at RT for 3 hours.
  • Amorphous Compound I was first generated using the previous grinding method (350 mg). Ethanol (10% aqueous) was added (25 ml, 50 vol) and the resulting suspension was stirred at 5 °C for one day to generate Form 3. After this time, the sample was separated by filtration through a PTFE filter. Half of this sample was dried in a vacuum oven at RT for 1 hour. This sample was then dried in a vacuum oven at RT for a further 3 days and analyzed by XRPD.
  • Amorphous Compound I was charged to a 30 ml HEL vial. To this 24.25 ml (50 Vol) cold methanol:H2O (9: 1) was added and the suspension was stirred at 5 °C (600 rpm) for two days. Aliquots of the sample were removed at regular intervals and analyzed by XRPD. After two days, the sample (a sticky yellow solid) was isolated by filtration and dried under suction for 30 minutes.
  • Compound I Form 11 was prepared using the method described in Example 4, using ethanol, 5% water/ethanol mixture, or 10% water/ethanol mixture.
  • Example 8 Compound I Form 12, 2-propanol
  • Amorphous Compound I (60 mg) was weighed into a HPLC vial and 20 vol IPA added. The sample was matured in a heater-shaker incubator at 60 °C for 2 days, after which time the sample was a yellow, thick suspension. The suspension was separated by filtration through a polyethylene frit to Form a wet cake.
  • Compound I Form 14 was prepared using the method described in Example 4, using 1-propanol.
  • Crystalline Form 1 (25 mg) was weighed into 7 ml vial and the required volume of solvent added (DMSO) to Form a solution, while stirring at 25 °C, 600 rpm.
  • Antisolvent water, 120 vol, 3 ml
  • the sample was subsequently cooled to 5 °C and held isothermally for 24 hours.
  • additional antisolvent 80 vol, 2 ml
  • Suspensions obtained were filtered and dried under suction. The residues were analyzed by XRPD damp and dry.
  • Example 11 Compound I Form 24, l,3-dimethyl-2-imidazolidinone hydrate
  • Compound I Form 1 (30 mg) was weighed into HPLC vials and to each vial was added 300 pL (10 vol) of a saturated solution of Compound I Form 1 in N- methylpyrrolidinone. The sample was then stored in a platForm incubator-shaker at room temperature for 4 days. The resulting suspension was collected by filtration under vacuum into a polyethylene frit, then dried in a vacuum oven at room temperature for 30 minutes to provide Compound I Form 34. Compound I Form 34 showed 2.4 mol eq. of N- methylpyrrolidinone.
  • Method 1 Compound I Form 1 was weighted in an HPLC vial and 1 mL of 55% water/dimethylacetamide was added. The resulting yellow suspension was stirred overnight at 35 °C and 300 rpm. After this, the suspension was separated by centrifuge and 0.5 mL of the supernatant was filtered into a 0.45 um PTFE filter into a HPLC vial. This was allowed to stand at room temperature for 2 h to Form the super saturated solution.
  • Method 2 Amorphous Compound I (200 mg) or Compound 1 Form 10 (20 mg) was added to 15% w/w water in N, AMimethylacetamide. to which was added a saturated solution of Compound I Form 1 in 15% w/w water in A. A-dimethylacetamide. The resulting suspension was stirred at 25 °C, 300 rpm for 3 days, then separated by filtration through a PE frit, dried using compressed air and stored in a vacuum oven at room temperature for 30 minutes.

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Abstract

La présente invention concerne des formes cristallines solvatées et des formes solvatées/hydratées de 3-((1R,3s,5S)-3-((7-((5-méthyl-1H-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile et des procédés de fabrication et d'utilisation de ceux-ci.
PCT/US2021/054016 2020-10-09 2021-10-07 Formes solvatées d'un inhibiteur pan-jak Ceased WO2022076717A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9725470B2 (en) 2015-05-28 2017-08-08 Theravance Biopharma R&D Ip, Llc Substituted naphthyridines as JAK kinase inhibitors

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Publication number Priority date Publication date Assignee Title
US9725470B2 (en) 2015-05-28 2017-08-08 Theravance Biopharma R&D Ip, Llc Substituted naphthyridines as JAK kinase inhibitors
US10072026B2 (en) 2015-05-28 2018-09-11 Theravance Biopharma R&D Ip, Llc Crystalline form of 3-((1R,3s,5S)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-naphthyridin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile
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