WO2016044576A1 - Sels, co-cristaux, formes amorphes, et formes cristallines d'un inhibiteur d'arginine méthyltransférase - Google Patents

Sels, co-cristaux, formes amorphes, et formes cristallines d'un inhibiteur d'arginine méthyltransférase Download PDF

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WO2016044576A1
WO2016044576A1 PCT/US2015/050659 US2015050659W WO2016044576A1 WO 2016044576 A1 WO2016044576 A1 WO 2016044576A1 US 2015050659 W US2015050659 W US 2015050659W WO 2016044576 A1 WO2016044576 A1 WO 2016044576A1
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crystalline form
compound
thermogram
theta
dsc
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PCT/US2015/050659
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English (en)
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Edward James Olhava
Brett Franklin TRUITT
Richard Chesworth
Lorna Helen Mitchell
Gideon Shapiro
Kerren Kalai SWINGER
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Epizyme, Inc.
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Publication of WO2016044576A1 publication Critical patent/WO2016044576A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings

Definitions

  • Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
  • epigenetic regulation is mediated by selective and reversible modification (e.g. , methylation) of DNA and proteins (e.g. , histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
  • methylation e.g. , methylation
  • proteins e.g. , histones
  • methyltransferases e.g., arginine methyltransferases
  • many of which are associated with specific genetic alterations that can cause human disease are associated with specific genetic alterations that can cause human disease.
  • methyltransferases play a role in diseases such as proliferative disorders, autoimmune disorders, muscular disorders, vascular disorders, metabolic disorders, and neurological disorders.
  • diseases such as proliferative disorders, autoimmune disorders, muscular disorders, vascular disorders, metabolic disorders, and neurological disorders.
  • small molecules that are capable of inhibiting the activity of arginine methyltransferases.
  • Embodiments B 1-B9 are Embodiments B 1-B9:
  • Embodiment B 1. A crystalline form A (Form A) of compound 133 of the formula:
  • Embodiment B2 The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising three or more
  • Embodiment B3 The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising four or more
  • Embodiment B4 The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising five or more
  • Embodiment B5. The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 16.68, 17.08, 19.00, 14.52, 15.73, 8.71, 17.76, 5.59, and 19.88.
  • Embodiment B6 The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 16.68, 17.08, 19.00, 14.52, 15.73, 8.71, 17.76, 5.59, and 19.88.
  • Embodiment B7 The crystalline form A of Embodiment Bl, wherein the crystalline form A is characterized by an XRPD pattern comprising eight or more
  • Embodiment B8 The crystalline form A of any one of embodiments B1-B7, wherein the crystalline form A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 118.3 + 2 °C.
  • Embodiment B9. The crystalline form A of any one of embodiments B1-B7, wherein the crystalline form A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature (r m ) of 118.7 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiments C1-C9 are Embodiments C1-C9:
  • Embodiment CI A crystalline form H-A (Form H-A) of compound 133, wherein the crystalline form H-A comprises hydrogen chloride (HC1).
  • Embodiment C2 The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C3 The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C4 The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C5. The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising six or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C6 The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C7 The crystalline form H-A of Embodiment CI, wherein the crystalline form H-A is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.46, 18.48, 6.98, 24.33, 17.52, 17.15, 14.07, 15.80, and 20.23.
  • Embodiment C8 The crystalline form H-A of any one of embodiments C1-C7, wherein the crystalline form H-A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature (r m ) of 200.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment C9 The crystalline form H-A of any one of embodiments C1-C7, wherein the crystalline form H-A is characterized by a differential scanning calorimetry
  • thermogram comprising an endotherm comprising an onset temperature (r m ) of about
  • Embodiments D1-D9 are Embodiments D1-D9:
  • Embodiment Dl A crystalline form H-B (Form H-B) of compound 133, wherein the crystalline form H-B comprises hydrogen chloride (HC1).
  • Embodiment D2 The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D3 The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D4 The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D5. The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D6 The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D7 The crystalline form H-B of Embodiment Dl, wherein the crystalline form H-B is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 15.85, 19.63, 6.16, 18.31, 31.63, 16.07, 5.66, 15.56, and 20.69.
  • Embodiment D8 The crystalline form H-B of any one of embodiments D1-D7, wherein the crystalline form H-B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature (r m ) of 141.4 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment D9 The crystalline form H-B of any one of embodiments D1-D7, wherein the crystalline form H-B is characterized by a differential scanning calorimetry
  • thermogram comprising an endotherm comprising an onset temperature (r m ) of about
  • Embodiments E1-E9 are Embodiments E1-E9:
  • Embodiment El A crystalline form S-A (Form S-A) of compound 133, wherein the crystalline form S-A comprises sulfuric acid.
  • Embodiment E2 The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E3 The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E4 The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E5. The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E6 The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E7 The crystalline form S-A of Embodiment El, wherein the crystalline form S-A is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 17.96, 17.67, 22.37, 14.51, 21.83, 23.66, 7.39, 15.09, and 15.63.
  • Embodiment E8 The crystalline form S-A of any one of embodiments E1-E7, wherein the crystalline form S-A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature (r m ) of 193.2 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment E9 The crystalline form S-A of any one of embodiments E1-E7, wherein the crystalline form S-A is characterized by a differential scanning calorimetry
  • thermogram comprising an endotherm comprising an onset temperature (r m ) of about
  • Embodiments Fl-Fl 1 are Embodiments Fl-Fl 1:
  • Embodiment Fl A crystalline form S-B (Form S-B) of compound 133, wherein the crystalline form S-B comprises sulfuric acid.
  • Embodiment F2 The crystalline form S-B of Embodiment Fl, wherein the crystalline form S-B is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58.
  • Embodiment F3 The crystalline form S-B of Embodiment Fl, wherein the crystalline form S-B is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58.
  • Embodiment F4 The crystalline form S-B of Embodiment Fl, wherein the crystalline form S-B is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58.
  • Embodiment F5. The crystalline form S-B of Embodiment Fl, wherein the crystalline form S-B is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58.
  • Embodiment F6 The crystalline form S-B of Embodiment Fl, wherein the crystalline form S-B is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58. [0052] Embodiment F7.
  • the crystalline form S-B of Embodiment Fl wherein the crystalline form S-B is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 4.92, 9.94, 22.08, 17.70, 19.87, 15.66, 26.68, 16.79, and 21.58.
  • Embodiment F8 The crystalline form S-B of any one of embodiments F1-F7, wherein the crystalline form S-B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 202.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment F9 The crystalline form S-B of any one of embodiments F1-F7, wherein the crystalline form S-B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of about 30.8 + 2 °C and another endotherm comprising a T m of about 202.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment F10 The crystalline form S-B of any one of embodiments F1-F7, wherein the crystalline form S-B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 204.7 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment Fl 1.
  • DSC differential scanning calorimetry
  • Embodiment II A crystalline form M (Form M) of compound 133, wherein the crystalline form M comprises maleic acid.
  • Embodiment 12 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.14, 25.67, 6.26, 23.34, 12.70, 16.47, 17.53, 22.40, and 10.08.
  • Embodiment 13 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising four or more
  • Embodiment 14 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.14, 25.67, 6.26, 23.34, 12.70, 16.47, 17.53, 22.40, and 10.08.
  • Embodiment 15 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.14, 25.67, 6.26, 23.34, 12.70, 16.47, 17.53, 22.40, and 10.08.
  • Embodiment 16 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.14, 25.67, 6.26, 23.34, 12.70, 16.47, 17.53, 22.40, and 10.08.
  • Embodiment 17 The crystalline form M of Embodiment II, wherein the crystalline form M is characterized by an XRPD pattern comprising eight or more
  • Embodiment 18 The crystalline form M of any one of embodiments 11-17, wherein the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 162.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment 19 The crystalline form M of any one of embodiments 11-17, wherein the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of about 52.3 + 2 °C and another endotherm comprising a T m of about 162.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiments J1-J9 are Embodiments J1-J9:
  • Embodiment Jl A crystalline form F-A (Form F-A) of compound 133, wherein the crystalline form F-A comprises fumaric acid.
  • Embodiment J2 The crystalline form F-A of Embodiment Jl, wherein the crystalline form F-A is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29.
  • Embodiment J3 The crystalline form F-A of Embodiment Jl, wherein the crystalline form F-A is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29. [0071] Embodiment J4.
  • the crystalline form F-A of Embodiment Jl wherein the crystalline form F-A is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29.
  • Embodiment J5. The crystalline form F-A of Embodiment Jl, wherein the crystalline form F-A is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29.
  • Embodiment J6 The crystalline form F-A of Embodiment Jl, wherein the crystalline form F-A is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29.
  • Embodiment J7 The crystalline form F-A of Embodiment Jl, wherein the crystalline form F-A is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.88, 14.61, 15.61, 20.24, 10.01, 12.63, 23.32, 19.54, and 18.29.
  • Embodiment J8 The crystalline form F-A of any one of embodiments J1-J7, wherein the crystalline form F-A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 162.1 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment J9 The crystalline form F-A of any one of embodiments J1-J7, wherein the crystalline form F-A is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 160.7 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiments K1-K9 are Embodiments K1-K9:
  • Embodiment Kl A crystalline form F-B (Form F-B) of compound 133, wherein the crystalline form F-B comprises fumaric acid.
  • Embodiment K2 The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K3 The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K4 The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K5. The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K6 The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K7 The crystalline form F-B of Embodiment Kl, wherein the crystalline form F-B is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 3.22, 26.46, 13.14, 18.14, 16.55, 6.50, 23.09, 24.10, and 19.68.
  • Embodiment K8 The crystalline form F-B of any one of embodiments K1-K7, wherein the crystalline form F-B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising a peak temperature (r max ) of about 161.1 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment K9 The crystalline form F-B of any one of embodiments K1-K7, wherein the crystalline form F-B is characterized by a DSC thermogram comprising an endotherm comprising a peak temperature (r max ) of about 155.6 + 2 °C and another endotherm comprising a max of about 161.1 + 2 °C.
  • Embodiments L1-L8 are Embodiments L1-L8:
  • Embodiment LI A crystalline form F-C (Form F-C) of compound 133, wherein the crystalline form F-C comprises fumaric acid.
  • Embodiment L2 The crystalline form F-C of Embodiment LI, wherein the crystalline form F-C is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27. [0090] Embodiment L3.
  • the crystalline form F-C of Embodiment LI wherein the crystalline form F-C is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27.
  • Embodiment L4 The crystalline form F-C of Embodiment LI, wherein the crystalline form F-C is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27.
  • Embodiment L5. The crystalline form F-C of Embodiment LI, wherein the crystalline form F-C is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27.
  • Embodiment L6 The crystalline form F-C of Embodiment LI, wherein the crystalline form F-C is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27.
  • Embodiment L7 The crystalline form F-C of Embodiment LI, wherein the crystalline form F-C is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 24.40, 27.52, 11.85, 3.17, 8.96, 5.91, 23.87, 36.49, and 18.27.
  • Embodiment L8 The crystalline form F-C of any one of embodiments L1-L7, wherein the crystalline form F-C is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 166.8 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiments M1-M7 are Embodiments M1-M7:
  • Embodiment Ml A crystalline form T-A (Form T-A) of compound 133, wherein the crystalline form T-A comprises L-tartaric acid.
  • Embodiment M2 The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiment M3 The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiment M4 The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiment M5. The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiment M6 The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiment M7 The crystalline form T-A of Embodiment Ml, wherein the crystalline form T-A is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 22.75, 39.11, 20.60, 36.86, 36.66, 18.84, 25.51, 28.70, and 22.02.
  • Embodiments P1-P10 are Embodiments P1-P10:
  • Embodiment PI A crystalline form Ma (Form Ma) of compound 133, wherein the crystalline form Ma comprises L-malic acid.
  • Embodiment P2 The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising three or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P3 The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising four or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P4 The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising five or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P5. The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising six or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P6 The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P7 The crystalline form Ma of Embodiment PI, wherein the crystalline form Ma is characterized by an XRPD pattern comprising eight or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 19.67, 9.54, 17.25, 15.13, 13.10, 16.69, 17.84, 20.46, and 13.35.
  • Embodiment P8 The crystalline form Ma of any one of embodiments P1-P7, wherein the crystalline form Ma is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 138.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment P9 The crystalline form Ma of any one of embodiments P1-P7, wherein the crystalline form Ma is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 137.0 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment P10 The crystalline form Ma of any one of embodiments P1-P7, wherein the crystalline form Ma is characterized by a DSC thermogram comprising an endotherm comprising an onset temperature ( m ) of about 32.3 + 2 °C and another endotherm comprising a T m of about 137.0 + 2 °C.
  • Embodiments Q1-Q9 are Embodiments Q1-Q9:
  • Embodiment Ql A crystalline form N (Form N) of compound 133, wherein the crystalline form N comprises nicotinic acid.
  • Embodiment Q2 The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising three or more
  • Embodiment Q3 The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising four or more
  • Embodiment Q4 The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising five or more
  • Embodiment Q5. The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 7.19, 18.29, 17.95, 11.72, 15.79, 23.58, 18.71, 29.27, and 30.41.
  • Embodiment Q6 The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising seven or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 7.19, 18.29, 17.95, 11.72, 15.79, 23.58, 18.71, 29.27, and 30.41.
  • Embodiment Q7 The crystalline form N of Embodiment Ql, wherein the crystalline form N is characterized by an XRPD pattern comprising eight or more
  • Embodiment Q8 The crystalline form N of any one of embodiments Q1-Q7, wherein the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 158.5 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiment Q9 The crystalline form N of any one of embodiments Q1-Q7, wherein the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 158.0 + 2 °C.
  • DSC differential scanning calorimetry
  • Embodiments R1-R8 are Embodiments R1-R8:
  • Embodiment Rl A crystalline form B (Form B) of compound 133, wherein the crystalline form B comprises benzoic acid.
  • Embodiment R2 The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising three or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 18.34, 7.16, 15.49, 17.91, 18.54, 23.64, 11.75, 21.61, and 22.42.
  • Embodiment R3 The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising four or more
  • Embodiment R4 The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising five or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 18.34, 7.16, 15.49, 17.91, 18.54, 23.64, 11.75, 21.61, and 22.42.
  • Embodiment R5. The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising six or more characteristic peaks, expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 18.34, 7.16, 15.49, 17.91, 18.54, 23.64, 11.75, 21.61, and 22.42.
  • Embodiment R6 The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising seven or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 18.34, 7.16, 15.49, 17.91, 18.54, 23.64, 11.75, 21.61, and 22.42.
  • Embodiment R7 The crystalline form B of Embodiment Rl, wherein the crystalline form B is characterized by an XRPD pattern comprising eight or more
  • characteristic peaks expressed in degrees 2-theta (+ 0.2), independently selected from the group consisting of 18.34, 7.16, 15.49, 17.91, 18.54, 23.64, 11.75, 21.61, and 22.42.
  • Embodiment R8 The crystalline form B of any one of embodiments R1-R7, wherein the crystalline form B is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm comprising an onset temperature ( m ) of 156.6 + 2 °C.
  • DSC differential scanning calorimetry
  • Figure 1A depicts an exemplary X-Ray Powder Diffraction (XRPD) pattern of Form A.
  • Figure IB depicts an exemplary differential scanning calorimetry (DSC) thermogram of Form A (bottom-left curve) and a thermogravimetric analysis (TGA) thermogram of Form A (top-right curve).
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figure 1C depicts another exemplary DSC thermogram of Form A (bottom-left curve) and a thermogravimetric analysis (TGA) thermogram of Form A (top-right curve).
  • Figure ID shows exemplary thermodynamic solubilities of Form A in select solvents at 25 + 3 °C.
  • IPA isopropanol.
  • ACN acetonitrile.
  • MTBE methyl-iert-butyl ether.
  • IP Ac isopropyl acetate.
  • MIBK methyl isobutyl ketone.
  • THF tetrahydrofuran.
  • 2-MeTHF 2- methyl-tetrahydrofuran.
  • NMP N-methyl-2-pyrrolidone.
  • DMSO dimethyl sulfoxide.
  • DMAc dimethylacetamide .
  • Figure 2 shows the pH and state of mixtures of a select solid form and water or a bio-relevant medium (e.g., simulated gastric fluid (SGF), fed state simulated intestinal fluid (FeSSIF), or fasted state simulated intestinal fluid (FaSSIF)) at room temperature.
  • a bio-relevant medium e.g., simulated gastric fluid (SGF), fed state simulated intestinal fluid (FeSSIF), or fasted state simulated intestinal fluid (FaSSIF)
  • Figure 3 A depicts exemplary XRPD patterns of Form H-A and Form H-B.
  • Figure 3B depicts an exemplary DSC thermogram of Form H-A (bottom-left curve) and a TGA thermogram of Form H-A (top-right curve).
  • Figure 3C depicts an exemplary DSC thermogram of Form H-B (bottom- left curve) and a TGA thermogram of Form H-B (top-right curve).
  • Figure 4A depicts exemplary XRPD patterns of Form S-A and Form S-B.
  • Figure 4B depicts an exemplary DSC thermogram of Form S-A (bottom-left curve) and a TGA thermogram of Form S-A (top-right curve).
  • Figure 4C depicts an exemplary DSC thermogram of Form S-B (bottom-left curve) and a TGA thermogram of Form S-B (top-right curve).
  • Figure 4D depicts an exemplary dynamic vapor sorption (DVS) isotherm of a scaled-up sample of Form S-B.
  • Form S-B was highly hygroscopic and deliquescent at high relative humidity.
  • Temp temperature.
  • RH relative humidity.
  • Ref reference.
  • Figure 4E depicts an exemplary overlay of XRPD patterns of a sample of Form S-
  • Form S-B was converted to an amorphous form (e.g., Form S-C) after the DVS measurement.
  • Figure 4F depicts an exemplary overlay of XRPD patterns of Form S-B.
  • Figure 4G depicts an exemplary DSC thermogram (bottom-left curve) and TGA thermogram (top-right curve) of a sample of Form S-B.
  • Figure 4H depicts other exemplary XRPD patterns of Form S-A and Form S-B.
  • Figure 5A depicts an exemplary XRPD pattern of Form M.
  • Figure 5B depicts an exemplary DSC thermogram of Form M (bottom- left curve) and a TGA thermogram of Form M (top-right curve).
  • Figure 6 A depicts exemplary XRPD patterns of Form F-A, Form F-B, and Form F-C.
  • Figure 6B depicts an exemplary DSC thermogram of Form F-A (bottom- left curve) and a TGA thermogram of Form F-A (top-right curve).
  • Figure 6C depicts an exemplary proton nuclear magnetic resonance ( 1 H-NMR) spectrum of a sample of Form F-A. The molar ratio of fumaric acid to compound 133 in Form F-A was calculated to be about 1.1: 1 according to the 1H-NMR spectrum.
  • Figure 6D depicts an exemplary DSC thermogram of Form F-B (bottom- left curve) and a TGA thermogram of Form F-B (top-right curve).
  • Figure 6E depicts an exemplary DSC thermogram of Form F-C (bottom-left curve) and a TGA thermogram of Form F-C (top-right curve).
  • Figure 6F depicts an exemplary XRPD pattern of a sample of Form F-A. Changes in line- width are likely due to sample size and/or particle size effects. No amorphous content is obvious.
  • Figure 6G depicts an exemplary DSC thermogram (bottom-left curve) and TGA thermogram of a sample of Form F-A (top-right curve).
  • Figure 6H depicts an exemplary overlay of XRPD patterns of a sample of Form F- A before and after being subjected to a DVS measurement.
  • Form F-A was converted to an amorphous form (as evidenced by the presence of halogen) and/or another crystalline after the DVS measurement.
  • Figure 6J depicts an exemplary DVS isotherm of a sample of Form F-A.
  • Form F- A was hygroscopic at high relative humidity.
  • Figure 7 depicts an exemplary XRPD pattern of Form T-A.
  • Figure 8A depicts exemplary XRPD patterns of Form Ma.
  • Figure 8B depicts an exemplary DSC thermogram of Form Ma (bottom-left curve) and a TGA thermogram of Form Ma (top-right curve).
  • Figure 8C depicts an exemplary overlay of XRPD patterns of Form Ma.
  • Figure 8D depicts an exemplary DSC thermogram (bottom-left curve) and TGA thermogram (top-right curve) of a sample of Form Ma.
  • the endothermic peak at about 32.3 °C indicates the loss of solvent, and the endothermic peak at about 137.0 °C indicates melting.
  • Figure 8E depicts an exemplary DVS isotherm of a sample of Form Ma.
  • Form Ma was highly hygroscopic and deliquescent at high relative humidity.
  • Figure 8F depicts an exemplary overlay of XRPD patterns of a sample of Form Ma before and after being subjected to a DVS measurement.
  • Form Ma was converted to an amorphous form after the DVS measurement.
  • Figure 8G depicts an exemplary 1H-NMR spectrum of a sample of Form Ma.
  • the molar ratio of L- malic acid to compound 133 in Form Ma was calculated to be about 1.1: 1 according to the 1H-NMR spectrum.
  • Figure 9 A depicts exemplary XRPD patterns of Form N.
  • Figure 9B depicts an exemplary DSC thermogram of Form N (bottom-left curve) and a TGA thermogram of Form N (top-right curve).
  • Figure 9C depicts an exemplary DVS isotherm of Form N.
  • Form N was hygroscopic and tends to absorb water quickly at high relative humidity.
  • Figure 9D depicts an exemplary 1H-NMR spectrum of Form N.
  • the molar ratio of nicotinic acid to compound 133 in Form N was calculated to be about 1 : 1 according to the 1H-NMR spectrum.
  • Figure 9E depicts an exemplary overlay of XRPD patterns of Form N before and after being subjected to a DVS measurement. No form change was observed from XRPD after the DVS measurement.
  • Figure 9F depicts another exemplary XRPD pattern of Form N.
  • Figure 9G depicts another exemplary DSC thermogram of Form N (bottom-left curve) and a TGA thermogram of Form N (top-right curve).
  • Figure 10 A depicts exemplary XRPD patterns of Form B.
  • Figure 10B depicts an exemplary DSC thermogram of Form B (bottom-left curve) and a TGA thermogram of Form B (top-right curve).
  • Figure IOC depicts an exemplary 1H-NMR spectrum of Form B.
  • the molar ratio of benzoic acid to compound 133 in Form B was calculated to be about 1.1 : 1 according to the 1H-NMR spectrum.
  • Figure 10D depicts another exemplary XRPD pattern of Form B.
  • compositions thereof are useful in treating and/or preventing arginine methyltransferase-mediated disorders (e.g. , proliferative disorders, neurological disorders, autoimmune disorders, vascular disorders, and metabolic disorders).
  • arginine methyltransferase-mediated disorders e.g. , proliferative disorders, neurological disorders, autoimmune disorders, vascular disorders, and metabolic disorders.
  • the present disclosure provides solid forms (e.g. , salts, co-crystals, amorphous forms, and crystalline forms) of compound 133.
  • salts e.g. , hydrochloride salts, sulfates, phosphates, maleates, fumarate, L- tartrates, citrates, L-malates, nicotinates, and benzoates
  • salts e.g. , hydrochloride salts, sulfates, phosphates, maleates, fumarate, L- tartrates, citrates, L-malates, nicotinates, and benzoates
  • the salts described herein may be amorphous or crystalline.
  • the salts may be solvates (e.g. , hydrates, methanolates, isopropanolates, acetone solvates, and THF solvates) or may not contain any solvent.
  • the salts are substantially anhydrous.
  • co-crystals of compound 133 comprise compound 133 and hydrochloride , sulfuric acid, phosphoric acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, L-malic acid, nicotinic acid, or benzoic acid.
  • the co-crystals may be solvates (e.g. , hydrates, methanolates, isopropanolates, acetone solvates, and THF solvates) or may not contain any solvent.
  • the co-crystals are substantially anhydrous.
  • an amorphous form described herein comprises compound 133 and sulfuric acid, phosphoric acid, L-tartaric acid, or citric acid.
  • an amorphous form described herein is Form S-C, Form P, Form T-B, or Form C.
  • the amorphous forms may be solvates (e.g. , hydrates, methanolates, isopropanolates, acetone solvates, and THF solvates) or may not contain any solvent.
  • the amorphous forms are substantially anhydrous.
  • the amorphous forms may be salts or co- crystals.
  • a crystalline form described herein comprises compound 133 and optionally HC1, sulfuric acid, maleic acid, fumaric acid, L-tartaric acid, L-malic acid, nicotinic acid, or benzoic acid.
  • a crystalline form described herein is Form A, From H-A, From H-B, From S-A, From S-B, From M, From F-A, From F-B, From F-C, From T-A, From Ma, Form N, or Form B.
  • the crystalline forms may be solvates (e.g., hydrates, methanolates, isopropanolates, acetone solvates, and THF solvates) or may not contain any solvent. In certain embodiments, the crystalline forms are substantially anhydrous. The crystalline forms may be neat, salts, or co-crystals.
  • the salts, co-crystals, amorphous forms, and crystalline forms described herein may inhibit the activity of an arginine methyltransferase (RMT) (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8).
  • RMT arginine methyltransferase
  • compositions that comprise a salt, co- crystal, amorphous form, or crystalline form described herein.
  • pharmaceutical compositions that comprise a salt, co-crystal, amorphous form, or crystalline form described herein, and optionally a pharmaceutically acceptable excipient.
  • arginine methyltransferase comprising contacting the arginine methyltransferase with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or composition (e.g., pharmaceutical composition) described herein.
  • the RMT may be purified or crude, and may be present in a cell, tissue, or a subject. Thus, such methods encompass inhibition of RMT activity both in vitro and in vivo.
  • the RMT is wild-type.
  • the RMT is overexpressed.
  • the RMT is a mutant.
  • the RMT is in a cell.
  • the RMT is expressed at normal levels in a subject, but the subject would benefit from RMT inhibition (e.g., because the subject has one or more mutations in an RMT substrate that causes an increase in methylation of the substrate with normal levels of RMT).
  • the RMT is in a subject known or identified as having abnormal RMT activity (e.g., overexpression).
  • methods of modulating gene expression in a cell comprising contacting a cell with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • the cell is in vitro. In certain embodiments, the cell is in vivo. In certain embodiments, the cell is in a subject, e.g., a human. [00193] In another aspect, methods of modulating transcription in a cell are provided, the methods comprising contacting a cell with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • an RMT-mediated disorder e.g. , a PRMT1-, PRMT3-, CARM1-, PRMT6-, or PRMT8-mediated disorder
  • the methods comprising administering to a subject suffering from an RMT-mediated disorder an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical
  • the RMT-mediated disorder is a proliferative disorder, such as cancer (e.g. , breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or leukemia).
  • the RMT-mediated disorder is a muscular disorder.
  • the RMT-mediated disorder is an autoimmune disorder.
  • the RMT-mediated disorder is a neurological disorder.
  • the RMT-mediated disorder is a vascular disorder.
  • the RMT-mediated disorder is a metabolic disorder.
  • the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein are also useful for the study of arginine methyltransferases in biological and pathological phenomena, the study of intracellular signal transduction pathways mediated by arginine methyltransferases, and the comparative evaluation of new RMT inhibitors.
  • X refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.
  • the term “about 100” or “about 100.0” refers to between 99.5 and 100.5, between 99 and 101, between 98 and 102, between 97 and 103, between 96 and 104, between 95 and 105, between 92 and 108, or between 90 and 110, inclusive.
  • Y is a characteristic (e.g., anhydrous) refers to a characteristic that is at least 99.5%, at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 92%, or at least 90% the same as Y, unless expressly provided otherwise.
  • room temperature refers to about 25 °C or 25 + 3 °C. In certain embodiments, room temperature is about 25 °C. In certain embodiments, room temperature is 25 + 3 °C (e.g., between 22 and 28 °C, inclusive).
  • salt refers to ionic compounds that result from the neutralization reaction of an acid and a base (e.g. , compound 133).
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge).
  • Salts of the compounds of this invention include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrogen chloride, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, L-tartaric acid, R-tartaric acid, citric acid, succinic acid, fumaric acid, L-malic acid, D-malic acid, or malonic acid, or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrogen chloride, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, L-tartaric acid, R-tartaric acid, citric acid, succinic acid, fumaric acid, L-malic acid, D-malic acid, or malonic acid, or by using other methods known in the art such as ion
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
  • ethanesulfonate formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, L-malate, D-malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1 ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • the salt is a hydrochloride salt, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-malate, nicotinate, or benzoate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • a pharmaceutically acceptable salt of a compound ⁇ e.g., compound 133) is a salt described herein, e.g., a hydrochloride salt, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-malate, nicotinate, or benzoate.
  • solvate refers to a form of a compound ⁇ e.g., compound 133), or a salt or co-crystal thereof, that is associated with a solvent, usually by a solvolysis reaction. This association may include hydrogen bonding.
  • solvents include water, methanol, isopropanol, THF, and acetone.
  • solvates are formed using Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).
  • a compound ⁇ e.g., compound 133), or a salt or co-crystal thereof may be prepared, e.g., in an amorphous or crystalline form, and may be solvated. Suitable solvates include
  • solvates and further include both stoichiometric solvates and non- stoichiometric solvates.
  • the solvate are capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • Solvates includes both solution-phase and isolable solvates.
  • the solvate is a hydrate.
  • the solvate is a methanolate (methanol solvate) or isopropanolate (isopropanol solvate).
  • the solvate is an acetone solvate or THF solvate.
  • stoichiometric solvate refers to a solvate, which comprises a compound
  • non- stoichiometric solvate refers to a solvate, which comprises a compound ⁇ e.g., compound 133), or a salt or co-crystal thereof, and a solvent, wherein the solvent content may vary without major changes in the crystal structure.
  • the amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere.
  • non- stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound, or salt or co-crystal thereof.
  • a portion of the solvent may be removed without significantly disturbing the crystal network, and the resulting solvate can
  • hydrate refers to a compound (e.g., compound 133), or a salt or co- crystal thereof, that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound, or a salt or co-crystal thereof is in a definite ratio to the number of molecules of the compound, or a salt or co-crystal thereof, in the hydrate. Therefore, a hydrate of a compound, or a salt or co-crystal thereof, may be represented, for example, by the general formula R x H 2 0, wherein R is the compound, or salt or co-crystal thereof, and x is a number greater than 0.
  • a given compound, or a salt or co-crystal thereof may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • crystalline refers to a solid form substantially exhibiting three-dimensional order.
  • a crystalline form of a solid is a solid form that is substantially not amorphous.
  • the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.
  • amorphous refers to a form of a solid ("solid form"), the form lacking long-range order.
  • an amorphous form of a solid is a solid form that is substantially not crystalline.
  • the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band comprising a peak at 2 ⁇ of, e.g., between 20 and 70°, inclusive, using CuKa radiation.
  • the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures.
  • the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2 ⁇ of between 20 and 70°, inclusive is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band.
  • the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., compound 133 and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent.
  • At least one of the components is a solvent.
  • a co-crystal comprising compound 133 and an acid is different from a salt formed from compound 133 and the acid.
  • compound 133 is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to compound 133 easily occurs at room temperature.
  • compound 133 is complexed with the acid in a way that proton transfer from the acid to compound 133 does not easily occur at room
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of compound 133.
  • the term "impurity" refers to extraneous matter included in a desired substance (e.g. , a compound (e.g., compound 133), or a salt, solvate, hydrate, co- crystal, amorphous form, or crystalline form thereof).
  • Extraneous matter includes one or more substances that are different from the desired substance.
  • the extraneous matter is undesired extraneous matter.
  • a solvent e.g., water
  • an amorphous form of the compound included in or with the crystalline compound is an impurity.
  • the desired substance is a certain solid form of a compound
  • a different solid form of the compound included in or with the solid form of the compound is an impurity
  • the desired substance is a salt of a compound
  • a different salt of the compound included in or with the salt of the compound is an impurity.
  • substantially free of impurities means that a desired substance does not contain a significant amount of extraneous matter (e.g., undesired extraneous matter). What amount of the extraneous matter constitutes a significant amount depends on the subject matter and is understood in the art.
  • the amount of impurities may be determined using high-performance liquid chromatography (HPLC) with, e.g. , an ultraviolet (UV) detector at, e.g. , about 214 or about 220 nm.
  • HPLC high-performance liquid chromatography
  • UV ultraviolet
  • a desired substance and each impurity are separated after HPLC, and the areas of the peaks of the resulting HPLC chromatogram may be determined.
  • the weight ratio of the amount of an impurity to the amount of a desired substance is the ratio of the peak area of the impurity to the peak area of the desired substance.
  • kinetic solubility refers to the amount of a substance (e.g. , a salt, co- crystal, amorphous form, or crystalline form described herein) that will dissolve in a fluid (e.g., water, simulated gastric fluid (SGF), fed state simulated intestinal fluid (FeSSIF), or fasted state simulated intestinal fluid (FaSSIF)) under given conditions (e.g., temperature, pressure, and agitation) in a period of time less than what is required for an equilibrium between the substance and the solvent to be reached.
  • a fluid e.g., water, simulated gastric fluid (SGF), fed state simulated intestinal fluid (FeSSIF), or fasted state simulated intestinal fluid (FaSSIF)
  • a fluid e.g., water, simulated gastric fluid (SGF), fed state simulated intestinal fluid (FeSSIF), or fasted state simulated intestinal fluid (FaSSIF)
  • a fluid e.g., water, simulated gastric fluid (
  • a "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g. , pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g. , primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • a "patient” refers to a human subject in need of treatment of a disease.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, or a pharmaceutically acceptable salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition thereof, in or on a subject.
  • the terms “in combination” and “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies
  • prophylactic and/or therapeutic agents are administered to a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition"
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • prevention refers to administering a medicament (e.g., compound 133, or a pharmaceutically acceptable salt, co- crystal, amorphous form, crystalline form, or pharmaceutical composition thereof) beforehand to avert or forestall the appearance of one or more symptoms of a disease or disorder.
  • a medicament e.g., compound 133, or a pharmaceutically acceptable salt, co- crystal, amorphous form, crystalline form, or pharmaceutical composition thereof.
  • prevention prevention
  • prevent prevent
  • preventing are not absolute terms. In the medical art these terms are understood to refer to the prophylactic administration of a medicament to substantially diminish the likelihood or seriousness of a condition, or symptom of the condition, and this is the sense intended in this disclosure.
  • condition As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • an "effective amount" of a salt, co-crystal, amorphous form, or crystalline form described herein refers to an amount sufficient to elicit the desired biological response, e.g. , treating a condition.
  • the effective amount of a salt, co-crystal, amorphous form, or crystalline form described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of an inventive compound may provide a therapeutic and/or prophylactic benefit in the treatment and/or prevention of the arginine methyltransferase-mediated disorder or to delay or minimize one or more symptoms associated with the arginine methyltransferase-mediated disorder.
  • a “therapeutically effective amount” of a salt, co-crystal, amorphous form, or crystalline form described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition (e.g., an arginine methyltransferase-mediated disorder) or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount" of a salt, co-crystal, amorphous form, or crystalline form described herein is an amount sufficient to prevent a condition (e.g., an arginine methyltransferase-mediated disorder), or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • methyltransferase represents transferase class enzymes that are able to transfer a methyl group from a donor molecule to an acceptor molecule, e.g., an amino acid residue of a protein or a nucleic base of a DNA molecule.
  • Methytransferases typically use a reactive methyl group bound to sulfur in S-adenosyl methionine (SAM) as the methyl donor.
  • SAM S-adenosyl methionine
  • a methyltransferase described herein is a protein methyltransferase.
  • a methyltransferase described herein is a histone methyltransferase.
  • Histone methyltransferases are histone-modifying enzymes, (including histone-lysine N-methyltransf erase and histone-arginine N-methyl transferase), that catalyze the transfer of one or more methyl groups to lysine and/or arginine residues of histone proteins.
  • a methyltransferase described herein is a histone-arginine N-methyltransferase.
  • RMT-mediated disorder means any disease, disorder, or other pathological condition in which an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) is known to play a role. Accordingly, in some embodiments, the present disclosure relates to treating or lessening the severity of one or more diseases in which an RMT is known to play a role.
  • HC1 sulfuric acid, phosphoric acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, L- malic acid, nicotinic acid, or benzoic acid have been found to exist in a variety of solid forms, such as salts, co-crystals, amorphous forms, and crystalline forms described herein.
  • the different solid forms may even result in different pharmacokinetic and/or pharmacodynamic properties.
  • the salts, co- crystals, amorphous forms, and crystalline forms may improve one or more physical, chemical, pharmacokinetic, and/or pharmacodynamic characteristics (e.g., increased solubility (e.g.
  • aqueous solubility compared with compound 133, an amorphous form of compound 133, an amorphous form of a salt of compound 133, a different crystalline form of compound 133, a different crystalline form of a salt of compound 133, and/or a different co-crystal comprising compound 133 and an acid.
  • Different solid forms of a compound can be typically distinguished by X-ray diffraction, in particular X-ray powder diffraction (XRPD, obtained by, e.g., a method described herein), and by other methods, such as, differential scanning calorimetry (DSC, obtained by, e.g., a method described herein), thermal gravimetric analysis (TGA, obtained by, e.g., a method described herein), dynamic vapor sorption (DVS, obtained by, e.g., a method described herein), and/or solubility (e.g., kinetic solubility and/or thermodynamic solubility, obtained by, e.g., a method described herein).
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • DVD dynamic vapor sorption
  • solubility e.g., kinetic solubility and/or thermodynamic solubility, obtained by, e.g., a method described herein
  • Compound 133 may be in a crystalline form. In certain embodiments, compound
  • 133 is substantially free of any amorphous forms of compound 133. In certain embodiments, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight of compound 133 (e.g., in a composition) is in a crystalline form.
  • Compound 133 may be in a neat (e.g. , substantially anhydrous) crystal form and thus does not have any solvent (e.g., water) incorporated into the crystal structure. It has been found that compound 133 can exist in at least one neat crystalline form, i.e. , Form A.
  • the present disclosure provides crystalline form A (Form A) of compound 133.
  • Form A is substantially not a salt (e.g. , salt formed between compound 133 and an acid) or co-crystal (e.g. , co-crystal comprising compound 133 and an acid).
  • Form A is substantially free of impurities.
  • Form A is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities.
  • Form A is substantially free of amorphous forms of compound 133.
  • Form A is substantially free of other crystalline forms of compound 133.
  • Form A is substantially free of salts of compound 133.
  • Form A is substantially free of solvents (e.g., water).
  • Form A can be characterized by one or more of the characteristics described herein, including, but not limited to, X-ray powder diffraction (XRPD) pattern, differential scanning calorimetry (DSC) thermogram, thermal gravimetric analysis (TGA) thermogram, thermodynamic solubility, and kinetic solubility.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • thermodynamic solubility thermodynamic solubility
  • kinetic solubility thermodynamic solubility
  • Form A is characterized by an XRPD pattern substantially similar to the one depicted in Figure 1A.
  • Form A is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 1.
  • Form A is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 1.
  • Form A is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 1, respectively.
  • Form A is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 1, respectively.
  • Form A is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 1, respectively.
  • Form A is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 1.
  • Table 1 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form A has a DSC thermogram substantially similar to the one depicted in Figure IB. In some embodiments, Form A is characterized in that it has a DSC thermogram comprising an endotherm comprising an onset temperature (r m ) of about 118.3 ⁇ 2 °C. In some embodiments, Form A is characterized in that it has a DSC
  • thermogram comprising an endotherm comprising a peak temperature ( max ) of about 120.5 + 2 °C.
  • Form A is characterized in that it has a DSC thermogram comprising an enthalpy of the endothermic transition (AH) of about 79.43 J/g.
  • Form A has a DSC thermogram substantially similar to the one depicted in Figure 1C. In some embodiments, Form A is characterized in that it has a DSC thermogram comprising an endotherm comprising an onset temperature (r m ) of about 118.7 + 2 °C. In some embodiments, Form A is characterized in that it has a DSC
  • thermogram comprising an endotherm comprising a peak temperature ( max ) of about 120.9 + 2 °C.
  • Form A is characterized in that it has a DSC thermogram comprising an enthalpy of the endothermic transition (AH) of about 74.26 J/g.
  • Form A is characterized in that it has (1) an XRPD pattern described herein for Form A and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form A. In certain embodiments, Form A is characterized in that it has (1) an XRPD pattern described herein for Form A and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form A.
  • Form A is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure IB or 1C. In certain embodiments, Form A is characterized in that it has a TGA thermogram comprising a weight loss of about 6.4% up to 135 °C.
  • Form A is characterized in that it has one or more thermodynamic solubilities as shown in Figure ID.
  • Form A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in water at 25 °C. In some embodiments, Form A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in simulated gastric fluid (SGF) at 25 °C. In some embodiments, Form A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in fed state simulated intestinal fluid (FeSSIF) at 25 °C. In some embodiments, Form A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in fasted state simulated intestinal fluid
  • Form A is characterized in that it has a kinetic solubility of at least 10 mg/ml in water, SGF, FeSSIF, and/or FaSSIF, at 25 °C.
  • Form A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure also provides various salts (salt forms) of compound 133.
  • HCl salts of compound 133 In another aspect, described herein are HCl salts of compound 133. In certain embodiments, the molar ratio of HCl to compound 133 in an HCl salt of compound 133 is about 1 : 1. In certain embodiments, the molar ratio of HCl to compound 133 in an HCl salt of compound 133 is about 2: 1. [00239] In certain embodiments, an HCl salt of compound 133 is substantially free of impurities.
  • an HCl salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133).
  • an HCl salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • an HCl salt of compound 133 is a THF solvate or acetone solvate.
  • an HCl salt of compound 133 does not include a solvent.
  • an HCl salt of compound 133 is substantially anhydrous.
  • An HCl salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure also provides co-crystals of compound 133 and one or more additional components (e.g., an acid and/or a solvent).
  • the present disclosure provides co-crystals comprising compound 133 and HCl.
  • the molar ratio of HCl to compound 133 in a co-crystal comprising compound 133 and HCl is about 1 : 1.
  • the molar ratio of HCl to compound 133 in a co-crystal comprising compound 133 and HCl is about 2: 1.
  • a co-crystal comprising compound 133 and HCl is substantially free of impurities. In certain embodiments, a co-crystal comprising compound 133 and HCl is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g. , other salts of compound 133). In some
  • a co-crystal comprising compound 133 and HCl is a solvate (e.g.,
  • a co-crystal comprising compound 133 and HCl is a THF solvate or acetone solvate.
  • a co-crystal comprising compound 133 and HCl does not include a solvent. In some embodiments, a co-crystal comprising compound 133 and HCl is substantially anhydrous.
  • the present disclosure provides crystalline form H-A (Form H-
  • Form H-A comprises HCl.
  • Form H-A is an HCl salt of compound 133.
  • Form H-A is a co-crystal of compound 133 and HCl.
  • Form H-A is about 2: 1 (i.e., Form H-A is a di-HCl salt of compound 133).
  • Form H-A is obtained by recrystallization of an HCl salt
  • Form H-A is obtained by recrystallization of compound 133 from a solution of HCl in THF (e.g. , a solution containing at least two equivalents of HC1, where the amount of compound 133 is one equivalent). In some embodiments, Form H-A is obtained by recrystallization of an HC1 salt
  • Form H-A is obtained by recrystallization of compound 133 from a solution of HC1 in acetone (e.g. , a solution containing at least two equivalents of HC1, where the amount of compound 133 is one equivalent).
  • Form H-A is obtained by recrystallization of an HC1 salt (e.g., di-HCl salt) of compound 133 from acetone.
  • Form H-A is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a solvate e.g., stoichiometric solvate or non- stoichiometric solvate.
  • Form H-A is a THF solvate or acetone solvate. In some embodiments, Form H-A does not include a solvent. In some embodiments, Form H-A is substantially anhydrous.
  • Form H-A is substantially free of impurities. In certain embodiments, Form H-A is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form H-A is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form H-A is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form H-A is substantially free of other salts of compound 133. In certain embodiments, Form H-A is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form H-A can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form H-A is characterized by an XRPD pattern substantially similar to the one depicted in Figure 3A. In some embodiments, Form H-A is characterized by an
  • Form H-A is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 2.
  • Form H-A is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 2, respectively.
  • Form H-A is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 2, respectively. In some embodiments, Form H-A is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 2, respectively.
  • Form H-A is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 2.
  • Table 2 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form H-A has a DSC thermogram substantially similar to the one depicted in Figure 3B. In some embodiments, Form H-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 200.5 + 2 °C. In some embodiments, Form H-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 30.2 + 2 °C and another endotherm comprising a T m of about 200.5 + 2 °C. In some embodiments, Form H-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 205.3 + 2 °C.
  • Form H-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 67.5 + 2 °C and another endotherm comprising a max of about 205.3 + 2 °C. In some embodiments, Form H-A is characterized in that it has a DSC thermogram comprising a AH of about 80.93 J/g. In some embodiments, Form ⁇ - ⁇ is characterized in that it has a DSC thermogram comprising a AH of about 62.74 J/g and a AH of about 80.93 J/g.
  • Form H-A is characterized in that it has (1) an XRPD pattern described herein for Form H-A and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form H-A. In certain embodiments, Form H-A is characterized in that it has (1) an XRPD pattern described herein for Form H-A and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form H- A.
  • Form H-A is characterized in that it has a TGA
  • Form H-A is characterized in that it has a TGA thermogram comprising a weight loss of about 5.1% up to 150 °C.
  • Form H-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form H- A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form H-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form H-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure provides crystalline form H-B (Form H-B) of compound 133, wherein Form H-B comprises HCl.
  • Form H-B is an HCl salt of compound 133.
  • Form H-B is a co-crystal of compound 133 and HCl.
  • the molar ratio of HCl to compound 133 in Form H-B is about 1 : 1.
  • Form H-B is obtained by recrystallization of an HCl salt (e.g., mono-HCl salt) of compound 133 from acetone.
  • Form H-B is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form H-B is an acetone solvate.
  • Form H-B does not include a solvent.
  • Form H-B is substantially anhydrous.
  • Form H-B is substantially free of impurities.
  • Form H-B is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form H-B is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form H-B is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form H-B is substantially free of other salts of compound 133. In certain embodiments, Form H-B is substantially free of solvent (e.g. , water).
  • solvent e.g. , water
  • Form H-B can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form H-B is characterized by an XRPD pattern substantially similar to the one depicted in Figure 3A.
  • Form H-B is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 3.
  • Form H-B is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 3. In some embodiments, Form H-B is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 3, respectively. In some embodiments, Form H-B is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 3, respectively.
  • Form H-B is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 3, respectively.
  • Form H-B is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 3.
  • Table 3 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form H-B has a DSC thermogram substantially similar to the one depicted in Figure 3C. In some embodiments, Form H-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 141.4 + 2 °C. In some embodiments, Form H-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 64.9 + 2 °C and another endotherm comprising a T m of about 141.4 + 2 °C. In some embodiments, Form H-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 144.9 + 2 °C.
  • Form H-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 85.8 + 2 °C and another endotherm comprising a max of about 144.9 + 2 °C. In some embodiments, Form H-B is characterized in that it has a DSC thermogram comprising a AH of about 69.60 J/g. In some embodiments, Form ⁇ - ⁇ is characterized in that it has a DSC thermogram comprising a AH of about 55.29 J/g and a AH of about 69.60 J/g.
  • Form ⁇ - ⁇ is characterized in that it has (1) an XRPD pattern described herein for Form ⁇ - ⁇ and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form ⁇ - ⁇ .
  • Form ⁇ - ⁇ is characterized in that it has (1) an XRPD pattern described herein for Form ⁇ - ⁇ and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form ⁇ - B.
  • Form ⁇ - ⁇ is characterized in that it has a TGA
  • Form H-B is characterized in that it has a TGA thermogram comprising a weight loss of about 12.0% up to 110 °C.
  • Form H-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form H- B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form H-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form H-B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • a sulfate salt of compound 133 is substantially free of impurities. In certain embodiments, a sulfate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, a sulfate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, a sulfate salt of compound 133 is a methanol (MeOH) solvate or acetone solvate.
  • MeOH methanol
  • a sulfate salt of compound 133 is a THF solvate. In some embodiments, a sulfate salt of compound 133 does not include a solvent. In some embodiments, a sulfate salt of compound 133 is substantially anhydrous.
  • a sulfate salt of compound 133 described herein may be amorphous or crystalline.
  • the present disclosure provides amorphous form S-C (Form S-C) of compound 133, wherein Form S-C comprises sulfuric acid.
  • Form S-C is a sulfate salt of compound 133.
  • the molar ratio of H 2 S0 4 to compound 133 in Form S-C is about 1: 1.
  • Form S-C is obtained by precipitation of a sulfate salt (e.g., mono-sulfate salt) of compound 133 from THF.
  • Form S-C is obtained by recrystallization of compound 133 from a solution of H 2 SO 4 in THF (e.g., a solution containing at least one equivalent of H 2 SO 4 , where the amount of compound 133 is one equivalent).
  • Form S-C is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form S-C is a THF solvate.
  • Form S-C does not include a solvent.
  • Form S-C is substantially anhydrous.
  • Form S-C is substantially free of impurities. In certain embodiments, Form S-C is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form S-C is substantially free of crystalline forms of compound 133 or crystalline forms of a salt of compound 133. In certain embodiments, Form S-C is substantially free of other salts of compound 133. In certain embodiments, Form S-C is substantially free of co-crystals comprising compound 133. In certain embodiments, Form S-C is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • the present disclosure provides co-crystals comprising compound 133 and H 2 S0 4 .
  • the molar ratio of H 2 S0 4 to compound 133 in a co-crystal comprising compound 133 and H 2 S0 4 is about 1 : 1.
  • a co-crystal comprising compound 133 and H 2 S0 4 is substantially free of impurities. In certain embodiments, a co-crystal comprising compound 133 and H 2 S0 4 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, a co-crystal comprising compound 133 and H 2 S0 4 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a solvate e.g., stoichiometric solvate or non- stoichiometric solvate.
  • a co-crystal comprising compound 133 and H 2 S0 4 is a methanolate or acetone solvate. In some embodiments, a co-crystal comprising compound 133 and H 2 S0 4 does not include a solvent. In some embodiments, a co-crystal comprising compound 133 and H 2 S0 4 is substantially anhydrous.
  • the present disclosure provides crystalline form S-A (Form S-A) of compound 133, wherein Form S-A comprises sulfuric acid.
  • Form S-A is a sulfate salt of compound 133.
  • Form S-A is a co-crystal of compound 133 and H 2 S0 4 .
  • the molar ratio of H 2 S0 4 to compound 133 in Form S-A is about 1 : 1.
  • Form S-A is obtained by recrystallization of a sulfate salt (e.g., monosulfate salt) of compound 133 from methanol.
  • Form S-A is obtained by recrystallization of compound 133 from a solution of H 2 SO 4 in methanol (e.g., a solution containing at least one equivalent of H 2 SO 4 , where the amount of compound 133 is one equivalent).
  • Form S-A is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form S-A is a methanolate.
  • Form S-A does not include a solvent.
  • Form S-A is substantially anhydrous.
  • Form S-A is substantially free of impurities. In certain embodiments, Form S-A is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form S-A is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form S-A is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form S-A is substantially free of other salts of compound 133. In certain embodiments, Form S-A is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form S-A can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form S-A is characterized by an XRPD pattern substantially similar to the one depicted in Figure 4A or 4H. In some embodiments, Form S-A is characterized by an
  • Form S-A is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 4.
  • Form S-A is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 4, respectively.
  • Form S-A is characterized by an
  • Form S-A is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3.
  • Form S-A is characterized by an
  • Table 4 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form S-A has a DSC thermogram substantially similar to the one depicted in Figure 4B. In some embodiments, Form S-A is characterized in that it has a DSC thermogram comprising an endo therm comprising a T m of about 193.2 + 2 °C. In some embodiments, Form S-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 180.7 + 2 °C and another endotherm comprising a T m of about 193.2 + 2 °C. In some embodiments, Form S-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 197.5 + 2 °C.
  • Form S-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 181.7 + 2 °C and another endotherm comprising a max of about 197.5 + 2 °C. In some embodiments, Form S-A is characterized in that it has a DSC thermogram further comprising an endotherm comprising a max of about 86.2 + 2 °C. In some embodiments, Form S-A is characterized in that it has a DSC thermogram comprising a AH of about 33.49 J/g. In some embodiments, Form S-A is characterized in that it has a DSC thermogram comprising a AH of about 2.63 J/g and a AH of about 33.49 J/g.
  • Form S-A is characterized in that it has (1) an XRPD pattern described herein for Form S-A and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form S-A. In certain embodiments, Form S-A is characterized in that it has (1) an XRPD pattern described herein for Form S-A and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form S-A.
  • Form S-A is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 4B. In certain embodiments, Form S-A is characterized in that it has a TGA thermogram comprising a weight loss of about 14.6% up to 130 °C.
  • Form S-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form S-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form S-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form S-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure provides crystalline form S-B (Form S-B) of compound 133, wherein Form S-B comprises sulfuric acid.
  • Form S-B is a sulfate salt of compound 133.
  • Form S-B is a co-crystal of compound 133 and H 2 S0 4 .
  • the molar ratio of H 2 S0 4 to compound 133 in Form S-B is about 1:1.
  • Form S-B is obtained by recrystallization of a sulfate salt (e.g., monosulfate salt) of compound 133 from acetone.
  • a sulfate salt e.g., monosulfate salt
  • Form S-B is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form S-B is an acetone solvate.
  • Form S-B does not include a solvent.
  • Form S-B is substantially anhydrous.
  • Form S-B is substantially free of impurities. In certain embodiments, Form S-B is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form S-B is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form S-B is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form S-B is substantially free of other salts of compound 133. In certain embodiments, Form S-B is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form S-B can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, TGA thermogram, dynamic vapor sorption (DVS) isotherm, and kinetic solubility.
  • Form S-B is characterized by an XRPD pattern substantially similar to the one depicted in Figure 4A, 4F, or 4H.
  • Form S-B is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 5.
  • Form S-B is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 5. In some embodiments, Form S-B is characterized by an XRPD pattern comprising two characteristic peaks having angle 2- theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 5, respectively. In some embodiments, Form S-B is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2- theta values of Peak Numbers 1 to 3 shown in Table 5, respectively.
  • Form S-B is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 5, respectively.
  • Form S-B is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 5.
  • Table 5 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form S-B has a DSC thermogram substantially similar to the one depicted in Figure 4C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 202.5 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 30.8 + 2 °C and another endotherm comprising a T m of about 202.5 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 208.9 + 2 °C.
  • Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 68.3 + 2 °C and another endotherm comprising a max of about 208.9 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising a AH of about 95.75 J/g. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising a AH of about 62.57 J/g and a AH of about 95.75 J/g.
  • Form S-B has a DSC thermogram substantially similar to the one depicted in Figure 4G. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 204.7 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 34.1 + 2 °C and another endotherm comprising a T m of about 204.7 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 210.4 + 2 °C.
  • Form S-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 72.4 + 2 °C and another endotherm comprising a max of about 210.4 + 2 °C. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising a AH of about 94.48 J/g. In some embodiments, Form S-B is characterized in that it has a DSC thermogram comprising a AH of about 119.46 J/g and a AH of about 94.48 J/g.
  • Form S-B is characterized in that it has (1) an XRPD pattern described herein for Form S-B and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form S-B. In certain embodiments, Form S-B is characterized in that it has (1) an XRPD pattern described herein for Form S-B and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form S-B.
  • Form S-B is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 4C. In certain embodiments, Form S-B is characterized in that it has a TGA thermogram comprising a weight loss of about 4.3% up to 200 °C.
  • Form S-B is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 4G. In certain embodiments, Form S-B is characterized in that it has a TGA thermogram comprising a weight loss of about 5.7% up to 200 °C.
  • Form S-B is characterized in that it has a DVS isotherm substantially similar to the one depicted in Figure 4D. In certain embodiments, Form S-B is characterized in that it has a DVS isotherm comprising an about 34.11% or about 31.28% increase in mass at a relative humidity of about 80%, compared to the mass at a relative humidity of about 0%. An increase in the mass of a solid form described herein at a relative humidity of about 80%, compared to the mass at a relative humidity of about 0%, may be obtained by comparing to the standard from European Pharmacopoeia 5.0.
  • Form S-B is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in water at 25 °C. In some embodiments, Form S-B is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in SGF at 25 °C. In some embodiments, Form S-B is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in FeSSIF at 25 °C. In some embodiments, Form S-B is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in
  • Form S-B is characterized in that it has a kinetic solubility of at least 10 mg/ml in water, SGF, FeSSIF, and/or FaSSIF, at 25 °C. [00288] In some embodiments, Form S-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form S-B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form S-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form S-B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • phosphate salts of compound 133 are phosphate salts of compound 133.
  • the molar ratio of phosphoric acid (H 3 PO 4 ) to compound 133 in a phosphate salt of compound 133 is about 1: 1.
  • a phosphate salt of compound 133 is substantially free of impurities.
  • a phosphate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133).
  • a phosphate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some
  • a phosphate salt of compound 133 is an acetone solvate.
  • a phosphate salt of compound 133 does not include a solvent. In some embodiments, a phosphate salt of compound 133 is substantially anhydrous.
  • a phosphate salt of compound 133 described herein may be amorphous.
  • the present disclosure provides amorphous form P (Form P) of compound 133, wherein Form P comprises phosphoric acid.
  • Form P is a phosphate salt of compound 133.
  • the molar ratio of H 3 PO 4 to compound 133 in Form P is about 1: 1.
  • Form P is obtained by precipitation of a phosphate salt
  • Form P is obtained by recrystallization of compound 133 from a solution of H 3 PO 4 in acetone (e.g., a solution containing at least one equivalent of H 3 PO 4 , where the amount of compound 133 is one equivalent).
  • Form P is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form P is an acetone solvate.
  • Form P does not include a solvent.
  • Form P is substantially anhydrous.
  • Form P is substantially free of impurities. In certain embodiments, Form P is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form P is
  • Form P is substantially free of crystalline forms of compound 133 or crystalline forms of a salt of compound 133. In certain embodiments, Form P is substantially free of other salts of compound 133. In certain embodiments, Form P is substantially free of co-crystals comprising compound 133. In certain embodiments, Form P is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • maleate salts of compound 133 In another aspect, described herein are maleate salts of compound 133. In certain embodiments, the molar ratio of maleic acid to compound 133 in a maleate salt of compound 133 is about 1: 1.
  • a maleate salt of compound 133 is substantially free of impurities. In certain embodiments, a maleate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, a maleate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, a maleate salt of compound 133 is an acetone solvate. In some embodiments, a maleate salt of compound 133 does not include a solvent. In some embodiments, a maleate salt of compound 133 is substantially anhydrous.
  • a maleate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides co-crystals comprising compound 133 and maleic acid.
  • the molar ratio of maleic acid to compound 133 in a co-crystal comprising compound 133 and maleic acid is about 1: 1.
  • a co-crystal comprising compound 133 and maleic acid is substantially free of impurities. In certain embodiments, a co-crystal comprising compound
  • a co-crystal comprising compound 133 and maleic acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133).
  • a co-crystal comprising compound 133 and maleic acid is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and maleic acid is an acetone solvate.
  • a co- crystal comprising compound 133 and maleic acid does not include a solvent.
  • a co-crystal comprising compound 133 and maleic acid is substantially anhydrous.
  • the present disclosure provides crystalline form M (Form M) of compound 133, wherein Form M comprises maleic acid.
  • Form M is a maleate salt of compound 133.
  • Form M is a co-crystal of compound 133 and maleic acid.
  • the molar ratio of maleic acid to compound 133 in Form M is about 1 : 1.
  • Form M is obtained by recrystallization of a maleate salt (e.g., mono-maleate salt) of compound 133 from acetone. In some embodiments, Form M is obtained by recrystallization of compound 133 from a solution of maleic acid in acetone (e.g. , a solution containing at least one equivalent of maleic acid, where the amount of compound 133 is one equivalent). In some embodiments, Form M is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, Form M is an acetone solvate. In some embodiments, Form M does not include a solvent. In some embodiments, Form M is substantially anhydrous.
  • a maleate salt e.g., mono-maleate salt
  • Form M is obtained by recrystallization of compound 133 from a solution of maleic acid in acetone (e.g. , a solution containing at least one equivalent of maleic acid, where the amount of
  • Form M is substantially free of impurities. In certain embodiments, Form M is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form M is
  • Form M is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form M is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form M is substantially free of other salts of compound 133. In certain embodiments, Form M is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • Form M can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form M is characterized by an XRPD pattern substantially similar to the one depicted in Figure 5A. In some embodiments, Form M is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which
  • Form M is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 6. In some embodiments, Form M is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 6, respectively. In some embodiments, Form M is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 6, respectively.
  • Form M is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 6, respectively.
  • Form M is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 6.
  • Table 6 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form M has a DSC thermogram substantially similar to the one depicted in Figure 5B. In some embodiments, Form M is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 162.5 + 2 °C. In some embodiments, Form M is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 52.3 + 2 °C and another endotherm comprising a T m of about 162.5 + 2 °C. In some embodiments, Form M is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 169.2 + 2 °C.
  • Form M is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 60.6 + 2 °C and another endotherm comprising a max of about 169.2 + 2 °C. In some embodiments, Form M is characterized in that it has a DSC thermogram comprising a AH of about 53.64 J/g. In some embodiments, Form M is characterized in that it has a DSC thermogram comprising a AH of about 10.71 J/g and a AH of about 53.64 J/g.
  • Form M is characterized in that it has (1) an XRPD pattern described herein for Form M and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form M. In certain embodiments, Form M is characterized in that it has (1) an XRPD pattern described herein for Form M and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form M.
  • Form M is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 5B. In certain embodiments, Form M is characterized in that it has a TGA thermogram comprising a weight loss of about 3.0% up to 135 °C.
  • Form M is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form M has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form M is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form M has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Fumarate Salts, Form F-A, Form F-B, Form F-C, and Co-crystals comprising Fumaric Acid
  • fumarate salts of compound 133 In another aspect, described herein are fumarate salts of compound 133. In certain embodiments, the molar ratio of fumaric acid to compound 133 in a fumarate salt of compound 133 is about 1 : 1 or about 1.1: 1.
  • a fumarate salt of compound 133 is substantially free of impurities.
  • a fumarate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities ⁇ e.g., other salts of compound 133).
  • a fumarate salt of compound 133 is a solvate ⁇ e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a fumarate salt of compound 133 is an acetone solvate. In some embodiments, a fumarate salt of compound 133 is a THF solvate. In some embodiments, a fumarate salt of compound 133 is an isopropanolate. In some embodiments, a fumarate salt of compound 133 is a hydrate. In some embodiments, a fumarate salt of compound 133 does not include a solvent. In some embodiments, a fumarate salt of compound 133 is substantially anhydrous.
  • a fumarate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides co-crystals comprising compound 133 and fumaric acid.
  • the molar ratio of fumaric acid to compound 133 in a co-crystal comprising compound 133 and fumaric acid is about 1 : 1 or about 1.1: 1.
  • a co-crystal comprising compound 133 and fumaric acid is substantially free of impurities.
  • a co-crystal comprising compound 133 and fumaric acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities ⁇ e.g., other salts of compound 133).
  • a co-crystal comprising compound 133 and fumaric acid is a solvate ⁇ e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and fumaric acid is an acetone solvate. In some embodiments, a co-crystal comprising compound 133 and fumaric acid is a THF solvate. In some
  • a co-crystal comprising compound 133 and fumaric acid is an isopropanolate. In some embodiments, a co-crystal comprising compound 133 and fumaric acid is a hydrate. In some embodiments, a co-crystal comprising compound 133 and fumaric acid does not include a solvent. In some embodiments, a co-crystal comprising compound 133 and fumaric acid is substantially anhydrous. [00312] In another aspect, the present disclosure provides crystalline form F-A (Form F-A) of compound 133, wherein Form F-A comprises fumaric acid. In some embodiments, Form F-A is a fumarate salt of compound 133.
  • Form F-A is a co-crystal of compound 133 and fumaric acid. In some embodiments, the molar ratio of fumaric acid to compound 133 in Form F-A is about 1 : 1 or about 1.1 : 1.
  • Form F-A is obtained by recrystallization of a fumarate salt (e.g., mono-fumarate salt) of compound 133 from acetone. In some embodiments, Form F-A is obtained by recrystallization of compound 133 from a solution of fumaric acid in acetone (e.g., a solution containing at least one equivalent of fumaric acid, where the amount of compound 133 is one equivalent). In some embodiments, Form F-A is a solvate (e.g. , stoichiometric solvate or non- stoichiometric solvate). In some embodiments, Form F-A is an acetone solvate. In some embodiments, Form F-A does not include a solvent. In some embodiments, Form F-A is substantially anhydrous.
  • a fumarate salt e.g., mono-fumarate salt
  • Form F-A is obtained by recrystallization of compound 133 from a solution of fumaric acid in acetone (e
  • Form F-A is substantially free of impurities. In certain embodiments, Form F-A is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form F-A is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form F-A is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form F-A is substantially free of other salts of compound 133. In certain embodiments, Form F-A is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form F-A can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, TGA thermogram,
  • Form F-A is characterized by an XRPD pattern substantially similar to the one depicted in Figure 6A or
  • Form F-A is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 7.
  • Form F-A is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle
  • Form F-A is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 7, respectively. In some embodiments, Form F-A is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2- theta values of Peak Numbers 1 to 3 shown in Table 7, respectively. In some embodiments, Form F-A is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 7, respectively.
  • Form F-A is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 7.
  • Table 7 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form F-A has a DSC thermogram substantially similar to the one depicted in Figure 6B. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 162.1 + 2 °C. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 164.4 + 2 °C. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising a AH of about 104.89 J/g.
  • Form F-A has a DSC thermogram substantially similar to the one depicted in Figure 6G. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 160.7 + 2 °C. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 162.9 + 2 °C. In some embodiments, Form F-A is characterized in that it has a DSC thermogram comprising a AH of about 105.27 J/g.
  • Form F-A is characterized in that it has (1) an XRPD pattern described herein for Form F-A and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form F-A. In certain embodiments, Form F-A is characterized in that it has (1) an XRPD pattern described herein for Form F-A and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form F-A.
  • Form F-A is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 6B. In certain embodiments, Form F-A is characterized in that it has a TGA thermogram comprising a weight loss of about 1.5% up to 130 °C.
  • Form F-A is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 6G. In certain embodiments, Form F-A is characterized in that it has a TGA thermogram comprising a weight loss of about 4.4% up to 130 °C.
  • Form F-A is characterized in that it has a DVS isotherm substantially similar to the one depicted in Figure 6J. In certain embodiments, Form F-A is characterized in that it has a DVS isotherm comprising an about 34.26% or about 2.39% increase in mass at a relative humidity of about 80%, compared to the mass at a relative humidity of about 0%.
  • Form F-A changes to another solid form ⁇ e.g. , another crystalline form and/or an amorphous form) after being subjected to a DVS measurement.
  • Form F-A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in water at 25 °C. In some embodiments, Form F-A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in SGF at 25 °C. In some embodiments, Form F- A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in FeSSIF at 25 °C.
  • Form F-A is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in FaSSIF at 25 °C. In some embodiments, Form F-A is characterized in that it has a kinetic solubility of at least 10 mg/ml in water, SGF, FeSSIF, and/or FaSSIF, at 25 °C. [00324] In some embodiments, Form F-A is characterized in that it has a proton nuclear magnetic resonance ( 1 H-NMR ) spectrum substantially similar to the one depicted in Figure 6C.
  • 1 H-NMR proton nuclear magnetic resonance
  • Form F-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form F-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form F-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form F-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure provides crystalline form F-B (Form F-B) of compound 133, wherein Form F-B comprises fumaric acid.
  • Form F-B is a fumarate salt of compound 133.
  • Form F-B is a co-crystal of compound 133 and fumaric acid.
  • the molar ratio of fumaric acid to compound 133 in Form F-B is about 1 : 1.
  • Form F-B is obtained by recrystallization of a fumarate salt (e.g., mono-fumarate salt) of compound 133 from THF.
  • a fumarate salt e.g., mono-fumarate salt
  • Form F-B is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form F-B is a THF solvate.
  • Form F-B does not include a solvent.
  • Form F-B is substantially anhydrous.
  • Form F-B is substantially free of impurities. In certain embodiments, Form F-B is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form F-B is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form F-B is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form F-B is substantially free of other salts of compound 133. In certain embodiments, Form F-B is substantially free of solvents (e.g. , water). [00330] Form F-B can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form F-B is characterized by an XRPD pattern substantially similar to the one depicted in Figure 6A. In some embodiments, Form F-B is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which
  • Form F-B is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 8. In some embodiments, Form F-B is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 8, respectively. In some embodiments, Form F-B is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 8, respectively.
  • Form F-B is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 8, respectively.
  • Form F-B is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 8.
  • Table 8 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form F-B has a DSC thermogram substantially similar to the one depicted in Figure 6D. In some embodiments, Form F-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 161.1 ⁇ 2 °C. In some embodiments, Form F-B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 155.6 + 2 °C and another endotherm comprising a T max of about 161.1 + 2 °C.
  • Form F-B is characterized in that it has (1) an XRPD pattern described herein for Form F-B and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form F-B. In certain embodiments, Form F-B is characterized in that it has (1) an XRPD pattern described herein for Form F-B and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form F-B.
  • Form F-B is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 6D. In certain embodiments, Form F-B is characterized in that it has a TGA thermogram comprising a weight loss of about 3.4% up to 140 °C.
  • Form F-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form F-B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form F-B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form F-B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure provides crystalline form F-C (Form F-C) of compound 133, wherein Form F-C comprises fumaric acid.
  • Form F-C is a fumarate salt of compound 133.
  • Form F-C is a co-crystal of compound 133 and fumaric acid.
  • the molar ratio of fumaric acid to compound 133 in Form F-C is about 1 : 1.
  • Form F-C is obtained by recrystallization of a fumarate salt (e.g., mono-fumarate salt) of compound 133 from a mixture of isopropanol and water (e.g. , at about 9: 1 or about 19: 1 by volume).
  • a fumarate salt e.g., mono-fumarate salt
  • Form F-C is obtained by recrystallization of compound 133 from a solution of fumaric acid in a mixture of isopropanol and water (e.g., at about 9: 1 or about 19: 1 by volume), wherein: the solution contains at least one equivalent of fumaric acid, the amount of compound 133 is one equivalent.
  • Form F-C is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, Form F-C is an isopropanolate or hydrate. In some embodiments, Form F-C does not include a solvent. In some embodiments, Form F-C is substantially anhydrous.
  • Form F-C is substantially free of impurities. In certain embodiments, Form F-C is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form F-C is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form F-C is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form F-C is substantially free of other salts of compound 133. In certain embodiments, Form F-C is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form F-C can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, and TGA thermogram.
  • Form F-C is characterized by an XRPD pattern substantially similar to the one depicted in Figure 6A. In some embodiments, Form F-C is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which
  • Form F-C is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 9. In some embodiments, Form F-C is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 9, respectively. In some embodiments, Form F-C is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 9, respectively. In some embodiments, Form F-C is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 9, respectively. In some embodiments, Form F-C is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values
  • Form F-C is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 9, respectively.
  • Form F-C is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 9.
  • Table 9 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form F-C has a DSC thermogram substantially similar to the one depicted in Figure 6E. In some embodiments, Form F-C is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 166.8 + 2 °C. In some embodiments, Form F-C is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 175.6 + 2 °C. In some embodiments, Form F-C is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 115.4 + 2 °C and another endotherm comprising a max of about 175.6 + 2 °C.
  • Form F-C is characterized in that it has a DSC thermogram comprising a AH of about 53.90 J/g.
  • Form F-C is characterized in that it has (1) an XRPD pattern described herein for Form F-C and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form F-C.
  • Form F-C is characterized in that it has (1) an XRPD pattern described herein for Form F-C and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form F-C.
  • Form F-C is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 6E. In certain embodiments, Form F-C is characterized in that it has a TGA thermogram comprising a weight loss of about 10.2% up to 140 °C.
  • Form F-C is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form F-C has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form F-C is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form F-C has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • L-tartrate salts of compound 133 In another aspect, described herein are L-tartrate salts of compound 133. In certain embodiments, the molar ratio of L-tartaric acid to compound 133 in an L-tartrate salt of compound 133 is about 1: 1.
  • an L-tartrate salt of compound 133 is substantially free of impurities. In certain embodiments, an L-tartrate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, an L-tartrate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, an L-tartrate salt of compound 133 is an acetone solvate.
  • an L-tartrate salt of compound 133 is a methanolate, isopropanolate, or hydrate. In some embodiments, an L-tartrate salt of compound 133 does not include a solvent. In some embodiments, an L-tartrate salt of compound 133 is substantially anhydrous.
  • An L-tartrate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides amorphous form T-B (Form T-B) of compound 133, wherein Form T-B comprises L-tartaric acid.
  • Form T-B is an L-tartrate salt of compound 133.
  • the molar ratio of L-tartaric acid to compound 133 in Form T-B is about 1 : 1.
  • Form T-B is obtained by precipitation of an L-tartrate salt (e.g., mono-L-tartrate salt) of compound 133 from acetone.
  • Form T-B is obtained by recrystallization of compound 133 from a solution of L-tartaric acid in acetone (e.g., a solution containing at least one equivalent of L-tartaric acid, where the amount of compound 133 is one equivalent).
  • Form T-B is a solvate (e.g. , stoichiometric solvate or non- stoichiometric solvate).
  • Form T-B is an acetone solvate.
  • Form T-B does not include a solvent.
  • Form T-B is substantially anhydrous.
  • Form T-B is substantially free of impurities. In certain embodiments, Form T-B is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form T-B is substantially free of crystalline forms of compound 133 or crystalline forms of a salt of compound 133. In certain embodiments, Form T-B is substantially free of other salts of compound 133. In certain embodiments, Form T-B is substantially free of co-crystals comprising compound 133. In certain embodiments, Form T-B is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • the present disclosure provides co-crystals comprising compound 133 and L-tartaric acid.
  • the molar ratio of L-tartaric acid to compound 133 in a co-crystal comprising compound 133 and L-tartaric acid is about 1 : 1.
  • a co-crystal comprising compound 133 and L-tartaric acid is substantially free of impurities. In certain embodiments, a co-crystal comprising compound
  • a co-crystal comprising compound 133 and L-tartaric acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g. , other salts of compound 133).
  • a co-crystal comprising compound 133 and L-tartaric acid is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and L-tartaric acid is a methanolate, isopropanolate, or hydrate.
  • a co-crystal comprising compound 133 and L-tartaric acid does not include a solvent.
  • a co-crystal comprising compound 133 and L- tartaric acid is substantially anhydrous.
  • the present disclosure provides crystalline form T-A (Form T-A) of compound 133, wherein Form T-A comprises L-tartaric acid.
  • Form T-A is an L-tartrate salt of compound 133.
  • Form T-A is a co-crystal of compound 133 and L-tartaric acid.
  • the molar ratio of L-tartaric acid to compound 133 in Form T-A is about 1 : 1.
  • Form T-A is obtained by recrystallization of an L-tartrate salt (e.g., mono-L-tartrate salt) of compound 133 from methanol.
  • L-tartrate salt e.g., mono-L-tartrate salt
  • Form T-A is obtained by recrystallization of compound 133 from a solution of L-tartaric acid in methanol (e.g., a solution containing at least one equivalent of L-tartaric acid, where the amount of compound 133 is one equivalent).
  • Form T-A is obtained by recrystallization of an L-tartrate salt (e.g. , mono-L-tartrate salt) of compound 133 from a mixture of isopropanol and water (e.g., at about 9: 1 or about 19: 1 by volume).
  • Form T-A is obtained by recrystallization of compound 133 from a solution of
  • Form T-A is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form T-A is a methanolate, isopropanolate, or hydrate.
  • Form T-A does not include a solvent.
  • Form T-A is substantially anhydrous.
  • Form T-A is substantially free of impurities. In certain embodiments, Form T-A is at least 95%, at least 96%, at least 97%, at least 98%, at least
  • Form T-A is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form T-A is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form T-A is substantially free of other salts of compound 133. In certain embodiments, Form T-A is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • Form T-A can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern.
  • Form T-A is characterized by an XRPD pattern substantially similar to the one depicted in Figure 7.
  • Form T-A is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 10.
  • Form T-A is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 10.
  • Form T-A is
  • Form T-A is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 10, respectively.
  • Form T-A is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2- theta values of Peak Numbers 1 to 3 shown in Table 10, respectively.
  • Form T-A is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 10, respectively.
  • Form T-A is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 10.
  • Table 10 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form T-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form T-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form T-A is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form T-A has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • citrate salts of compound 133 In another aspect, described herein are citrate salts of compound 133. In certain embodiments, the molar ratio of citric acid to compound 133 in a citrate salt of compound 133 is about 1: 1.
  • a citrate salt of compound 133 is substantially free of impurities. In certain embodiments, a citrate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, a citrate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, a citrate salt of compound 133 is a THF solvate. In some embodiments, a citrate salt of compound 133 does not include a solvent. In some embodiments, a citrate salt of compound 133 is substantially anhydrous.
  • a citrate salt of compound 133 described herein may be amorphous.
  • the present disclosure provides amorphous form C (Form C) of compound 133, wherein Form C comprises citric acid.
  • Form C is a citrate salt of compound 133.
  • the molar ratio of citric acid to compound 133 in Form C is about 1: 1.
  • Form C is obtained by precipitation of a citrate salt (e.g., mono-citrate salt) of compound 133 from THF. In some embodiments, Form C is obtained by recrystallization of compound 133 from a solution of citric acid in THF (e.g., a solution containing at least one equivalent of citric acid, where the amount of compound 133 is one equivalent). In some embodiments, Form C is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some embodiments, Form C is a THF solvate. In some embodiments, Form C does not include a solvent. In some embodiments, Form C is substantially anhydrous.
  • a citrate salt e.g., mono-citrate salt
  • Form C is obtained by recrystallization of compound 133 from a solution of citric acid in THF (e.g., a solution containing at least one equivalent of citric acid, where the amount of compound 133 is one
  • Form C is substantially free of impurities. In certain embodiments, Form C is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form C is
  • Form C is substantially free of crystalline forms of compound 133 or crystalline forms of a salt of compound 133. In certain embodiments, Form C is substantially free of other salts of compound 133. In certain embodiments, Form C is substantially free of co-crystals comprising compound 133. In certain embodiments, Form C is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • L-malate salts of compound 133 are L-malate salts of compound 133.
  • the molar ratio of L-malic acid to compound 133 in an L-malate salt of compound 133 is about 1 : 1 or about 1.1: 1.
  • an L-malate salt of compound 133 is substantially free of impurities. In certain embodiments, an L-malate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, an L-malate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate). In some
  • an L-malate salt of compound 133 is an acetone solvate.
  • an L-malate salt of compound 133 does not include a solvent. In some embodiments, an L-malate salt of compound 133 is substantially anhydrous.
  • An L-malate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides co-crystals comprising compound 133 and L-malic acid.
  • the molar ratio of L-malic acid to compound 133 in a co-crystal comprising compound 133 and L-malic acid is about 1 : 1 or about 1.1: 1.
  • a co-crystal comprising compound 133 and L-malic acid is substantially free of impurities. In certain embodiments, a co-crystal comprising compound
  • a co-crystal comprising compound 133 and L-malic acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133).
  • a co-crystal comprising compound 133 and L-malic acid is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and L-malic acid is an acetone solvate.
  • a co-crystal comprising compound 133 and L-malic acid does not include a solvent.
  • a co-crystal comprising compound 133 and L-malic acid is substantially anhydrous.
  • the present disclosure provides crystalline form Ma (Form Ma) of compound 133, wherein Form Ma comprises L-malic acid.
  • Form Ma is an L-malate salt of compound 133.
  • Form Ma is a co-crystal of compound 133 and L-malic acid.
  • the molar ratio of L-malic acid to compound 133 in Form Ma is about 1 : 1 or about 1.1 : 1.
  • Form Ma is obtained by recrystallization of an L-malate salt (e.g., mono-L-malate salt) of compound 133 from acetone.
  • Form Ma is obtained by recrystallization of compound 133 from a solution of L-malic acid in acetone (e.g., a solution containing at least one equivalent of L-malic acid, where the amount of compound 133 is one equivalent).
  • Form Ma is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form Ma is an acetone solvate.
  • Form Ma does not include solvent.
  • Form Ma is substantially anhydrous.
  • Form Ma is substantially free of impurities. In certain embodiments, Form Ma is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form Ma is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form Ma is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form Ma is substantially free of other salts of compound 133. In certain embodiments, Form Ma is substantially free of solvents (e.g. , water).
  • solvents e.g. , water
  • Form Ma can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, TGA thermogram,
  • Form Ma is characterized by an XRPD pattern substantially similar to the one depicted in Figure 8A or
  • Form Ma is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 11.
  • Form Ma is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 11.
  • Form Ma is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 11, respectively.
  • Form Ma is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2- theta values of Peak Numbers 1 to 3 shown in Table 11, respectively. In some embodiments, Form Ma is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 11, respectively.
  • Form Ma is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 11.
  • Table 11 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form Ma has a DSC thermogram substantially similar to the one depicted in Figure 8B. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 138.5 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 141.9 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 141.9 + 2 °C and another endotherm comprising a max of about 198.4 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising a AH of about 80.57 J/g.
  • Form Ma has a DSC thermogram substantially similar to the one depicted in Figure 8D. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 137.0 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 32.3 + 2 °C and another endotherm comprising a T m of about 137.0 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 141.4 + 2 °C.
  • Form Ma is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 51.8 + 2 °C and another endotherm comprising a max of about 141.4 + 2 °C. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising a AH of about 90.83 J/g. In some embodiments, Form Ma is characterized in that it has a DSC thermogram comprising a AH of about 31.91 J/g and a AH of about 90.83 J/g.
  • Form Ma is characterized in that it has (1) an XRPD pattern described herein for Form Ma and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form Ma. In certain embodiments, Form Ma is characterized in that it has (1) an XRPD pattern described herein for Form Ma and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form Ma.
  • Form Ma is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 8B. In certain embodiments, Form Ma is characterized in that it has a TGA thermogram comprising a weight loss of about 0.7% up to 140 °C.
  • Form Ma is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 8D. In certain embodiments, Form Ma is characterized in that it has a TGA thermogram comprising a weight loss of about 3.7% up to 140 °C.
  • Form Ma is characterized in that it has a DVS isotherm substantially similar to the one depicted in Figure 8E. In certain embodiments, Form Ma is characterized in that it has a DVS isotherm comprising an about 35.16% or about 31.62% increase in mass at a relative humidity of about 80%, compared to the mass at a relative humidity of about 0%.
  • Form Ma is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in water at 25 °C. In some embodiments, Form Ma is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in SGF at 25 °C. In some embodiments, Form Ma is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in FeSSIF at 25 °C.
  • Form Ma is characterized in that it has a kinetic solubility of at least 10, at least 30, at least 100, or at least 300 mg/ml in FaSSIF at 25 °C. In some embodiments, Form Ma is characterized in that it has a kinetic solubility of at least 10 mg/ml in water, SGF, FeSSIF, and/or FaSSIF, at 25 °C.
  • Form Ma is characterized in that it has a proton nuclear magnetic resonance (1H-NMR ) spectrum substantially similar to the one depicted in Figure 8C.
  • Form Ma is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form Ma has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form Ma is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form Ma has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • nicotinate salts of compound 133 In another aspect, described herein are nicotinate salts of compound 133. In certain embodiments, the molar ratio of nicotinic acid to compound 133 in a nicotinate salt of compound 133 is about 1: 1.
  • a nicotinate salt of compound 133 is substantially free of impurities. In certain embodiments, a nicotinate salt of compound 133 is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133). In some embodiments, a nicotinate salt of compound 133 is a solvate (e.g. , stoichiometric solvate or non- stoichiometric solvate). In some
  • a nicotinate salt of compound 133 is a THF solvate. In some embodiments, a nicotinate salt of compound 133 does not include a solvent. In some embodiments, a nicotinate salt of compound 133 is substantially anhydrous.
  • a nicotinate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides co-crystals comprising compound 133 and nicotinic acid.
  • the molar ratio of nicotinic acid to compound 133 in a co-crystal comprising compound 133 and nicotinic acid is about 1 : 1.
  • a co-crystal comprising compound 133 and nicotinic acid is substantially free of impurities.
  • a co-crystal comprising compound 133 and nicotinic acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g. , other salts of compound 133).
  • a co-crystal comprising compound 133 and nicotinic acid is a solvate (e.g. , stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and nicotinic acid is a THF solvate. In some embodiments, a co- crystal comprising compound 133 and nicotinic acid does not include a solvent. In some embodiments, a co-crystal comprising compound 133 and nicotinic acid is substantially anhydrous.
  • the present disclosure provides crystalline form N (Form N) of compound 133, wherein Form N comprises nicotinic acid.
  • Form N is a nicotinate salt of compound 133.
  • Form N is a co-crystal of compound 133 and nicotinic acid.
  • the molar ratio of nicotinic acid to compound 133 in Form N is about 1 : 1.
  • Form N is obtained by recrystallization of a nicotinate salt (e.g., mono-nicotinate salt) of compound 133 from THF.
  • a nicotinate salt e.g., mono-nicotinate salt
  • Form N is obtained by recrystallization of compound 133 from a solution of nicotinic acid in THF (e.g., a solution containing at least one equivalent of nicotinic acid, where the amount of compound 133 is one equivalent).
  • Form N is a solvate (e.g. , stoichiometric solvate or non- stoichiometric solvate).
  • Form N is a THF solvate.
  • Form N does not include a solvent.
  • Form N is substantially anhydrous. [00387] In certain embodiments, Form N is substantially free of impurities. In certain embodiments, Form N is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form N is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form N is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form N is substantially free of other salts of compound 133. In certain embodiments, Form N is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • Form N can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, TGA thermogram, DVS isotherm, and 1H-NMR spectrum.
  • Form N is characterized by an XRPD pattern substantially similar to the one depicted in Figure 9A or 9F.
  • Form N is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 12.
  • Form N is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 12. In some embodiments, Form N is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 12, respectively. In some
  • Form N is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 12, respectively. In some embodiments, Form N is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 12, respectively.
  • Form N is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 12.
  • Table 12 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form N has a DSC thermogram substantially similar to the one depicted in Figure 9B. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 158.5 + 2 °C. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 161.4 + 2 °C. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising a AH of about 102.35 J/g.
  • Form N has a DSC thermogram substantially similar to the one depicted in Figure 9G. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 158.0 + 2 °C. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 159.6 + 2 °C. In some embodiments, Form N is characterized in that it has a DSC thermogram comprising a AH of about 87.51 J/g.
  • Form N is characterized in that it has (1) an XRPD pattern described herein for Form N and (2) a DSC thermogram comprising an endotherm comprising a T m described herein for Form N. In certain embodiments, Form N is characterized in that it has (1) an XRPD pattern described herein for Form N and (2) a DSC thermogram comprising an endotherm comprising a max described herein for Form N.
  • Form N is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 9B. In certain embodiments, Form N is characterized in that it has a TGA thermogram comprising a weight loss of about 1.5% up to 158 °C. [00393] In some embodiments, Form N is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 9G. In certain embodiments, Form N is characterized in that it has a TGA thermogram comprising a weight loss of about 4.0% up to 140 °C.
  • Form N is characterized in that it has a DVS isotherm substantially similar to the one depicted in Figure 9C. In certain embodiments, Form N is characterized in that it has a DVS isotherm comprising an about 26.29% or about 2.34% increase in mass at a relative humidity of about 80%, compared to the mass at a relative humidity of about 0%.
  • Form N is characterized in that it has a 1H-NMR spectrum substantially similar to the one depicted in Figure 9D.
  • Form N is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity. In some embodiments, Form N has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form N is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form N has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • benzoate salts of compound 133 In another aspect, described herein are benzoate salts of compound 133. In certain embodiments, the molar ratio of benzoic acid to compound 133 in a benzoate salt of compound 133 is about 1 : 1 or about 1.1: 1.
  • a benzoate salt of compound 133 is substantially free of impurities. In certain embodiments, a benzoate salt of compound 133 is at least 95%, at least
  • a benzoate salt of compound 133 is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a benzoate salt of compound 133 is a THF solvate.
  • a benzoate salt of compound 133 does not include a solvent.
  • a benzoate salt of compound 133 is substantially anhydrous.
  • a benzoate salt of compound 133 described herein may be amorphous or in a crystalline form.
  • the present disclosure provides co-crystals comprising compound 133 and benzoic acid.
  • the molar ratio of benzoic acid to compound 133 in a co-crystal comprising compound 133 and benzoic acid is about 1 : 1 or about 1.1 : 1.
  • a co-crystal comprising compound 133 and benzoic acid is substantially free of impurities.
  • a co-crystal comprising compound 133 and benzoic acid is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities (e.g., other salts of compound 133).
  • a co-crystal comprising compound 133 and benzoic acid is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • a co-crystal comprising compound 133 and benzoic acid is a THF solvate. In some embodiments, a co- crystal comprising compound 133 and benzoic acid does not include a solvent. In some embodiments, a co-crystal comprising compound 133 and benzoic acid is substantially anhydrous.
  • the present disclosure provides crystalline form B (Form B) of compound 133, wherein Form B comprises benzoic acid.
  • Form B is a benzoate salt of compound 133.
  • Form B is a co-crystal of compound 133 and benzoic acid.
  • the molar ratio of benzoic acid to compound 133 in Form B is about 1 : 1 or about 1.1 : 1.
  • Form B is obtained by recrystallization of a benzoate salt (e.g., mono-benzoate salt) of compound 133 from THF.
  • Form B is obtained by recrystallization of compound 133 from a solution of benzoic acid in THF (e.g. , a solution containing at least one equivalent of benzoic acid, where the amount of compound 133 is one equivalent).
  • Form B is a solvate (e.g., stoichiometric solvate or non- stoichiometric solvate).
  • Form B is a THF solvate.
  • Form B does not include a solvent.
  • Form B is substantially anhydrous.
  • Form B is substantially free of impurities. In certain embodiments, Form B is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight free of impurities. In certain embodiments, Form B is substantially free of amorphous forms of compound 133 or amorphous forms of a salt of compound 133. In certain embodiments, Form B is substantially free of other crystalline forms of compound 133 or other crystalline forms of a salt of compound 133. In certain embodiments, Form B is substantially free of other salts of compound 133. In certain embodiments, Form B is substantially free of solvents (e.g., water).
  • solvents e.g., water
  • Form B can be characterized by one or more of the characteristics described herein, including, but not limited to, XRPD pattern, DSC thermogram, TGA thermogram, and 1H-NMR spectrum.
  • Form B is characterized by an XRPD pattern substantially similar to the one depicted in Figure 10A or 10D.
  • Form B is characterized by an XRPD pattern comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine characteristic peaks, each of which independently has an angle 2-theta value shown in Table 13.
  • Form B is characterized by an XRPD pattern comprising a characteristic peak having an angle 2-theta value the same as the angle 2-theta value of Peak Number 1 shown in Table 13.
  • Form B is characterized by an XRPD pattern comprising two characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 and 2 shown in Table 13, respectively.
  • Form B is characterized by an XRPD pattern comprising three characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 3 shown in Table 13, respectively.
  • Form B is characterized by an XRPD pattern comprising four characteristic peaks having angle 2-theta values the same as the angle 2-theta values of Peak Numbers 1 to 4 shown in Table 13, respectively.
  • Form B is characterized by an XRPD pattern where the angle 2-theta value of the most intense peak, each of the first to second most intense peaks, each of the first to third most intense peaks, each of the first to fourth most intense peaks, each of the first to fifth most intense peaks, each of the first to sixth most intense peaks, each of the first to seventh most intense peaks, each of the first to eighth most intense peaks, or each of the first to ninth most intense peaks independently is the same as an angle 2-theta value shown in Table 13.
  • Table 13 Exemplary characteristic peaks from the X-ray powder diffraction pattern.
  • Form B has a DSC thermogram substantially similar to the one depicted in Figure 10B. In some embodiments, Form B is characterized in that it has a DSC thermogram comprising an endotherm comprising a T m of about 156.6 + 2 °C. In some embodiments, Form B is characterized in that it has a DSC thermogram comprising an endotherm comprising a max of about 158.6 + 2 °C. In some embodiments, Form B is characterized in that it has a DSC thermogram comprising a AH of about 95.78 J/g.
  • Form B is characterized in that it has (1) an XRPD pattern described herein for Form B and (2) a DSC thermogram comprising an endotherm
  • Form B is
  • Form B is characterized in that it has a TGA thermogram substantially similar to the one depicted in Figure 10B. In certain embodiments, Form B is characterized in that it has a TGA thermogram comprising a weight loss of about 1.5% up to 139 °C.
  • Form B is characterized in that it has a 1H-NMR spectrum substantially similar to the one depicted in Figure IOC.
  • Form B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 3 years at 25 °C and about 60% relative humidity.
  • Form B is stable for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • Form B has substantially the same XRPD pattern post storage for at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months at 40 °C and about 75% relative humidity.
  • the present disclosure provides pharmaceutical compositions comprising a salt, co-crystal, amorphous form, or crystalline form described herein, and optionally a pharmaceutically acceptable excipient.
  • a provided pharmaceutical composition comprises two or more salts, co-crystals, amorphous forms, and/or crystalline forms described herein.
  • a salt, co-crystal, amorphous form, or crystalline form described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is an amount effective for inhibiting an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8).
  • the effective amount is an amount effective for treating an RMT- mediated disorder (e.g., a PRMT1-, PRMT3-, CARM1-, PRMT6-, and/or PRMT8-mediated disorder). In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to prevent an RMT-mediated disorder.
  • an RMT- mediated disorder e.g., a PRMT1-, PRMT3-, CARM1-, PRMT6-, and/or PRMT8-mediated disorder.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective to prevent an RMT-mediated disorder.
  • compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired.
  • solvents diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a salt, co-crystal, amorphous form, or crystalline form described herein (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the present disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered.
  • the pharmaceutical composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • a pharmaceutical composition described herein is sterilized.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers
  • colloidal clays e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)
  • long chain amino acid derivatives high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxy
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, L- malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury,
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the salts, co-crystals, amorphous forms, and crystalline forms described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and
  • Solid pharmaceutical compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding pharmaceutical compositions which can be used include polymeric substances and waxes.
  • Solid pharmaceutical compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a provided salt, co- crystal, amorphous form, or crystalline form may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any desired preservatives and/or buffers as can be required.
  • the present disclosure encompasses the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically- administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
  • compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9%
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for buccal
  • formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable pharmaceutical composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of
  • compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • the salts, co-crystals, amorphous forms, and crystalline forms provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of provided pharmaceutical compositions will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific pharmaceutical composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal,
  • routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a salt, co-crystal, amorphous form, or crystalline form required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular salt, co-crystal, amorphous form, or crystalline form, mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g. , two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a salt, co-crystal, amorphous form, or crystalline form for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a salt, co-crystal, amorphous form, or crystalline form per unit dosage form.
  • a salt, co-crystal, amorphous form, or crystalline form described herein may be administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • a salt, co-crystal, amorphous form, or crystalline form described herein is administered one or more times per day, for multiple days. In some embodiments, the dosing regimen is continued for days, weeks, months, or years.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a salt, co-crystal, amorphous form, or crystalline form, or a pharmaceutical composition thereof can be administered in combination with one or more additional therapeutically active agents.
  • a salt, co-crystal, amorphous form, or crystalline form, or a pharmaceutical composition thereof is
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the salt, co-crystal, amorphous form, or crystalline form, or pharmaceutical composition thereof can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single
  • compositions or administered separately in different pharmaceutical compositions are administered separately in different pharmaceutical compositions.
  • the particular combination to employ in a regimen will take into account compatibility of a provided salt, co-crystal, amorphous form, or crystalline form with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized
  • Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • peptides e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (
  • an additional therapeutically active agent is prednisolone, dexamethasone, doxorubicin, vincristine, mafosfamide, cisplatin, carboplatin, Ara-C, rituximab, azacitadine, panobinostat, vorinostat, everolimus, rapamycin, ATRA (all- trans retinoic acid), daunorubicin, decitabine, Vidaza, mitoxantrone, or IBET-151.
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise a provided salt, co-crystal, amorphous form, or crystalline form, or a pharmaceutical composition thereof, and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a provided salt, co-crystal, amorphous form, or crystalline form, or a pharmaceutical composition thereof.
  • a provided salt, co-crystal, amorphous form, or crystalline form, or a pharmaceutical composition thereof, provided in the container and the second container are combined to form one unit dosage form.
  • a provided kit further includes instructions for use (e.g., for using the salt, co-crystal, amorphous form, or crystalline form, or pharmaceutical composition thereof).
  • Salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein are useful for the inhibition of an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8).
  • RMT e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8.
  • a provided salt, co- crystal, amorphous form, or crystalline form inhibits wild- type PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8.
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits a mutant RMT.
  • a provided salt, co- crystal, amorphous form, or crystalline form inhibits PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8, e.g., as measured in an assay described herein.
  • the RMT is from a human.
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 10 ⁇ .
  • a provided salt, co- crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 1 ⁇ . In certain embodiments, a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 0.1 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 0.01 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g. , PRMTl, PRMT3, CARM1, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 10 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g.
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMTl, PRMT3, CARM1, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 3 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits PRMTl in a cell at an EC 3 o less than or equal to 12 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits PRMTl in a cell at an EC 30 less than or equal to 3 ⁇ . In certain embodiments, a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g. , PRMTl, PRMT3, CARM1, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 1 ⁇ .
  • RMT e.g. , PRMTl, PRMT3, CARM1, PRMT6, and/or PRMT8
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits an RMT (e.g., PRMTl, PRMT3, CARM1, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 0.1 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits cell proliferation at an EC 50 less than or equal to 10 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits cell proliferation at an EC 50 less than or equal to 1 ⁇ .
  • a provided salt, co-crystal, amorphous form, or crystalline form inhibits cell proliferation at an EC 50 less than or equal to 0.1 ⁇ .
  • a RMT described herein can be wild-type, or any mutant or variant.
  • methods of treating an RMT-mediated disorder in a subject comprises administering an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical
  • the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the subject is suffering from a RMT-mediated disorder. In certain embodiments, the subject is susceptible to a RMT- mediated disorder.
  • the present disclosure provides a method of inhibiting an
  • RMT (e.g. , inhibiting the activity (e.g., in vitro activity or in vivo activity) of an RMT) comprising contacting the RMT with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • the RMT may be purified or crude, and may be present in a cell, tissue, or subject.
  • the method is an in vitro method, e.g., an assay method. Inhibition of an RMT does not necessarily require that all of the RMT be occupied by an inhibitor at once.
  • Exemplary levels of inhibition of an RMT include at least 10% inhibition, about 10% to about 25% inhibition, about 25% to about 50% inhibition, about 50% to about 75% inhibition, at least 50% inhibition, at least 75% inhibition, about 80% inhibition, about 90% inhibition, and greater than 90% inhibition.
  • a method of inhibiting RMT activity in a subject in need thereof comprising administering to the subject an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • a method of modulating gene expression in a cell comprising contacting a cell with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • a cell described herein is in vitro. In certain embodiments, a cell described herein is in vivo. In certain embodiments, a cell described herein is in a subject, e.g., a human. In certain embodiments, a cell described herein is in a subject in need of treatment.
  • a method of modulating transcription in a cell comprising contacting a cell with an effective amount of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein.
  • a method of selecting a therapy for a subject having a disease associated with an RMT-mediated disorder or mutation comprising the steps of determining the presence of an RMT-mediated disorder or gene mutation in an RMT gene (e.g., a PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8 gene) and selecting, based on the presence of an RMT-mediated disorder or gene mutation in the RMT gene, a therapy that includes the administration of a provided salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition.
  • the disease is proliferative disease.
  • the disease is cancer.
  • a method of treatment in a subject in need thereof comprising the steps of determining the presence of an RMT- mediated disorder or a gene mutation in the RMT gene and treating the subject in need thereof, based on the presence of a RMT-mediated disorder or gene mutation in the RMT gene, with a therapy that includes the administration of a provided salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition to the subject.
  • the subject is a cancer patient.
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating a proliferative disorder, such as cancer.
  • a proliferative disorder such as cancer.
  • protein arginine methylation by PRMTs is a modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others; and overexpression of PRMTs within these pathways is often associated with various cancers.
  • compositions which inhibit the action of PRMTs are effective in the treatment of cancer.
  • salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein are effective in treating cancer through the inhibition of PRMT1.
  • PRMT1 overexpression has been observed in various human cancers, including, but not limited to, breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, and leukemia.
  • PRMT1 specifically deposits an asymmetric dimethylarginine (aDMA) mark on histone H4 at arginine 3 (H4R3me2a), and this mark is associated with transcriptional activation.
  • aDMA asymmetric dimethylarginine
  • inhibitors of PRMT1 such as the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, are useful in treating cancers associated with the methylation status of H4R3, e.g., prostate cancer.
  • TDRD3 methylarginine effector molecule
  • H4R3me2a mark overexpression of TDRD3 is linked to poor prognosis for the survival of patients with breast cancer
  • inhibitors of PRMT1 such as the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, are useful in treating cancers associated with overexpression of TDRD3, e.g., breast cancer, as inhibition of PRMT1 leads to a decrease in methylation of H4R3, thereby preventing the association of overexpressed TDRD3 with
  • PRMT1 is known to have non-histone substrates.
  • PRMT1 when localized to the cytoplasm, methylates proteins that are involved in signal transduction pathways, e.g., the estrogen receptor (ER).
  • ER estrogen receptor
  • the expression status of ER in breast cancer is critical for prognosis of the disease, and both genomic and non-genomic ER pathways have been implicated in the pathogenesis of breast cancer.
  • SRC proto-oncogene tyro sine-protein kinase
  • FAK focal adhesion kinase
  • inhibitors of PRMTl such as the salts, co- crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, are useful in treating cancers associated with ERa methylation, e.g., breast cancer.
  • PRMTl has been shown to be involved in the regulation of leukemia development.
  • SRC-associated in mitosis 68 kDa protein is a well-characterized PRMTl substrate, and when either SAM68 or PRMTl is fused directly to the myeloid/lymphoid leukemia (MLL) gene, these fusion proteins can activate MLL oncogenic properties, implying that the methylation of SAM68 by PRMTl is a critical signal for the development of leukemia (Cheung et ah, Nature Cell Biol. 2007 9, 1208-1215).
  • inhibitors of PRMTl are useful in treating cancers associated with SAM68 methylation, e.g., leukemia.
  • PRMTl is implicated in leukemia development through its interaction with AE9a, a splice isoform of AML1-ETO (Shia et al, Blood 2012 119:4953-62).
  • AE9a recruits PRMTl to AE9a activated gene promoters, which leads to increased H4 Arg3 methylation, H3 Lys9/14 acetylation, and transcription activated.
  • inhibitors of PRMTl such as the salts, co-crystals, amorphous forms, crystalline forms, and
  • compositions described herein are useful in treating cancers associated with AML1-ETO, e.g., leukemia.
  • AML1-ETO e.g., leukemia.
  • the inhibition of PRMTl e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, is beneficial in the treatment of cancer.
  • salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein are effective in treating cancer through the inhibition of PRMT3.
  • the DALl tumor suppressor protein has been shown to interact with PRMT3 and inhibits its methyltransferase activity (Singh et al., Oncogene 2004 23, 7761-7771).
  • Epigenetic downregulation of DALl has been reported in several cancers ⁇ e.g., meningiomas and breast cancer), thus PRMT3 is expected to display increased activity, and cancers that display DALl silencing may, in some aspects, be good targets for PRMT3 inhibitors, e.g., those described herein.
  • the inhibition of PRMT3, e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein is beneficial in the treatment of cancer.
  • salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein are effective in treating cancer through the inhibition of PRMT4, also known as CARMl.
  • PRMT4 levels have been shown to be elevated in castration-resistant prostate cancer (CRPC), as well as in aggressive breast tumors (Hong et al, Cancer 2004 101, 83-89; Majumder et al, Prostate 2006 66, 1292- 1301).
  • inhibitors of PRMT4 such as the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, are useful in treating cancers associated with PRMT4 overexpression.
  • PRMT4 has also been shown to affect ERa-dependent breast cancer cell differentiation and proliferation (Al- Dhaheri et al, Cancer Res. 2011 71, 2118-2128), thus in some aspects PRMT4 inhibitors, such as the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, are useful in treating ERa-dependent breast cancer by inhibiting cell differentiation and proliferation.
  • PRMT4 has been shown to be recruited to the promoter of E2F1 (which encodes a cell cycle regulator) as a transcriptional co-activator (Frietze et al., Cancer Res. 2008 68, 301-306).
  • PRMT4- mediated upregulation of E2F1 expression may contribute to cancer progression and chemoresistance as increased abundance of E2F1 triggers invasion and metastasis by activating growth receptor signaling pathways, which in turn promote an antiapoptotic tumor environment (Engelmann and Piitzer, Cancer Res 2012 72; 571). Accordingly, in some embodiments, the inhibition of PRMT4, e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein, is useful in treating cancers associated with E2F1 upregulation.
  • the inhibition of PRMT4 e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, is beneficial in the treatment of cancer.
  • salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein are effective in treating cancer through the inhibition of PRMT6.
  • PRMT6 has been reported to be overexpressed in a number of cancers, e.g., bladder and lung cancer (Yoshimatsu et al., Int. J. Cancer 2011 128, 562-573).
  • the inhibition of PRMT6, by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein is useful in treating cancers associated with PRMT6 overexpression.
  • PRMT6 is primarily thought to function as a transcriptional repressor, although it has also been reported that PRMT6 functions as a co-activator of nuclear receptors.
  • PRMT6 suppresses the expression of thrombospondin 1 (TSPl; also known as THBS1; a potent natural inhibitor of angiogenesis and endothelial cell migration) and p21 (a natural inhibitor of cyclin dependent kinase), thereby contributing to cancer development and progression (Michaud-Levesque and Richard, J. Biol. Chem. 2009 284, 21338-21346; Kleinschmidt et al., PLoS ONE 2012 7, e41446).
  • TSPl thrombospondin 1
  • p21 a natural inhibitor of cyclin dependent kinase
  • the inhibition of PRMT6, by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein is useful in treating cancer by preventing the repression of THBsl and/or p21.
  • the inhibition of PRMT6, e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein is beneficial in the treatment of cancer.
  • salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein are effective in treating cancer through the inhibition of PRMT8.
  • deep- sequencing efforts of cancer genomes e.g.,
  • PRMT8 Because of its high rate of mutation in cancer, PRMT8 is thought to contribute to the initiation or progression of cancer. Thus, without being bound by any particular mechanism, the inhibition of PRMT8, e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, is beneficial in the treatment of cancer.
  • cancers that are treated by the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein include, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer,
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendothelio sarcoma, hemangio sarcoma
  • appendix cancer benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; meduUoblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal cancer (
  • adenocarcinoma epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach
  • adenocarcinoma adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • head and neck cancer e.g., head and neck squamous cell carcinoma
  • oral cancer e.g., oral squamous cell carcinoma (OSCC)
  • throat cancer e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer
  • hematopoietic cancers e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B- cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell
  • ALL acute lymphocytic leukemia
  • AML acute myelocytic leukemia
  • CML chronic myelocytic leukemia
  • lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma
  • B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B- cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom's macro globulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and
  • DLCL diffuse large cell lympho
  • angioimmunoblastic T-cell lymphoma extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma
  • MM multiple myeloma
  • heavy chain disease e.g., alpha chain disease, gamma chain disease, mu chain disease
  • hemangioblastoma e.g., inflammatory myofibroblastic tumors, immunocytic amyloidosis
  • kidney cancer e.g., nephroblastoma a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
  • pancreatic cancer e.g., pancreatic
  • IPMN intraductal papillary mucinous neoplasm
  • Islet cell tumors intraductal papillary mucinous neoplasm
  • penile cancer e.g., Paget' s disease of the penis and scrotum
  • pinealoma e.g., primitive neuroectodermal tumor (PNT)
  • prostate cancer e.g., prostate adenocarcinoma
  • rectal cancer e.g., intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer e.g., Paget' s disease of the penis and scrotum
  • pinealoma e.g., primitive neuroectodermal tumor (PNT)
  • prostate cancer e.g., prostate adenocarcinoma
  • rectal cancer e.g., prostate adenocarcinoma
  • rhabdomyosarcoma salivary gland cancer
  • skin cancer e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)
  • small bowel cancer e.g., appendix cancer
  • soft tissue sarcoma e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma
  • sebaceous gland carcinoma sweat gland carcinoma, synovioma
  • testicular cancer e.g., seminoma, testicular embryonal carcinoma
  • thyroid cancer e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
  • urethral cancer vaginal cancer and vulvar cancer (e.g., Paget' s disease of the vul
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating diseases associated with increased levels of circulating asymmetric dimethylarginine (aDMA), e.g., cardiovascular disease, diabetes, kidney failure, renal disease, pulmonary disease, etc.
  • Circulating aDMA is produced by the proteolysis of asymmetrically dimethylated proteins.
  • PRMTs which mediate aDMA methylation include, e.g., PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8.
  • aDMA levels are directly involved in various diseases as aDMA is an endogenous competitive inhibitor of nitric oxide synthase (NOS), thereby reducing the production of nitric oxide (NO)
  • PRMT1 is a major enzyme that generates aDMA
  • the dysregulation of its activity is likely to regulate cardiovascular diseases (Boger et ah, Ann. Med. 2006 38: 126-36), and other pathophysiological conditions such as diabetes mellitus (Sydow et ah, Vase. Med. 2005 10(Suppl.
  • the inhibition of PRMTs results in the decrease of circulating aDMA, which is beneficial in the treatment of diseases associated with increased levels of circulating aDMA, e.g., cardiovascular disease, diabetes, kidney failure, renal disease, pulmonary disease, etc.
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful for treating or preventing vascular diseases.
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating metabolic disorders.
  • PRMT1 has been shown to enhance mRNA levels of FoxOl target genes in gluconeogenesis, which results in increased hepatic glucose production, and knockdown of PRMT promotes inhibition of FoxOl activity and thus inhibition of hepatic gluconeogenesis (Choi et ah, Hepatology 2012 56: 1546-56).
  • genetic haploinsufficiency of Prmtl has been shown to reduce blood glucose levels in mouse models.
  • the inhibition of PRMT1 is beneficial in the treating of metabolic disorders, such as diabetes.
  • a provided salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition is useful in treating Type I diabetes.
  • a provided salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition is useful in treating Type II diabetes.
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating muscular dystrophies.
  • PRMT1 methylate the nuclear poly (A) -binding protein (PABPN1) in a region located near its C-terminus (Perreault et ah, J. Biol. Chem. 2007 282:7552-62).
  • PABPN1 nuclear poly (A) -binding protein
  • This domain is involved in the aggregation of the PABPN1 protein, and abnormal aggregation of this protein is involved in the disease oculopharyngeal muscular dystrophy (Davies et ah, Int. J. Biochem. Cell. Biol.
  • the inhibition of PRMTs is beneficial in the treatment of muscular dystrophies, e.g., oculopharyngeal muscular dystrophy, by decreasing the amount of methylation of PABPN1, thereby decreasing the amount of PABPNl aggregation.
  • CARM1 is also the most abundant PRMT expressed in skeletal muscle cells, and has been found to selectively control the pathways modulating glycogen metabolism, and associated AMPK (AMP-activated protein kinase) and p38 MAPK (mitogen-activated protein kinase) expression. See, e.g., Wang et al., Biochem (2012) 444:323-331.
  • inhibitors of CARM1, such as the salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein are useful in treating metabolic disorders, e.g., for example skeletal muscle metabolic disorders, e.g., glycogen and glucose metabolic disorders.
  • Exemplary skeletal muscle metabolic disorders include, but are not limited to, Acid Maltase Deficiency (Glycogenosis type 2; Pompe disease), Debrancher deficiency (Glycogenosis type 3), Phosphorylase deficiency (McArdle's; GSD 5), X-linked syndrome (GSD9D), Autosomal recessive syndrome (GSD9B), Tarui's disease (Glycogen storage disease VII; GSD 7), Phosphoglycerate Mutase deficiency (Glycogen storage disease X; GSDX; GSD 10), Lactate dehydrogenase A deficiency (GSD 11), Branching enzyme deficiency (GSD 4), Aldolase A (muscle) deficiency, ⁇ -Enolase deficiency, Triosephosphate isomerase (TIM) deficiency, Lafora's disease (Progressive myoclonic epilepsy 2), Glycogen storage disease (Mus
  • Glycogenin Deficiency (GSD 15).
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating autoimmune diseases.
  • PRMT inhibitors may be valuable for the treatment of autoimmune diseases, e.g., rheumatoid arthritis.
  • PRMTs are known to modify and regulate several critical immunomodulatory proteins. For example, post- translational modifications (e.g., arginine methylation), within T cell receptor signaling cascades allow T lymphocytes to initiate a rapid and appropriate immune response to pathogens.
  • Co-engagement of the CD28 co stimulatory receptor with the T cell receptor elevates PRMT activity and cellular protein arginine methylation, including methylation of the guanine nucleotide exchange factor Vavl (Blanchet et ah, J. Exp. Med. 2005 202:371- 377).
  • PRMT inhibitors are thus expected to diminish methylation of the guanine exchange factor Vavl, resulting in diminished IL-2 production.
  • siRNA directed against PRMT5 was shown to both inhibit NFAT-driven promoter activity and IL-2 secretion (Richard et ah, Biochem J. 2005 388:379-386).
  • PRMT1 is known to cooperate with PRMT4 to enhance NFkB p65-driven transcription and facilitate the transcription of p65 target genes like TNFa (Covic et ah, Embo. J. 2005 24:85-96).
  • PRMT1 and/or PRMT4 inhibitors are useful in treating autoimmune disease by decreasing the transcription of p65 target genes like TNFa.
  • PRMTs e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein, is beneficial in the treatment of autoimmune diseases.
  • a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein is useful in treating neurological disorders, such as amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • TLS/FUS a gene involved in ALS, TLS/FUS, often contains mutated arginines in certain familial forms of this disease (Kwiatkowski et ah, Science 2009 323: 1205-8). These mutants are retained in the cytoplasm, which is similar to reports documenting the role arginine methylation plays in nuclear-cytoplasmic shuffling (Shen et al, Genes Dev. 1998 12:679-91).
  • PRMT e.g., PRMT1
  • TLS/FUS is methylated on at least 20 arginine residues
  • the inhibition of PRMTs e.g., by salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions provided herein, are useful in treating ALS by decreasing the amount of TLS/FUS arginine methylation.
  • the present disclosure provides uses of a salt, co-crystal, amorphous form, crystalline form, or pharmaceutical composition described herein in a method described herein.
  • the present disclosure provides salts, co-crystals, amorphous forms, crystalline forms, and pharmaceutical compositions described herein for use in a method described herein.
  • Form A was prepared according to the method of preparing compound 133 as described in International PCT Application
  • XRPD was performed with Panalytical Empyrean XRPD on a Si single crystal holder. The 2 ⁇ (2 theta) position was calibrated against Panalytical 640 Si powder standard.
  • TGA Thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • TGA was conducted at 10 °C/min ramping from RT to desired temperature in open platinum pans using a TA Instruments Q5000 TGA. The temperature was calibrated using nickel and the weight using TA-supplied standard weights and verified against calcium oxalate monohydrate dehydration and decomposition.
  • DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic.
  • the relative humidity (RH) at 25 °C was calibrated against deliquescence point of LiCl, Mg(N0 3 ) 2 , and KCl.
  • Exemplary DVS parameters used in the experiments are as shown in Table 16 below.
  • thermodynamic solubilities of the solid forms described herein were determined at room temperature (RT, 25 + 3 °C).
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

Abstract

La présente invention concerne des formes solides (par exemple<i />, des sels, des co-cristaux, des formes amorphes et des formes cristallines) de N 1-((3-((5s,8s)-3,3-diméthyl-1-oxaspiro[4.5]décan-8-yl)-lH-pyrazol-4-yl)méthyl)-N 1,N 2-diméthyléthane-1,2-diamine (composé 133). L'invention concerne en outre des compositions pharmaceutiques, des kits, des procédés et des utilisations qui comprennent ou mettent en œuvre les formes solides pour inhiber l'activité arginine méthyltransférase et pour traiter des troubles médiés par l'arginine méthyltransférase, par exemple, pour le traitement de troubles à médiation par l'arginine méthyltransférase (par exemple, des troubles prolifératifs, des troubles neurologiques, des troubles auto-immuns, des troubles vasculaires et des troubles métaboliques).<i />
PCT/US2015/050659 2014-09-17 2015-09-17 Sels, co-cristaux, formes amorphes, et formes cristallines d'un inhibiteur d'arginine méthyltransférase WO2016044576A1 (fr)

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