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WO2024222796A1 - Crystalline sars-cov-2 inhibitor and uses thereof - Google Patents

Crystalline sars-cov-2 inhibitor and uses thereof Download PDF

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Publication number
WO2024222796A1
WO2024222796A1 PCT/CN2024/089801 CN2024089801W WO2024222796A1 WO 2024222796 A1 WO2024222796 A1 WO 2024222796A1 CN 2024089801 W CN2024089801 W CN 2024089801W WO 2024222796 A1 WO2024222796 A1 WO 2024222796A1
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Prior art keywords
crystalline form
compound
xrpd
radiation
ray powder
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French (fr)
Inventor
Congcong Zhu
Yushu YIN
Xing LIANG
Jingjing PENG
Xiao DING
Feng Ren
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • SARS-CoV-2 (also known as 2019-nCoV or COVID-19) first appeared in 2019. Symptoms linked with the disease include fever, myalgia, cough, dyspnea, and fatigue (Huang et al., 2020) . Nevertheless, treatments with well-known drugs such as chloroquine or investigational drugs such as remdesivir are suggested for this disease (Colson et al., 2020; Wang et al., 2020) .
  • HAV human immunodeficiency virus
  • lopinavir/ritonavir is also being investigated as a therapy for SARS-CoV-2 as they exhibited anti-coronavirus effect in vitro (Que et al., 2003; Chu et al., 2004; Chan et al., 2015; Li and De Clercq, 2020) .
  • SARS-CoV-2 is a beta-coronavirus and is member of the family Coronaviridae, which comprises the largest positive-sense, single-stranded RNA viruses. (Cui et al., 2019) .
  • the virus contains four non-structural proteins: papain-like (PL pro ) and 3-chymotrypsin-like (3CL pro ) proteases, RNA polymerase and helicase (Zumla et al., 2016) . Both proteases (PL pro and 3CL pro ) are involved with transcription and replication of the virus. Amongst the four types, the 3CL pro is considered to be mainly involved in the replication of the virus (de Wit et al., 2016) .
  • 3CLpro hydrolyses the viral polyproteins pp1a and pp1ab to produce functional proteins during coronavirus replication.
  • the solid state form is a crystalline form.
  • the solid state form is crystalline Compound 1 freebase Type A, crystalline Compound 1 freebase Type B, or crystalline Compound 1 freebase Type D.
  • the solid state form is crystalline Compound 1 freebase Type C.
  • the solid state form is crystalline Compound 1 tosylate salt Type A.
  • the solid state form is crystalline Compound 1 tosylate salt Type B.
  • composition comprising a therapeutically effective amount of a crystalline form disclosed herein and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a crystalline form disclosed herein or a pharmaceutical composition disclosed herein.
  • Also disclosed herein is a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof, comprising administering to the patient a crystalline form disclosed herein or a pharmaceutical composition disclosed herein.
  • the crystalline form or the pharmaceutical composition is administered to the patient until the infection is reduced or eliminated.
  • the method comprises treating one or more symptoms of SARS-CoV-2 in the patient in need thereof.
  • FIG. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 starting material.
  • FIG. 2 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 starting material
  • FIG. 3 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type A.
  • FIG. 4 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type B.
  • FIG. 5 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type C.
  • FIG. 6 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 freebase Type C.
  • FIG. 7 shows the 1 H NMR spectrum of Compound 1 freebase Type C.
  • FIG. 8 shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 freebase Type C
  • FIG. 9 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type D.
  • FIG. 10 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 tosylate salt Type A.
  • FIG. 11 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 tosylate salt Type A.
  • FIG. 12 shows the 1 H NMR spectrum of Compound 1 tosylate salt Type A.
  • FIG. 13 shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 tosylate salt Type A.
  • FIG. 14 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 tosylate salt Type B.
  • FIG. 15 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 tosylate salt Type B.
  • FIG. 16 shows the 1 H NMR spectrum of Compound 1 tosylate salt Type B.
  • polymorphism While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers.
  • Compound 1 is (2R) -2- (2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2-fluoroacetamido) -2- (pyrimidin-5-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide: (Compound 1) .
  • Compound 1 is in the form of a freebase.
  • Compound 1 is in the form of a pharmaceutically acceptable salt.
  • Compound 1 is in the form of a tosylate salt.
  • Compound 1 is in the form of a co-crystal.
  • the solid state form is a crystalline form.
  • the solid state form is crystalline Compound 1 freebase. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A, crystalline Compound 1 freebase Type B, or crystalline Compound 1 freebase Type D. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A. In some embodiments, the solid state form is crystalline Compound 1 freebase Type B. In some embodiments, the solid state form is crystalline Compound 1 freebase Type C. In some embodiments, the solid state form is crystalline Compound 1 freebase Type D.
  • the solid state form is crystalline Compound 1 tosylate salt. In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type A. In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type B.
  • Compound 1 freebase Type A Disclosed herein is Compound 1 freebase Type A.
  • the crystalline form is Compound 1 freebase Type A characterized as having at least one of the following properties:
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3 as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 1 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , and 14.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 9.1 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2°2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.3 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.1 ⁇ 0.2° 2 ⁇ , 11.0 ⁇ 0.2° 2 ⁇ , 14.3 ⁇ 0.2° 2 ⁇ , 16.9 ⁇ 0.2° 2 ⁇ , 20.4 ⁇ 0.2° 2 ⁇ , and 21.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • Compound 1 freebase Type B Disclosed herein is Compound 1 freebase Type B.
  • the crystalline form is Compound 1 freebase Type B characterized as having at least one of the following properties:
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 2 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , and 17.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 8.3 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 9.4 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , and 19.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2°2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2°2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 5.4 ⁇ 0.2° 2 ⁇ , 8.3 ⁇ 0.2° 2 ⁇ , 9.4 ⁇ 0.2° 2 ⁇ , 11.3 ⁇ 0.2° 2 ⁇ , 14.7 ⁇ 0.2° 2 ⁇ , 15.7 ⁇ 0.2° 2 ⁇ , 17.2 ⁇ 0.2° 2 ⁇ , 19.6 ⁇ 0.2° 2 ⁇ , and 20.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • Compound 1 freebase Type C Disclosed herein is Compound 1 freebase Type C.
  • the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 6;
  • thermogram exhibiting a mass loss of about 0.97%from the onset of heating up to approximately 120.0 °C;
  • the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 6;
  • the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
  • thermogram exhibiting a mass loss of about 0.97%from the onset of heating up to approximately 120.0 °C;
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 3 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.9 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.1 ⁇ 0.2° 2 ⁇ and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.4 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , and 17.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at seven two peaks selected from 10.4 ⁇ 0.2° 2 ⁇ , 10.9 ⁇ 0.2° 2 ⁇ , 12.1 ⁇ 0.2° 2 ⁇ , 13.1 ⁇ 0.2° 2 ⁇ , 15.0 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 21.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 6.
  • the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 52.7 °C.
  • the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 103.8 °C.
  • thermogram is substantially the same as shown in FIG. 6.
  • the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 0.97%from the onset of heating up to approximately 120.0 °C.
  • the crystalline form is an anhydrate.
  • the crystalline form is hygroscopic with a water uptake of 0.792%observed at 80%RH/25 °C.
  • the crystalline form is stable.
  • the crystalline form is more stable than Compound 1 freebase Type A, Compound 1 freebase Type B, or Compound 1 freebase Type D.
  • the crystalline form is chemically stable.
  • the crystalline form is thermodynamically stable.
  • Compound 1 freebase Type D Disclosed herein is Compound 1 freebase Type D.
  • the crystalline form is Compound 1 freebase Type D characterized as having at least one of the following properties:
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 9 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 4 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.0 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.0 ⁇ 0.2° 2 ⁇ and 19.8 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , and 17.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2°2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 5.0 ⁇ 0.2° 2 ⁇ , 10.0 ⁇ 0.2° 2 ⁇ , 10.8 ⁇ 0.2° 2 ⁇ , 11.9 ⁇ 0.2° 2 ⁇ , 14.8 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.6 ⁇ 0.2° 2 ⁇ , 19.8 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • Compound 1 Tosylate salt Type A Disclosed herein is Compound 1 Tosylate salt Type A.
  • the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 11;
  • thermogram exhibiting a mass loss of about 4.43%from the onset of heating up to approximately 110.0 °C;
  • the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 11;
  • the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
  • thermogram exhibiting a mass loss of about 4.43%from the onset of heating up to approximately 110.0 °C;
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 5 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 9.7 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , and 24.2 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , and 24.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.4 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , and 25.9 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2°2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least nine peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 10 peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 11 peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 12 peaks selected from 7.8 ⁇ 0.2° 2 ⁇ , 8.6 ⁇ 0.2° 2 ⁇ , 9.7 ⁇ 0.2° 2 ⁇ , 16.1 ⁇ 0.2° 2 ⁇ , 17.4 ⁇ 0.2° 2 ⁇ , 18.2 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 20.8 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 24.9 ⁇ 0.2° 2 ⁇ , 25.9 ⁇ 0.2° 2 ⁇ , and 27.6 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 132.7 °C.
  • thermogram is substantially the same as shown in FIG. 11.
  • the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 4.43%from the onset of heating up to approximately 110.0 °C.
  • the crystalline form is a hydrate.
  • the crystalline form has a water uptake of 0.2518%was observed at 80%RH/25 °C.
  • the molar ratio of Tosylate to Compound 1 freebase is about 1: 1.
  • the crystalline form is stable.
  • the crystalline form is more stable than Compound 1 Tosylate salt Type B.
  • the crystalline form is chemically stable.
  • the crystalline form is thermodynamically stable.
  • Compound 1 Tosylate salt Type B Disclosed herein is Compound 1 Tosylate salt Type B.
  • the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 15;
  • thermogram exhibiting a mass loss of about 3.03%from the onset of heating up to approximately 110.0 °C;
  • the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
  • thermogram substantially the same as shown in FIG. 15;
  • the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
  • thermogram exhibiting a mass loss of about 3.03%from the onset of heating up to approximately 110.0 °C;
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 14 as measured using Cu K ⁇ .radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 6 as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 8.1 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , and 20.3 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.1 ⁇ 0.2° 2 ⁇ and 23.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ .radiation.
  • the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.2 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2°2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 8.1 ⁇ 0.2° 2 ⁇ , 10.1 ⁇ 0.2° 2 ⁇ , 12.2 ⁇ 0.2° 2 ⁇ , 16.6 ⁇ 0.2° 2 ⁇ , 17.7 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 2 ⁇ , 23.1 ⁇ 0.2° 2 ⁇ , and 28.1 ⁇ 0.2° 2 ⁇ as measured using Cu K ⁇ . radiation.
  • XRPD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 15.
  • the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 137.7 °C.
  • thermogram is substantially the same as shown in FIG. 15.
  • the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 3.03%from the onset of heating up to approximately 110.0 °C.
  • the crystalline form is a hydrate.
  • the stoichiometric ratio of acid to freebase is 1.0.
  • the coronavirus infection is caused by the SARS-CoV-2 virus.
  • the coronavirus infection is caused by the MERS-CoV virus.
  • the coronavirus infection is caused by the SARS-CoV virus.
  • the coronavirus infection is caused by the HCoV-229E virus.
  • the coronavirus infection is caused by the HCoV-OC43 virus.
  • the coronavirus infection is caused by the HCoV-NL63 virus.
  • the coronavirus infection is caused by the HCoV-HKU1 virus.
  • a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof comprising administering to the patient a compound or a pharmaceutical composition comprising a compound described herein, for example, a compound of Formula (I) .
  • the compound disclosed herein is administered to the subject prophylactically.
  • the subject is suspected of having a SARS-CoV-2 infection before the SARS-CoV-2 infection is diagnosed.
  • the compounds of the present disclosure are administered to the subject until the infection is treated, inhibited, or reduced. In some embodiments, the compounds is administered to the subject until one or more symptoms of the SARS-CoV-2 infection is reduced.
  • a method of inhibiting a viral infection comprising providing a compound disclosed herein to the infection so as to inhibit the viral infection.
  • the viral infection is caused by SARS-CoV-2.
  • the viral infection is caused by MERS-CoV.
  • the viral infection is caused by SARS-CoV.
  • the viral infection is caused by HCoV-229E.
  • the viral infection is caused by HCoV-OC43.
  • the viral infection is caused by HCoV-NL63.
  • the viral infection is caused by HCoV-HKU1.
  • a method of inhibiting SARS-CoV-2 by binding with a protein thereof comprising providing a compound disclosed herein to a SARS-CoV-2 so as to inhibit the SARS-CoV-2.
  • the SARS-CoV-2 binds to a protease on the SARS-CoV-2.
  • the compounds disclosed herein bind with a cysteine residue of the main protease, thereby inhibiting the SARS-CoV-2.
  • the cysteine residue is at position 145 of a main protease.
  • the protease is 3CL.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the crystalline forms described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds described herein are administered to animals.
  • compositions comprising a crystalline form described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • compositions containing the crystalline form described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the effective amount of the crystalline form described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • an “effective amount” or “therapeutically effective amount, ” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • enhancement means to increase or prolong either in potency or duration a desired effect.
  • enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount, ” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature or pH. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3%of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and/or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the disclosure. In the context of the disclosure, when used or whether or not used the word, such as “about, ” it means that within a given value or range of 10%, appropriately within 5%, especially within 1%.
  • assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks. ” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.
  • Characteristic peaks are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition) . Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ⁇ 0.2 °2 ⁇ . Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
  • preferred orientation refers to an extreme case of non-random distribution of the crystallites of a solid state form.
  • XRPD XRPD
  • the ideal sample is homogenous and the crystallites are randomly distributed in the bulk solid.
  • each possible reflection from a given set of planes will have and equal number of crystallites contributing to it.
  • comparing the intensity between a randomly oriented diffraction pattern and a preferred oriented diffraction pattern can look entirely different. Quantitative analysis depending on intensity ratios are greatly distorted by preferred orientation. Careful sample preparation is important for decreasing the incidence of a preferred orientation.
  • salts of Compound 1 include compounds where the corresponding acid is in an ionized, non-ionized, associated, or unassociated form. In some embodiments, the corresponding acid is in an ionized and/or associated forms. In some embodiments, the corresponding acid is in a nonionized and/or unassociated forms. Salts of Compound 1 also include mono-acid, di-acid, etc. forms of the salts.
  • Compound 1obtained from example 1 used as starting material was characterized by XRPD, TGA, and DSC.
  • the XRPD pattern is shown in FIG. 1, which shows that the sample was weakly crystalline.
  • the TGA/DSC curves in FIG. 2 shows a weight loss of 1.10%when heated to 150 °C and two endotherms at 57.8 and 77.5 °C (peak temperature) .
  • Example 2 In vitro assay (SARS-CoV-2 M pro enzymatic assay)
  • the C-His6-tagged SARS-CoV-2 MPRO (NC_045512) was cloned, expressed in E. coli, and purified by WuXi.
  • the final concentrations of the Mpro protein and substrate were 25 nM and 25 ⁇ M, respectively, in the MPRO enzymatic assay.
  • Reference compound GC376 was provided by WuXi AppTec and was included in each plate to ensure assay robustness. Test compounds were tested at single dose or 10 doses titration, in duplicate. Compounds were added to an assay plate (384w format) using ECHO, in duplicate wells. The final concentration is 10 ⁇ M for the single dose experiment. As for the full dose response experiment, samples were 3-fold serially diluted starting from 25 ⁇ M for 10 doses and added to an assay plate, in duplicate wells. The final concentrations ( ⁇ M) of each compound was 25, 8.33, 2.778, 0.926, 0.309, 0.103, 0.034, 0.011, 0.0038, and 0.0013.
  • REU fluorescence signal
  • Inhibition% ( (CPD - BGHPE) - (ZPE - BGZPE) ) / ( (HPE - BGHPE) - (ZPE - BGZPE) ) ⁇ 100
  • HPE high percent effect controls (1 ⁇ M of GC376 + enzyme + substrate)
  • ZPE zero percent effective controls (enzyme + substrate, no compound)
  • CPD compound activity testing wells (compound + enzyme + substrate)
  • BG background control wells (no enzyme) .
  • IC50 values of compounds were calculated with the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response -variable slope (four parameters) . Representative biochemical data is presented in the table below.
  • IC50 (nM) 0 ⁇ A ⁇ 100; 100 ⁇ B ⁇ 1, 000; 1, 000 ⁇ C ⁇ 10, 000; 10, 000 ⁇ D
  • Compound 1 starting material was suspended in 0.5 mL MTBE/n-Heptane (v:v, 1: 4) . After the suspension was stirred magnetically at RT for 5 days, the remaining solids were isolated by centrifugation and air dried at RT before characterization.
  • the XRPD pattern was shown in FIG. 5 and Table 3.
  • the TGA/DSC curves in FIG. 6 showed a weight loss of 0.97%when heated to 120 °C and two endotherms at 52.7 and 103.8 °C (peak temperature) .
  • 1 H NMR result was shown in FIG. 7 showing that no signal of residual MTBE or n- heptane was detected.
  • Compound 1 freebase Type C was speculated as an anhydrate.
  • DVS plot in FIG. 8 showed that in the sorption curve from 0%RH to 95%RH, a water uptake of 0.792%was observed at 80%RH/25 °C, indicating that freebase Type C was slightly hygroscopic
  • Freebase Type D was only observed via heating freebase Type C to 60 °C under N 2 protection in VT XRPD, which was stable and converted back to freebase Type C after cooling to 30 °C. Therefore, freebase Type D was speculated to be a metastable anhydrate form.
  • the XRPD pattern is shown in FIG. 9 and Table 4.
  • Tosylate Type A was obtained by slurrying 300 mg of Compound 1 starting material and 1.0 eq.p-toluenesulfonic acid monohydrate in 6 mL IPAc at RT for 6 days. The solids were centrifuged and vacuum dried at RT overnight before characterization.
  • the XRPD pattern was shown in FIG. 10 and Table 5.
  • TGA/DSC curves in FIG. 11 showed a weight loss of 4.43%when heated to 110 °C and one endotherm at 132.7 °C (peak temp. ) .
  • 1 H NMR result in FIG. 12 showed that the molar ratio of acid/FB was 1.0, and no obvious residual IPAc was observed.
  • Tosylate Type A was speculated as a hydrate.
  • DVS plot in FIG. 13 showed that in the sorption curve from 0%RH to 95%RH, a water uptake of 0.2518%was observed at 80%RH/25 °C.
  • Tosylate Type B was obtained by slurrying 300 mg of Compound 1 starting material and 1.0 eq.p-toluenesulfonic acid monohydrate in 7 mL DCM at RT for 6 days. The solids were centrifuged and vacuum dried at RT overnight before characterization.
  • tosylate Type A sample was weighed into an HPLC vial, the corresponding solvents were added to prepare suspensions at RT. After slurry for 1 ⁇ 2 hrs, the suspension was filtered through a 0.45 ⁇ m PTFE membrane to obtain a saturated solution. ⁇ 5 mg of tosylate Type A and tosylate Type B were weighed into a new HPLC vial and 0.5 mL of pre-saturated solution was added. The mixtures were slurried at RT.
  • TGA data was collected using a TA Q5000/Discovery TGA 5500 from TA Instruments.
  • DSC was performed using a Discovery DSC 2500 from TA Instruments. Detailed parameters used are listed in Table 9.

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Abstract

Described herein are crystalline forms of a small molecule SARS-COV-2 inhibitor, as well as pharmaceutical compositions thereof, and methods of use thereof in the treatment of diseases or conditions that would benefit from treatment with a SARS-COV-2 inhibitor.

Description

CRYSTALLINE SARS-COV-2 INHIBITOR AND USES THEREOF
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2023/090983, filed April 26, 2023; which is incorporated herein by reference in its entirety.
BACKGROUND
SARS-CoV-2 (also known as 2019-nCoV or COVID-19) first appeared in 2019. Symptoms linked with the disease include fever, myalgia, cough, dyspnea, and fatigue (Huang et al., 2020) . Nevertheless, treatments with well-known drugs such as chloroquine or investigational drugs such as remdesivir are suggested for this disease (Colson et al., 2020; Wang et al., 2020) . A cocktail of human immunodeficiency virus (HIV) drugs, lopinavir/ritonavir is also being investigated as a therapy for SARS-CoV-2 as they exhibited anti-coronavirus effect in vitro (Que et al., 2003; Chu et al., 2004; Chan et al., 2015; Li and De Clercq, 2020) .
SARS-CoV-2 is a beta-coronavirus and is member of the family Coronaviridae, which comprises the largest positive-sense, single-stranded RNA viruses. (Cui et al., 2019) . The virus contains four non-structural proteins: papain-like (PLpro) and 3-chymotrypsin-like (3CLpro) proteases, RNA polymerase and helicase (Zumla et al., 2016) . Both proteases (PLpro and 3CLpro) are involved with transcription and replication of the virus. Amongst the four types, the 3CLpro is considered to be mainly involved in the replication of the virus (de Wit et al., 2016) . 3CLpro hydrolyses the viral polyproteins pp1a and pp1ab to produce functional proteins during coronavirus replication. A study reported that the cysteine protease 3CLpro of SARS-CoV-2 showed 96%sequence similarity with that of SARS-CoV (Xu et al., 2020) . Because of its highly conserved sequence and essential functional properties, 3CLpro has been validated as a potential target for the development of drugs to treat SARS-CoV-2.
Because viable treatments remain elusive, there is a need for a compound and/or method for inhibiting SARS-CoV-2 and for a treatment for a subject infected with the SARS-CoV-2, especially a stable crystalline form.
SUMMARY
Disclosed herein is a solid state form of (2R) -2- (2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2-fluoroacetamido) -2- (pyrimidin-5-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide:  (Compound 1) or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid state form is a crystalline form.
In some embodiments, the solid state form is crystalline Compound 1 freebase Type A, crystalline Compound 1 freebase Type B, or crystalline Compound 1 freebase Type D.
In some embodiments, the solid state form is crystalline Compound 1 freebase Type C.
In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type A.
In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type B.
Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form disclosed herein and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a crystalline form disclosed herein or a pharmaceutical composition disclosed herein.
Also disclosed herein is a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof, comprising administering to the patient a crystalline form disclosed herein or a pharmaceutical composition disclosed herein.
In some embodiments, the crystalline form or the pharmaceutical composition is administered to the patient until the infection is reduced or eliminated.
In some embodiments, the method comprises treating one or more symptoms of SARS-CoV-2 in the patient in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
FIG. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 starting material.
FIG. 2 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 starting material
FIG. 3 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type A.
FIG. 4 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type B.
FIG. 5 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type C.
FIG. 6 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 freebase Type C.
FIG. 7 shows the 1H NMR spectrum of Compound 1 freebase Type C.
FIG. 8 shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 freebase Type C
FIG. 9 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 freebase Type D.
FIG. 10 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 tosylate salt Type A.
FIG. 11 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 tosylate salt Type A.
FIG. 12 shows the 1H NMR spectrum of Compound 1 tosylate salt Type A.
FIG. 13 shows the Dynamic Vapor Sorption (DVS) plot of Compound 1 tosylate salt Type A.
FIG. 14 shows the X-Ray Powder Diffraction (XRPD) pattern of Compound 1 tosylate salt Type B.
FIG. 15 shows the Thermogravimetric Analysis (TGA) thermogram and Differential Scanning Calorimetry (DSC) thermogram of Compound 1 tosylate salt Type B.
FIG. 16 shows the 1H NMR spectrum of Compound 1 tosylate salt Type B.
DETAILED DESCRIPTION
While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers.
Compound 1
Compound 1 is (2R) -2- (2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2-fluoroacetamido) -2- (pyrimidin-5-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide:  (Compound 1) . In some embodiments, Compound 1 is in the form of a freebase. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is in the form of a tosylate salt. In some embodiments, Compound 1 is in the form of a co-crystal.
Solid State Form of Compound 1
In one aspect, provided herein is a solid state form of (2R) -2- (2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2-fluoroacetamido) -2- (pyrimidin-5-yl) -N- (tetrahydro-2H-pyran-4- yl) propanamide:  (Compound 1) or a pharmaceutically acceptable salt thereof.
In some embodiments, the solid state form is a crystalline form.
In some embodiments, the solid state form is crystalline Compound 1 freebase. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A, crystalline Compound 1 freebase Type B, or crystalline Compound 1 freebase Type D. In some embodiments, the solid state form is crystalline Compound 1 freebase Type A. In some embodiments, the solid state form is crystalline Compound 1 freebase Type B. In some embodiments, the solid state form is crystalline Compound 1 freebase Type C. In some embodiments, the solid state form is crystalline Compound 1 freebase Type D.
In some embodiments, the solid state form is crystalline Compound 1 tosylate salt. In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type A. In some embodiments, the solid state form is crystalline Compound 1 tosylate salt Type B.
Compound 1 Freebase Type A
Disclosed herein is Compound 1 freebase Type A. In some embodiments, the crystalline form is Compound 1 freebase Type A characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.3 ± 0.2° 2θ as measured using Cu Kα. radiation; or
(c) combinations thereof.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3 as measured using Cu Kα.radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 1 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 9.1 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2°2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ±0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.3 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.1 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 16.9 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
Table 1. X-Ray Powder Diffraction peaks of Compound 1 freebase Type A

Compound 1 Freebase Type B
Disclosed herein is Compound 1 freebase Type B. In some embodiments, the crystalline form is Compound 1 freebase Type B characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 5.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, and 17.2 ± 0.2° 2θ as measured using Cu Kα. radiation; or
(c) combinations thereof.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 4 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 2 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, and 17.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 8.3 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, and 20.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 9.4 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, and 19.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2°2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θ as measured using Cu Kα.radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θas measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θas measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θas measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θas measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ±0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2°2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 5.4 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 14.7 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, and 20.6 ± 0.2° 2θas measured using Cu Kα. radiation.
Table 2. X-Ray Powder Diffraction peaks of Compound 1 freebase Type B

Compound 1 Freebase Type C
Disclosed herein is Compound 1 freebase Type C. In some embodiments, the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 6;
(d) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 52.7 ℃;
(e) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 103.8 ℃;
(f) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 6;
(g) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 0.97%from the onset of heating up to approximately 120.0 ℃; or
(h) combinations thereof.
In some embodiments, the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 6;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 6; or
(e) combinations thereof.
In some embodiments, the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 52.7 ℃;
(c) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 103.8 ℃;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 0.97%from the onset of heating up to approximately 120.0 ℃; or
(e) combinations thereof.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 3 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.1 ± 0.2° 2θ and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.4 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, and 17.6 ± 0.2° 2θ as measured using Cu Kα.radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ±0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ,  12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at seven two peaks selected from 10.4 ± 0.2° 2θ, 10.9 ± 0.2° 2θ, 12.1 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type C, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 6.
In some embodiments of Compound 1 freebase Type C, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 52.7 ℃.
In some embodiments of Compound 1 freebase Type C, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 103.8 ℃.
In some embodiments of Compound 1 freebase Type C, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 6.
In some embodiments of Compound 1 freebase Type C, the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 0.97%from the onset of heating up to approximately 120.0 ℃.
In some embodiments of Compound 1 freebase Type C, the crystalline form is an anhydrate.
In some embodiments of Compound 1 freebase Type C, the crystalline form is hygroscopic with a water uptake of 0.792%observed at 80%RH/25 ℃.
In some embodiments of Compound 1 freebase Type C, the crystalline form is stable.
In some embodiments of Compound 1 freebase Type C, the crystalline form is more stable than Compound 1 freebase Type A, Compound 1 freebase Type B, or Compound 1 freebase Type D.
In some embodiments of Compound 1 freebase Type C, the crystalline form is chemically stable.
In some embodiments of Compound 1 freebase Type C, the crystalline form is thermodynamically stable.
Table 3. X-Ray Powder Diffraction peaks of freebase Type C

Compound 1 Freebase Type D
Disclosed herein is Compound 1 freebase Type D. In some embodiments, the crystalline form is Compound 1 freebase Type D characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 9 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 5.0 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation; or
(c) combinations thereof.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 9 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 4 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.0 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.0 ± 0.2° 2θ and 19.8 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 17.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2°2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα.radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 freebase Type D, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 5.0 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 11.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.8 ± 0.2° 2θ, and 20.3 ±0.2° 2θ as measured using Cu Kα. radiation.
Table 4. X-Ray Powder Diffraction peaks of Compound 1 freebase Type D

Compound 1 Tosylate salt Type A
Disclosed herein is Compound 1 Tosylate salt Type A. In some embodiments, the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 11;
(d) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 132.7 ℃;
(e) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 11;
(f) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 4.43%from the onset of heating up to approximately 110.0 ℃; or
(g) combinations thereof.
In some embodiments, the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 11;
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 11; or
(e) combinations thereof.
In some embodiments, the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
(b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 132.7 ℃;
(c) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 4.43%from the onset of heating up to approximately 110.0 ℃; or
(d) combinations thereof.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 as measured using Cu Kα.radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 5 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 24.9 ± 0.2° 2θas measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2°2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ±0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ±0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least nine peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 10 peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ±0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 11 peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ±0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least 12 peaks selected from 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 9.7 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.2 ± 0.2° 2θ, 24.9 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type A, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 11.
In some embodiments of Compound 1 Tosylate salt Type A, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 132.7 ℃.
In some embodiments of Compound 1 Tosylate salt Type A, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 11.
In some embodiments of Compound 1 Tosylate salt Type A, the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 4.43%from the onset of heating up to approximately 110.0 ℃.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form is a hydrate.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form has a water uptake of 0.2518%was observed at 80%RH/25 ℃.
In some embodiments of Compound 1 Tosylate salt Type A, the molar ratio of Tosylate to Compound 1 freebase is about 1: 1.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form is stable.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form is more stable than Compound 1 Tosylate salt Type B.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form is chemically stable.
In some embodiments of Compound 1 Tosylate salt Type A, the crystalline form is thermodynamically stable.
Table 5. X-Ray Powder Diffraction peaks of Compound 1 tosylate salt Type A

Compound 1 Tosylate salt Type B
Disclosed herein is Compound 1 Tosylate salt Type B. In some embodiments, the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 14 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 15;
(d) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 137.7 ℃;
(e) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 15;
(f) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 3.03%from the onset of heating up to approximately 110.0 ℃; or
(g) combinations thereof.
In some embodiments, the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 14 as measured using Cu Kα. radiation;
(b) an X-Ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 15; or
(d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 15;
(e) combinations thereof.
In some embodiments, the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
(a) an X-Ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
(b) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having a peak temperature at about 137.7 ℃;
(c) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 3.03%from the onset of heating up to approximately 110.0 ℃; or
(d) combinations thereof.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 14 as measured using Cu Kα.radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 6 as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.1 ± 0.2° 2θ and 23.1 ± 0.2° 2θ as measured using Cu Kα.radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.2 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2°2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least two peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least three peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ,  12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least four peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least five peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least seven peaks selected from 8.1 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
In some embodiments of Compound 1 Tosylate salt Type B, the Differential Scanning Calorimetry (DSC) thermogram is substantially the same as shown in FIG. 15.
In some embodiments of Compound 1 Tosylate salt Type B, the Differential Scanning Calorimetry (DSC) thermogram has an endothermic peak having a peak temperature at about 137.7 ℃.
In some embodiments of Compound 1 Tosylate salt Type B, the Thermogravimetric Thermal Analysis (TGA) thermogram is substantially the same as shown in FIG. 15.
In some embodiments of Compound 1 Tosylate salt Type B, the Thermogravimetric Thermal Analysis (TGA) thermogram exhibits a mass loss of about 3.03%from the onset of heating up to approximately 110.0 ℃.
In some embodiments of Compound 1 Tosylate salt Type B, the crystalline form is a hydrate.
In some embodiments of Compound 1 Tosylate salt Type B, the stoichiometric ratio of acid to freebase is 1.0.
Table 6. X-Ray Powder Diffraction peaks of Compound 1 tosylate salt Type B

Method of Treatment
Disclosed herein is a method of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a compound or a pharmaceutical composition comprising a compound described herein, for example, a compound of Formula (I) . In some embodiments, the coronavirus infection is caused by the SARS-CoV-2 virus. In some embodiments, the coronavirus infection is caused by the MERS-CoV virus. In some embodiments, the coronavirus infection is caused by the SARS-CoV virus. In some embodiments, the coronavirus infection is caused by the HCoV-229E virus. In some embodiments, the coronavirus infection is caused by the HCoV-OC43 virus. In some embodiments, the coronavirus infection is caused by the HCoV-NL63 virus. In some embodiments, the coronavirus infection is caused by the HCoV-HKU1 virus.
In another aspect, provided herein is a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof, comprising administering to the patient a compound or a pharmaceutical composition comprising a compound described herein, for example, a compound of Formula (I) .
In some embodiments, the compound disclosed herein is administered to the subject prophylactically. In some embodiments, the subject is suspected of having a SARS-CoV-2 infection before the SARS-CoV-2 infection is diagnosed.
In some embodiments, the compounds of the present disclosure are administered to the subject until the infection is treated, inhibited, or reduced. In some embodiments, the compounds is administered to the subject until one or more symptoms of the SARS-CoV-2 infection is reduced.
In another aspect, provided herein is a method of inhibiting a viral infection, comprising providing a compound disclosed herein to the infection so as to inhibit the viral infection. In some embodiments, the viral infection is caused by SARS-CoV-2. In some embodiments, the viral infection is caused by MERS-CoV. In some embodiments, the viral infection is caused by SARS-CoV. In some  embodiments the viral infection is caused by HCoV-229E. In some embodiments, the viral infection is caused by HCoV-OC43. In some embodiments, the viral infection is caused by HCoV-NL63. In some embodiments, the viral infection is caused by HCoV-HKU1.
In another aspect, provided herein is a method of inhibiting SARS-CoV-2 by binding with a protein thereof, comprising providing a compound disclosed herein to a SARS-CoV-2 so as to inhibit the SARS-CoV-2. In some embodiments, the SARS-CoV-2 binds to a protease on the SARS-CoV-2. In some embodiments, the compounds disclosed herein bind with a cysteine residue of the main protease, thereby inhibiting the SARS-CoV-2. In some embodiments, the cysteine residue is at position 145 of a main protease. In some embodiments, the protease is 3CL.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
Pharmaceutical Compositions/Formulations
The crystalline forms described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
In another aspect, provided herein are pharmaceutical compositions comprising a crystalline form described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure. Dosing
In certain embodiments, the compositions containing the crystalline form described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.  Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
In any of the aforementioned aspects are further embodiments in which the effective amount of the crystalline form described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
Definitions
Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include” , “includes, ” and “included, ” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
The terms “administer, ” “administering, ” “administration, ” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
The terms “effective amount” or “therapeutically effective amount, ” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
The terms “enhance” or “enhancing, ” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount, ” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
The term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature or pH. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, and even more typically within 3%of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and/or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the disclosure. In the context of the disclosure, when used or whether or not used the word, such as “about, ” it means that within a given value or range of 10%, appropriately within 5%, especially within 1%.
If multiple diffraction patterns are available, then assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks. ” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.
“Characteristic peaks, ” to the extent they exist, are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being  crystalline forms having the same chemical composition) . Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2 °2Θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
The term “preferred orientation” as used herein refers to an extreme case of non-random distribution of the crystallites of a solid state form. In XRPD, the ideal sample is homogenous and the crystallites are randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes will have and equal number of crystallites contributing to it. However, when the solid state form is in a preferred orientation this is not the case. Accordingly, comparing the intensity between a randomly oriented diffraction pattern and a preferred oriented diffraction pattern can look entirely different. Quantitative analysis depending on intensity ratios are greatly distorted by preferred orientation. Careful sample preparation is important for decreasing the incidence of a preferred orientation.
The term “substantially the same, ” as used herein to reference a figure is intended to mean that the figure is considered representative of the type and kind of characteristic data that is obtained by a skilled artisan in view of deviations acceptable in the art. Such deviations may be caused by factors related to sample size, sample preparation, particular instrument used, operation conditions, and other experimental condition variations known in the art. For example, one skilled in the art can appreciate that the endotherm onset and peak temperatures as measured by differential scanning calorimetry (DSC) may vary significantly from experiment to experiment. For example, one skilled in the art can readily identify whether two X-ray diffraction patterns or two DSC thermograms are substantially the same. In some embodiments, when characteristic peaks of two X-ray diffraction patterns do not vary more than ± 0.2° 2-θ, it is deemed that the X-ray diffraction patterns are substantially the same.
As used herein, salts of Compound 1 include compounds where the corresponding acid is in an ionized, non-ionized, associated, or unassociated form. In some embodiments, the corresponding acid is in an ionized and/or associated forms. In some embodiments, the corresponding acid is in a nonionized and/or unassociated forms. Salts of Compound 1 also include mono-acid, di-acid, etc. forms of the salts.
EXAMPLES
The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Example 1: Preparation of Compound 1 starting material
General procedure for preparation of compound INT1
A mixture of SM1 (1.15 g, 9.39 mmol, 1 eq) , SM2 (2 g, 10.33 mmol, 41.22 mL, 1.1 eq) and p-TsOH (243 mg, 1.41 mmol, 0.15 eq) in toluene (60 mL) was degassed and purged with N2 for 3 times, and then the mixture was heated to reflux (135 ℃) for 18 h with removal of water by Dean‐Stark trap under N2 atmosphere. The residue was purified by flash silica gel chromatography (Eluent: EA/petroleum ether = 0～100%) to give INT1 (1.5 g, 48.28%yield) as a yellow solid.
1H NMR (400 MHz, CDCl3) : 9.32 (s, 1H) , 9.29 (s, 2H) , 7.30 -7.27 (m, 1H) , 7.27 -7.25 (m, 1H) , 6.87 -6.80 (m, 2H) , 2.30 (s, 3H) .
General procedure for preparation of compound INT2
To a solution of INT1 (1.5 g, 5.04 mmol, 1 eq) in CF3CH2OH (7 mL) was added SM3 (1.15 g, 6.03 mmol, 59%w/w in MTBE, 1.20 eq) and SM4 (560 mg, 5.04 mmol, 1 eq) . The mixture was stirred at 20 ℃ for 18 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent: EA/petroleum ether = 0～100%) to give the product, which was further purified by prep-HPLC (Xtimate C18 150*40mm*10um; Mobile phase: A:water (FA) B: ACN; Gradient condition: from 28%B to 58%B; Flow rate: 60 mL/min) . The pure fractions were collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to afford INT2 (780 mg, 29.69%yield) as a white solid.
LCMS: Retention time: 0.858 min, (M+H) = 521.2, 5-95AB_220&254_Agilent.
SFC: Retention time: 1.794 min &2.185 min, OD_ETOH_DEA_5_40_28ML_8MIN.
1H NMR (400 MHz, DMSO-d6) : 9.11 -8.97 (m, 1H) , 8.88 -8.78 (m, 2H) , 7.93 -7.74 (m, 1H) , 7.73 -7.63 (m, 1H) , 7.59 -7.44 (m, 1H) , 7.43 -7.32 (m, 2H) , 6.48 -6.19 (m, 1H) , 3.95 -3.77 (m, 3H) , 3.39 -3.34 (m, 2H) , 1.90 -1.66 (m, 4H) , 1.65 -1.41 (m, 3H) .
General procedure for preparation of compound 1
The INT2 (780 mg, 1.50 mmol, 1 eq) was separated by SFC (DAICEL CHIRALPAK AD (250mm*30mm, 10um) ) , Mobile phase: A: Supercritical CO2, B: Neu-ETOH; Isocratic: A: B = 75: 25; Flow rate: 200 mL/min) to afford two fractions.
The residue was lyophilized to afford Compound 1 (780 mg, 29.69%yield) as a white solid. The absolute stereochemistry was determined with a single crystal Xray analysis.
LCMS: Retention time: 1.002 min, (M+H) =521.0, 10-80AB_2min_220&254.
HPLC: Retention time: 8.486 min, 10-80AB_15min. lcm.
SFC: Retention time: 1.803 min, OD_ETOH_DEA_5_40_28ML_8MIN.
1H NMR (400 MHz, DMSO-d6) : 9.05 (s, 1H) , 8.84 (s, 2H) , 7.84 (d, J = 7.6 Hz, 1H) , 7.76 (d, J = 8.0 Hz, 1H) , 7.46 (d, J = 8.4 Hz, 1H) , 7.43 -7.34 (m, 2H) , 6.52 -6.25 (m, 1H) , 4.00 -3.78 (m, 3H) , 3.39 -3.33 (m, 2H) , 1.77 -1.66 (m, 4H) , 1.66 -1.42 (m, 3H) .
1H NMR (400 MHz, CD3OD) : 9.05 (s, 1H) , 8.93 (s, 2H) , 7.78 -7.65 (m, 1H) , 7.48 -7.39 (m, 2H) , 7.38 -7.31 (m, 1H) , 6.38 -6.06 (m, 1H) , 4.12 -3.91 (m, 3H) , 3.49 (t, J = 12.0 Hz, 2H) , 1.91 -1.77 (m, 5H) , 1.71 -1.52 (m, 2H) .
19F NMR (376 MHz, DMSO-d6) : -25.06 (s, 2F) , -142.18 (br s, 1F) .
19F NMR (376 MHz, CD3OD) : -27.35 (br s, 2F) , -145.36 (s, 1F) .
Characterization of starting material
Compound 1obtained from example 1 used as starting material was characterized by XRPD, TGA, and DSC. The XRPD pattern is shown in FIG. 1, which shows that the sample was weakly crystalline. The TGA/DSC curves in FIG. 2 shows a weight loss of 1.10%when heated to 150 ℃ and two endotherms at 57.8 and 77.5 ℃ (peak temperature) .
Example 2: In vitro assay (SARS-CoV-2 Mpro enzymatic assay)
The C-His6-tagged SARS-CoV-2 MPRO (NC_045512) was cloned, expressed in E. coli, and purified by WuXi. The substrate of Dabcyl-KTSAVLQ∥SGFRKME- (Edans) was synthesized by Genscript. The assay buffer contained 20 mM of Tris-HCl (pH=7.3) , 100 mM of NaCl, 1 mM of EDTA, 5 mM of TCEP and 0.1%BSA. The final concentrations of the Mpro protein and substrate were 25 nM and 25 μM, respectively, in the MPRO enzymatic assay. Reference compound GC376 was provided by WuXi AppTec and was included in each plate to ensure assay robustness. Test compounds were tested at single dose or 10 doses titration, in duplicate. Compounds were added to an assay plate (384w format) using ECHO, in duplicate wells. The final concentration is 10 μM for the single dose experiment. As for the full dose response experiment, samples were 3-fold serially diluted starting from 25μM for 10 doses and added to an assay plate, in duplicate wells. The final concentrations (μM) of each compound was 25, 8.33, 2.778, 0.926, 0.309, 0.103, 0.034, 0.011, 0.0038, and 0.0013. MPRO protein (25 μL, 30 nM) was added to an assay plate containing test compounds using a Multidrop. The test compound and MPRO protein were pre-incubated at RT for 30 min. Then, substrate (5 μL, 150 μM) was added to an assay plate. For 100%inhibition controls (HPE, high percent effect) , 1 μM of GC376 was added. For no  inhibition controls (ZPE, zero percent effect) , the same volume of DMSO was added. The final DMSO concentration was 1%. Each activity testing point had a relevant background control without the enzyme to remove the fluorescence interference of the compound. After 60 min incubation at 30 ℃, the fluorescence signal (RFU) was detected using a microplate reader M2e (SpectraMax) at Ex/Em=340nm/490nm.
The inhibition activity was calculated using the formula below, IC50 values were calculated using the Inhibition%data.
Inhibition%= ( (CPD - BGHPE) - (ZPE - BGZPE) ) / ( (HPE - BGHPE) - (ZPE - BGZPE) ) × 100
where, HPE is high percent effect controls (1 μM of GC376 + enzyme + substrate) ; ZPE is zero percent effective controls (enzyme + substrate, no compound) ; CPD is compound activity testing wells (compound + enzyme + substrate; and BG is background control wells (no enzyme) .
IC50 values of compounds were calculated with the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response -variable slope (four parameters) . Representative biochemical data is presented in the table below.
IC50 (nM) : 0<A≤100; 100<B≤1, 000; 1, 000<C≤10, 000; 10, 000<D
Example 3: Polymorph Screening
Example 3a: Preparation of freebase Type A
501.6 mg Compound 1 starting material was weighed into a 20-mL vial. 5 mL IPA was added into the vial to form a suspension. Let the slurry stand for ～1 day. The wet sample was tested by XRPD (covered with Type C films) as shown in FIG. 3 and Table 1.
Example 3b: Preparation of Freebase Type B
About 20 mg of Compound 1 starting material was added into a 20-mL glass vial and dissolved with 2-MeTHF to obtain a clear solution. The solution was magnetically stirred with addition of n-heptane at RT until precipitates appeared. The obtained precipitates were air dried for XRPD analysis as shown in FIG. 4 and Table 2. Freebase Type B was speculated to be a metastable form.
Example 3c: Preparation of Freebase Type C
About 20 mg of Compound 1 starting material was suspended in 0.5 mL MTBE/n-Heptane (v:v, 1: 4) . After the suspension was stirred magnetically at RT for 5 days, the remaining solids were isolated by centrifugation and air dried at RT before characterization.
Characterization of Freebase Type C
The XRPD pattern was shown in FIG. 5 and Table 3. The TGA/DSC curves in FIG. 6 showed a weight loss of 0.97%when heated to 120 ℃ and two endotherms at 52.7 and 103.8 ℃ (peak temperature) . 1H NMR result was shown in FIG. 7 showing that no signal of residual MTBE or n- heptane was detected. Compound 1 freebase Type C was speculated as an anhydrate. DVS plot in FIG. 8 showed that in the sorption curve from 0%RH to 95%RH, a water uptake of 0.792%was observed at 80%RH/25 ℃, indicating that freebase Type C was slightly hygroscopic
Example 3d: Preparation of Freebase Type D
Freebase Type D was only observed via heating freebase Type C to 60 ℃ under N2 protection in VT XRPD, which was stable and converted back to freebase Type C after cooling to 30 ℃. Therefore, freebase Type D was speculated to be a metastable anhydrate form. The XRPD pattern is shown in FIG. 9 and Table 4.
Example 3e: Preparation of Tosylate Type A
Tosylate Type A was obtained by slurrying 300 mg of Compound 1 starting material and 1.0 eq.p-toluenesulfonic acid monohydrate in 6 mL IPAc at RT for 6 days. The solids were centrifuged and vacuum dried at RT overnight before characterization.
Characterization of Tosylate Type A
The XRPD pattern was shown in FIG. 10 and Table 5. TGA/DSC curves in FIG. 11 showed a weight loss of 4.43%when heated to 110 ℃ and one endotherm at 132.7 ℃ (peak temp. ) . 1H NMR result in FIG. 12 showed that the molar ratio of acid/FB was 1.0, and no obvious residual IPAc was observed. Tosylate Type A was speculated as a hydrate. DVS plot in FIG. 13 showed that in the sorption curve from 0%RH to 95%RH, a water uptake of 0.2518%was observed at 80%RH/25 ℃.
Example 3f: Preparation of Tosylate Type B
Tosylate Type B was obtained by slurrying 300 mg of Compound 1 starting material and 1.0 eq.p-toluenesulfonic acid monohydrate in 7 mL DCM at RT for 6 days. The solids were centrifuged and vacuum dried at RT overnight before characterization.
Characterization of Tosylate Type B
The XRPD overlay was displayed in FIG. 14 and Table 6. TGA/DSC curves in FIG. 15 showed a weight loss of 3.03%up to 110.0 ℃ and one endotherm at 137.7 ℃ (peak temp. ) . 1H NMR result in FIG. 16 showed that the stoichiometric ratio of acid to freebase was 1.0. Tosylate Type B was speculated a hydrate.
Example 4: Slurry Competition Experiments
To further study the inter-conversion relationship of tosylate Form A and Form B, slurry competition experiments were conducted. Detailed procedure for competitive slurry experiments are described as follows: tosylate Type A sample was weighed into an HPLC vial, the corresponding solvents were added to prepare suspensions at RT. After slurry for 1～2 hrs, the suspension was filtered through a 0.45 μm PTFE membrane to obtain a saturated solution. ～5 mg of tosylate Type A and tosylate Type B were weighed into a new HPLC vial and 0.5 mL of pre-saturated solution was added. The mixtures were slurried at RT.
The results of competitive slurry experiments are summarized in table 7. After RT slurry in IPAc for 3 days, the mixture of tosylate Type A+B converted to tosylate Type A; after RT slurry in  MTBE the mixture converted to tosylate Type A + extra peaks. Thus tosylate Type A was more stable than tosylate Type B under tested condition.
Table 7: Summary of competitive slurry experiments
Instrument and methods
For XRPD analysis, a PANalytical Empyrean and X’ Pert3 X-ray powder diffract meter was used. The XRPD parameters used are listed in Table 8.
Table 8: Parameters for XRPD test
TGA data was collected using a TA Q5000/Discovery TGA 5500 from TA Instruments. DSC was performed using a Discovery DSC 2500 from TA Instruments. Detailed parameters used are listed in Table 9.
Table 9: Parameters for TGA and DSC test

Claims (29)

  1. A solid state form of (2R) -2- (2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2-fluoroacetamido) -2- (pyrimidin-5-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide:
    or a pharmaceutically acceptable salt thereof.
  2. The solid state form of claim 1, wherein the solid state form is a crystalline form.
  3. The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 freebase Type A, crystalline Compound 1 freebase Type B, or crystalline Compound 1 freebase Type D.
  4. The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 freebase Type C.
  5. The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 tosylate salt Type A.
  6. The solid state form of claim 1 or 2, wherein the solid state form is crystalline Compound 1 tosylate salt Type B.
  7. The crystalline form of claim 2, wherein the crystalline form is Compound 1 freebase Type C characterized as having at least one of the following properties:
    (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 5 as measured using Cu Kα. radiation;
    (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
    (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 6;
    (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 6; or
    (e) combinations thereof.
  8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 3 as measured using Cu Kα. radiation.
  9. The crystalline form of claim 7 or 8, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 10.9 ± 0.2° 2θ, 15.0 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
  10. The crystalline form of any one of claims 7-9, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.1 ± 0.2° 2θ and 21.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
  11. The crystalline form of any one of claims 7-10, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.4 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, and 17.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
  12. The crystalline form of claim 2, wherein the crystalline form is Compound 1 Tosylate salt Type A characterized as having at least one of the following properties:
    (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 10 as measured using Cu Kα. radiation;
    (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation;
    (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 11;
    (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 11; or
    (e) combinations thereof.
  13. The crystalline form of claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 5 as measured using Cu Kα. radiation.
  14. The crystalline form of claim 12 or 13, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 9.7 ± 0.2° 2θ, 18.2 ± 0.2° 2θ, and 24.2 ± 0.2° 2θ as measured using Cu Kα. radiation.
  15. The crystalline form of any one of claims 12-14, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 7.8 ± 0.2° 2θ, 8.6 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, and 24.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
  16. The crystalline form of any one of claims 12-15, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 17.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, and 27.6 ± 0.2° 2θ as measured using Cu Kα. radiation.
  17. The crystalline form of any one of claims 12-16, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 16.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, and 25.9 ± 0.2° 2θ as measured using Cu Kα. radiation.
  18. The crystalline form of any one of claims 12-17, wherein the crystalline form is a hydrate.
  19. The crystalline form of claim 2, wherein the crystalline form is Compound 1 Tosylate salt Type B characterized as having at least one of the following properties:
    (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 14 as measured using Cu Kα. radiation;
    (b) an X-Ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation;
    (c) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG. 15;
    (d) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG. 15; or
    (e) combinations thereof.
  20. The crystalline form of claim 19, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 6 as measured using Cu Kα. radiation.
  21. The crystalline form of claim 19 or 20, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks at 8.1 ± 0.2° 2θ, 16.6 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ as measured using Cu Kα. radiation.
  22. The crystalline form of any one of claims 19-21, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 10.1 ± 0.2° 2θ and 23.1 ± 0.2° 2θ as measured using Cu Kα.radiation.
  23. The crystalline form of any one of claims 19-22, wherein the X-ray powder diffraction (XRPD) pattern further comprises peaks at 12.2 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ as measured using Cu Kα. radiation.
  24. The crystalline form of any one of claims 19-23, wherein the crystalline form is a hydrate.
  25. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of any one of claims 2-24 and a pharmaceutically acceptable excipient.
  26. A method of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a crystalline form of any one of claims 2-24 or the pharmaceutical composition of claim 25.
  27. A method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof, comprising administering to the patient a crystalline form of any one of claims 2-24 or the pharmaceutical composition of claim 25.
  28. The method of claim 26 or 27, wherein the crystalline form or the pharmaceutical composition is administered to the patient until the infection is reduced or eliminated.
  29. The method of claim 26 or 27, wherein the method comprises treating one or more symptoms of SARS-CoV-2 in the patient in need thereof.
PCT/CN2024/089801 2023-04-26 2024-04-25 Crystalline sars-cov-2 inhibitor and uses thereof Pending WO2024222796A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170313685A1 (en) * 2016-04-28 2017-11-02 Purdue Research Foundation Broad-spectrum non-covalent coronavirus protease inhibitors
WO2021219089A1 (en) * 2020-04-30 2021-11-04 Insilico Medicine Ip Limited Sars-cov-2 inhibitors having covalent modifications for treating coronavirus infections
WO2022119756A1 (en) * 2020-12-04 2022-06-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for inhibiting m pro protease activity and for preventing and treating sars-cov-2 infection
WO2023078238A1 (en) * 2021-11-02 2023-05-11 Insilico Medicine Ip Limited Sars-cov-2 inhibitors for treating coronavirus infections
WO2023078231A1 (en) * 2021-11-02 2023-05-11 Insilico Medicine Ip Limited Sars-cov-2 inhibitors for treating coronavirus infections

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170313685A1 (en) * 2016-04-28 2017-11-02 Purdue Research Foundation Broad-spectrum non-covalent coronavirus protease inhibitors
WO2021219089A1 (en) * 2020-04-30 2021-11-04 Insilico Medicine Ip Limited Sars-cov-2 inhibitors having covalent modifications for treating coronavirus infections
WO2022119756A1 (en) * 2020-12-04 2022-06-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for inhibiting m pro protease activity and for preventing and treating sars-cov-2 infection
WO2023078238A1 (en) * 2021-11-02 2023-05-11 Insilico Medicine Ip Limited Sars-cov-2 inhibitors for treating coronavirus infections
WO2023078231A1 (en) * 2021-11-02 2023-05-11 Insilico Medicine Ip Limited Sars-cov-2 inhibitors for treating coronavirus infections

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