Crystalline forms of TYK2 inhibitor

Abstract

Described herein are crystalline forms of a salt of 1-(5-((7-fluoro-2, 3-dihydrobenzo [b] [1, 4] dioxin-5-yl) amino)-7-(methylamino) pyrazolo [1, 5-a] pyrimidin-3-yl)-3-((1R, 2S)-2-fluorocyclopropyl) urea adipate and a solvate thereof.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,790, filed on July 6, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-STAT pathway. The four members of the JAK family are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), and have been shown to be key components of cytokine-mediated effects. Unlike JAK1-deficient mice, TYK2-deficient mice are viable, and TYK2 deficiency has been shown to be protective in various autoimmune models. Summary of the invention

[0004] In one aspect, described herein is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea or a pharmaceutically acceptable salt or solvate thereof.

[0005] In one embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is adipic acid salt (adipate) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Form 1 having at least one of the following properties:

[0006] (a) with Figure 1 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0007] (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ;

[0008] (c) with Figure 2Thermogravimetric analysis (TGA) substantially similar to that shown;

[0009] (d) with Figure 2 DSC thermograms substantially similar to those shown;

[0010] (e) a DSC thermogram having an exotherm starting at about 200° C.;

[0011] (f) non-hygroscopic; or

[0012] (g) combinations thereof.

[0013] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate or a solvate thereof has the same Figure 1 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0014] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ.

[0015] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 2 Thermogravimetric analysis (TGA) was substantially similar to that shown.

[0016] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 2 Substantially similar DSC thermograms are shown.

[0017] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form has a DSC thermogram with an exotherm starting at about 200°C.

[0018] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form is non-hygroscopic.

[0019] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is characterized by having the following properties: (a) Figure 1 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks located at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ; (c) and Figure 2 Thermogravimetric analysis (TGA) of the same type as shown in (d) Figure 2 The DSC thermograms shown are substantially similar; (e) a DSC thermogram having an exotherm onset at about 200°C; and (f) non-hygroscopic.

[0020] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form is obtained from acetone / water.

[0021] In some embodiments the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is non-hygroscopic.

[0022] In another embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is a salt of adipic acid (adipate salt) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt is Form 2 having at least one of the following properties:

[0023] (a) with Figure 3 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0024] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ;

[0025] (c) with Figure 4 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0026] (d) with Figure 4 DSC thermograms substantially similar to those shown;

[0027] (e) a DSC thermogram having an exotherm onset at about 194° C.;

[0028] (f) non-hygroscopic; or

[0029] (g) combinations thereof.

[0030] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 3 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0031] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ.

[0032] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 4 Thermogravimetric analysis (TGA) was substantially similar to that shown.

[0033] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 4 Substantially similar DSC thermograms are shown.

[0034] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form has a DSC thermogram with an exotherm starting at about 194°C.

[0035] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form is non-hygroscopic.

[0036] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate or a solvate thereof is characterized by having the following properties: (a) Figure 3 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ; (c) and Figure 4 Thermogravimetric analysis (TGA) of the same type as shown in (d) Figure 4 Shown are substantially similar DSC thermograms; (e) DSC thermogram with an exotherm onset at about 194°C; and (f) non-hygroscopic.

[0037] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form is obtained from acetone.

[0038] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form is anhydrous.

[0039] In another embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is a salt of adipic acid (adipate salt) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt is Form 3 having at least one of the following properties:

[0040] (a) with Figure 5 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0041] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ;

[0042] (c) with Figure 6 Thermogravimetric analysis (TGA) substantially similar to that shown in;

[0043] (d) with Figure 6 DSC thermograms substantially similar to those shown;

[0044] (e) a DSC thermogram having a first exotherm starting at about 133°C and a second exotherm starting at about 177°C; or

[0045] (f) combinations thereof.

[0046] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 5 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0047] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ.

[0048] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 6 Thermogravimetric analysis (TGA) was substantially similar to that shown.

[0049] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is Figure 6 Substantially similar DSC thermograms are shown.

[0050] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the crystalline form has a DSC thermogram with a first exotherm starting at about 133°C and a second exotherm starting at about 177°C.

[0051] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is characterized by having the following properties: (a) Figure 5 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ; (c) and Figure 6 Thermogravimetric analysis (TGA) of the same type as shown in (d) Figure 6 and (e) a DSC thermogram having a first exotherm onset at about 133°C and a second exotherm onset at about 177°C.

[0052] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is obtained from methyl tert-butyl ether.

[0053] In some embodiments is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate for use in medicine.

[0054] In some embodiments, it is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, wherein the 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is amorphous.

[0055] In another aspect, described herein is a pharmaceutical composition comprising a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate or a solvate thereof, and a pharmaceutically acceptable excipient.

[0056] In another aspect, described herein is a method of treating an inflammatory or autoimmune disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate or a solvate thereof as described herein.

[0057] Incorporation by reference

[0058] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 1.

[0060] Figure 2 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 1.

[0061] Figure 3 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 2.

[0062] Figure 4 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 2.

[0063] Figure 5 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 3.

[0064] Figure 6 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate, Form 3.

[0065] Figure 7 Shown is an X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) oxalate, Form 1.

[0066] Figure 8 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) oxalate, Form 1.

[0067] Fig. 9 Shown is an X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) phosphate, Form 1.

[0068] Fig.10 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) phosphate, Form 1.

[0069] Fig.11 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) methanesulfonate, Form 1.

[0070] Fig.12 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) methanesulfonate, Form 1.

[0071] Fig.13 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) free base, Form A.

[0072] Fig.14 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) free base, Form A.

[0073] Fig.15 Shown is the X-ray powder diffraction (XRPD) pattern of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) free base, Form B.

[0074] Fig.16 Shown are the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of crystalline 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) free base, Form B. DETAILED DESCRIPTION

[0075] As a member of the tyrosine kinase JAK family, TYK2 mediates the signal transduction of proinflammatory cytokines and therefore represents a target for the treatment of various inflammatory and autoimmune diseases. The iconic structural feature of the JAK family is the pseudokinase (JH2) domain adjacent to the N-terminus of the catalytic domain (JH1). Although the JH2 domain has the overall folding of a typical catalytic domain, a series of single residues and conformational differences between the TYK2 JH1 and JH2 domains indicate that the JH2 domain lacks catalytic activity. The JH2 domain of the JAK family has been shown to regulate the function of the JH1 domain. The overall evidence is consistent with the following: the TYK2 pseudokinase domain has an autoinhibitory effect, stabilizing the inactivated state of the kinase domain, and small molecule ligands can stabilize this autoinhibitory conformation, thereby preventing the protein from exerting its effect in an allosteric manner (Moslin et al., Med. Chem. Commun., 2017, 700-712).

[0076] The compounds of formula (I') described herein are TYK2 pseudokinase ligands. The compounds of formula (I') described herein and compositions comprising these compounds are useful for treating inflammatory or autoimmune diseases.

[0077] Described herein are crystalline forms of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), which is a TYK2 pseudokinase ligand. The crystalline forms of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea described herein and compositions comprising these crystalline forms are useful for treating inflammatory or autoimmune diseases.

[0078] Compound 1

[0079] In one embodiment, it is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea. "Compound 1" or "1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea" refers to a compound having the following structure:

[0080]

[0081] A variety of pharmaceutically acceptable salts are formed from Compound 1 and include:

[0082] - Acid addition salts formed by reacting compound 1 with an organic acid, the organic acid including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, and the like, and including, for example, acetic acid, adipic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

[0083] - Acid addition salts formed by reacting compound 1 with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0084] The term "pharmaceutically acceptable salt" with respect to Compound 1 refers to a salt of Compound 1 that does not cause significant irritation to a mammal to which the salt is administered and does not significantly abrogate the biological activity and properties of the compound.

[0085] It should be understood that the pharmaceutically acceptable salts mentioned include solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts of solvents and are formed with pharmaceutically acceptable solvents in product formation or separation processes, such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In one aspect, solvates are formed using (but not limited to) Class 3 solvents. The 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)". When the solvent is water, a hydrate is formed; or when the solvent is an alcohol, an alcoholate is formed. In some embodiments, a solvate of Compound 1 or a pharmaceutically acceptable salt thereof is conveniently prepared or formed in the process described herein. In some embodiments, a solvate of Compound 1 is anhydrous. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exists in a non-solvated form. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exists in a non-solvated form and is anhydrous.

[0086] In yet other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is prepared in various forms, including but not limited to an amorphous phase, a crystalline form, a ground form, and a nanoparticle form. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is amorphous and anhydrous. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.

[0087] Although not intended to be bound by any particular theory, some solid forms are characterized as physical properties suitable for drugs and therapeutic dosage forms, such as stability, solubility and dissolution rate. In addition, although not wishing to be bound by any particular theory, some solid forms are characterized as physical properties (such as density, compressibility, hardness, morphology, cracking, viscosity, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability and chemical stability) that affect specific processes (such as yield, filtration, washing, drying, grinding, mixing, tableting, flow, dissolution, formulation and lyophilization), which make some solid forms suitable for manufacturing solid dosage forms. These properties can be determined using specific analytical chemistry techniques (including solid-state analytical techniques (such as X-ray diffraction, microscopy, spectroscopy and thermal analysis) as described herein and known in the art).

[0088] Crystalline form

[0089] Identifying and selecting solid forms of pharmaceutical compounds is complex because changes in solid form can affect various physical and chemical properties that can provide benefits or disadvantages in processing, formulation, stability, bioavailability, storage and handling (e.g., transportation) and other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solids depends on the specific application; sometimes amorphous solids are selected based on, for example, enhanced dissolution characteristics, while crystalline solids can meet the needs because of properties such as physical or chemical stability.

[0090] Whether crystalline or amorphous, solid forms of pharmaceutical compounds include single-component and multi-component solids. Single-component solids are primarily composed of the pharmaceutical compound or active ingredient and do not contain other compounds. The diversity among single-component crystalline materials may potentially arise from polymorphism, where multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0091] It is noteworthy that it is impossible to predict a priori whether crystalline forms of a compound will exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun.: 3635-3645 (with respect to crystal engineering, if the instructions are not very precise and / or if other external factors influence the process, the results can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31: 875-879 (at present, it is generally impossible to predict computationally the number of observable polymorphs of even the simplest molecules); Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews 56: 301-319 ("Price"); and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism," ACA Transactions 39:14-23 (There is still much to learn and accomplish before one can predict crystal structures (let alone polymorphic forms) with any degree of confidence).

[0092] The diversity of possible solid forms creates a potential diversity of physical and chemical properties for a given drug compound. The discovery and selection of solid forms is critical to the development of effective, stable, and marketable drug products.

[0093] Crystalline Compound 1, Adipate Salt Form 1

[0094] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a salt of adipic acid (adipate salt), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate salt is Form 1. In some embodiments, the crystalline Compound 1 adipate salt is Form 1 having at least one of the following properties:

[0095] (a) with Figure 1 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0096] (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ;

[0097] (c) with Figure 2 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0098] (d) with Figure 2 DSC thermograms substantially similar to those shown;

[0099] (e) a DSC thermogram having an exotherm starting at about 200° C.;

[0100] (f) non-hygroscopic; or

[0101] (g) combinations thereof.

[0102] In some embodiments, crystalline compound 1 adipate salt form 1 is characterized as having at least two properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 1 is characterized as having at least three properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 1 is characterized as having at least four properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 1 is characterized as having at least five properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 1 is characterized as having properties (a) to (f).

[0103] In some embodiments, crystalline Compound 1 adipate salt Form 1 has Figure 1In some embodiments, the crystalline compound 1 adipate salt form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 adipate salt form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ. In some embodiments, the crystalline compound 1 adipate salt form 1 has a X-ray powder diffraction (XRPD) pattern substantially the same as shown. Figure 2 In some embodiments, the crystalline compound 1 adipate salt form 1 has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG. Figure 2 In some embodiments, the crystalline compound 1 adipate salt form 1 has a DSC thermogram with an exotherm starting at about 200°C. In some embodiments, the crystalline compound 1 adipate salt form 1 is non-hygroscopic. In some embodiments, the crystalline compound 1 adipate salt form 1 is obtained from acetone / water. In some embodiments, the crystalline compound 1 adipate salt form 1 is solvated. In some embodiments, the crystalline compound 1 adipate salt form 1 is non-solvated.

[0104] Crystalline Compound 1, adipate salt form 2

[0105] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a salt of adipic acid (adipate salt), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate salt is Form 2. In some embodiments, the crystalline Compound 1 adipate salt is Form 2 characterized by having at least one of the following properties:

[0106] (a) with Figure 3 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0107] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ;

[0108] (c) with Figure 4 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0109] (d) with Figure 4 DSC thermograms substantially similar to those shown;

[0110] (e) a DSC thermogram having an exotherm onset at about 194° C.;

[0111] (f) non-hygroscopic; or

[0112] (g) combinations thereof.

[0113] In some embodiments, crystalline compound 1 adipate salt form 2 is characterized as having at least two properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 2 is characterized as having at least three properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 2 is characterized as having at least four properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 2 is characterized as having at least five properties selected from (a) to (f). In some embodiments, crystalline compound 1 adipate salt form 2 is characterized as having properties (a) to (f).

[0114] In some embodiments, the crystalline Compound 1 adipate salt form 2 has Figure 3 In some embodiments, the crystalline compound 1 adipate salt form 2 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 adipate salt form 2 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ, and 25.6°2θ. In some embodiments, the crystalline compound 1 adipate salt form 2 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. Figure 4 In some embodiments, the crystalline compound 1 adipate salt form 2 has a thermal gravimetric analysis (TGA) thermogram substantially similar to that shown in FIG. Figure 4 In some embodiments, the crystalline compound 1 adipate salt form 2 has a DSC thermogram substantially similar to that shown in . In some embodiments, the crystalline compound 1 adipate salt form 2 has an exothermic DSC thermogram starting at about 194°C. In some embodiments, the crystalline compound 1 adipate salt form 2 is non-hygroscopic. In some embodiments, the crystalline compound 1 adipate salt form 2 is obtained from acetone. In some embodiments, the crystalline compound 1 adipate salt form 2 is solvated. In some embodiments, the crystalline compound 1 adipate acid form 2 is non-solvated.

[0115] Crystalline Compound 1, adipate salt form 3

[0116] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a salt of adipic acid (adipate salt), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate salt is Form 3. In some embodiments, the crystalline Compound 1 adipate salt is Form 3 characterized by having at least one of the following properties:

[0117] (a) with Figure 5 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0118] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ;

[0119] (c) with Figure 6 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0120] (d) with Figure 6 DSC thermograms substantially similar to those shown;

[0121] (e) a DSC thermogram having a first exotherm starting at about 133°C and a second exotherm starting at about 177°C; or

[0122] (f) combinations thereof.

[0123] In some embodiments, crystalline compound 1 adipate salt form 3 is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline compound 1 adipate salt form 3 is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline compound 1 adipate salt form 3 is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline compound 1 adipate salt form 3 is characterized as having properties (a) to (e).

[0124] In some embodiments, crystalline Compound 1 adipate salt form 3 has Figure 5In some embodiments, the crystalline compound 1 adipate salt form 3 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 adipate salt form 3 has a characteristic peak located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ. In some embodiments, the crystalline compound 1 adipate salt form 3 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. Figure 6 In some embodiments, the crystalline compound 1 adipate salt form 3 has a thermal gravimetric analysis (TGA) thermogram substantially similar to that shown in FIG. Figure 6 In some embodiments, the crystalline compound 1 adipate salt form 3 has a DSC thermogram with a first exotherm starting at about 133°C and a second exotherm starting at 177°C. In some embodiments, the crystalline compound 1 adipate salt form 3 is non-hygroscopic. In some embodiments, the crystalline compound 1 adipate salt form 3 is obtained from methyl tert-butyl ether. In some embodiments, the crystalline compound 1 adipate salt form 3 is solvated. In some embodiments, the crystalline compound 1 adipate acid form 3 is non-solvated.

[0125] Crystalline Compound 1, Oxalate Form 1

[0126] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is an oxalate salt (oxalate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) oxalate salt is Form 1. In some embodiments, the crystalline Compound 1 oxalate salt is Form 1 characterized by having at least one of the following properties:

[0127] (a) with Figure 7 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0128] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 5.4°2θ, 8.8°2θ, 12.9°2θ, 16.3°2θ, 17.8°2θ, 20.0°2θ, 21.7°2θ, 23.9°2θ, 26.4°2θ, 27.3°2θ and 28.4°2θ;

[0129] (c) with Figure 8 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0130] (d) with Figure 8 DSC thermograms substantially similar to those shown;

[0131] (e) a DSC thermogram having an endothermic signature starting at about 190°C and a subsequent exothermic signature; or

[0132] (f) combinations thereof.

[0133] In some embodiments, crystalline compound 1 oxalate form 1 is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline compound 1 oxalate form 1 is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline compound 1 oxalate form 1 is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline compound 1 oxalate form 1 is characterized as having properties (a) to (e).

[0134] In some embodiments, the crystalline Compound 1 oxalate salt form 1 has Figure 7 In some embodiments, the crystalline compound 1 oxalate form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 oxalate form 1 has characteristic peaks located at 5.4°2θ, 8.8°2θ, 12.9°2θ, 16.3°2θ, 17.8°2θ, 20.0°2θ, 21.7°2θ, 23.9°2θ, 26.4°2θ, 27.3°2θ and 28.4°2θ. In some embodiments, the crystalline compound 1 oxalate form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. Figure 8 In some embodiments, the crystalline compound 1 oxalate salt form 1 has a substantially similar thermogravimetric analysis (TGA) thermogram to that shown in FIG. Figure 8 In some embodiments, the crystalline compound 1 oxalate form 1 has a DSC thermogram with an endothermic signal starting at about 190°C and a subsequent exothermic signal. In some embodiments, the crystalline compound 1 oxalate form 1 is non-hygroscopic. In some embodiments, the crystalline compound 1 oxalate form 1 is obtained from acetone. In some embodiments, the crystalline compound 1 oxalate form 1 is solvated. In some embodiments, the crystalline compound 1 oxalate form 1 is non-solvated.

[0135] Crystalline Compound 1, Phosphate Form 1

[0136] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a phosphate (phosphate) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) phosphate is Form 1. In some embodiments, the crystalline Compound 1 phosphate is Form 1 characterized by having at least one of the following properties:

[0137] (a) with Fig. 9 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0138] (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 8.7°2θ, 14.3°2θ, 15.8°2θ, 17.0°2θ, 17.3°2θ, 21.1°2θ, 21.4°2θ and 22.3°2θ;

[0139] (c) with Fig.10 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0140] (d) with Fig.10 DSC thermograms substantially similar to those shown;

[0141] (e) a DSC thermogram having an exotherm with an onset at about 200°C; or

[0142] (f) combinations thereof.

[0143] In some embodiments, crystalline Compound 1 phosphate form 1 is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline Compound 1 phosphate form 1 is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline Compound 1 phosphate form 1 is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline Compound 1 phosphate form 1 is characterized as having properties (a) to (e).

[0144] In some embodiments, the crystalline Compound 1 phosphate salt form 1 has Fig. 9In some embodiments, the crystalline compound 1 phosphate form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 phosphate form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 8.7°2θ, 14.3°2θ, 15.8°2θ, 17.0°2θ, 17.3°2θ, 21.1°2θ, 21.4°2θ and 22.3°2θ. In some embodiments, the crystalline compound 1 phosphate form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. Fig.10 In some embodiments, the crystalline compound 1 phosphate salt form 1 has a substantially similar thermogravimetric analysis (TGA) thermogram to that shown in FIG. Fig.10 In some embodiments, the crystalline compound 1 phosphate form 1 has a DSC thermogram with an exotherm starting at about 200°C. In some embodiments, the crystalline compound 1 phosphate form 1 is non-hygroscopic. In some embodiments, the crystalline compound 1 phosphate form 1 is obtained from methanol. In some embodiments, the crystalline compound 1 phosphate form 1 is solvated. In some embodiments, the crystalline compound 1 phosphate form 1 is non-solvated.

[0145] Crystalline Compound 1, Mesylate Salt Form 1

[0146] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a mesylate salt (mesylate) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) mesylate salt is Form 1. In some embodiments, the crystalline Compound 1 mesylate salt is Form 1 characterized by having at least one of the following properties:

[0147] (a) with Fig.11 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0148] (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.5°2θ, 15.5°2θ, 17.8°2θ, 18.9°2θ, 19.3°2θ, 21.6°2θ, 22.2°2θ, 23.2°2θ, 24.7°2θ and 27.8°2θ;

[0149] (c) with Fig.12 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0150] (d) with Fig.12 DSC thermograms substantially similar to those shown;

[0151] (e) having a DSC thermogram with an exotherm greater than 195°C; or

[0152] (f) combinations thereof.

[0153] In some embodiments, crystalline compound 1 mesylate salt form 1 is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline compound 1 mesylate salt form 1 is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline compound 1 mesylate salt form 1 is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline compound 1 mesylate salt form 1 is characterized as having properties (a) to (e).

[0154] In some embodiments, the crystalline compound 1 mesylate salt form 1 has Fig.11 In some embodiments, the crystalline compound 1 mesylate salt form 1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 mesylate salt form 1 has a characteristic peak located at 7.5°2θ, 15.5°2θ, 17.8°2θ, 18.9°2θ, 19.3°2θ, 21.6°2θ, 22.2°2θ, 23.2°2θ, 24.7°2θ and 27.8°2θ. In some embodiments, the crystalline compound 1 mesylate salt form 1 has a X-ray powder diffraction (XRPD) pattern substantially the same as shown. Fig.12 In some embodiments, the crystalline compound 1 mesylate salt form 1 has a substantially similar thermogravimetric analysis (TGA) thermogram to that shown in FIG. Fig.12 In some embodiments, the crystalline compound 1 mesylate salt form 1 has a DSC thermogram that is exothermic above 195°C. In some embodiments, the crystalline compound 1 mesylate salt form 1 is non-hygroscopic. In some embodiments, the crystalline compound 1 mesylate salt form 1 is obtained from ethanol. In some embodiments, the crystalline compound 1 mesylate salt form 1 is solvated. In some embodiments, the crystalline compound 1 mesylate salt form 1 is non-solvated.

[0155] Crystalline Compound 1, Free Base Form A

[0156] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the free base and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is Form A. In some embodiments, crystalline Compound 1 is Form A characterized by having at least one of the following properties:

[0157] (a) with Fig.13 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0158] (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 8.5°2θ, 11.8°2θ, 12.3°2θ, 13.3°2θ, 17.1°2θ, 19.4°2θ, 23.7°2θ and 26.8°2θ;

[0159] (c) with Fig.14 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0160] (d) with Fig.14 DSC thermograms substantially similar to those shown;

[0161] (e) a DSC thermogram having an exotherm with an onset at about 210°C; or

[0162] (f) combinations thereof.

[0163] In some embodiments, crystalline Compound 1 Form A is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form A is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form A is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form A is characterized as having properties (a) to (e).

[0164] In some embodiments, crystalline Compound 1 Form A has Fig.13In some embodiments, the crystalline Compound 1 Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, the crystalline Compound 1 Form A has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 8.5°2θ, 11.8°2θ, 12.3°2θ, 13.3°2θ, 17.1°2θ, 19.4°2θ, 23.7°2θ, and 26.8°2θ. In some embodiments, the crystalline Compound 1 Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . Fig.14 In some embodiments, the crystalline Compound 1 Form A has a substantially similar thermogravimetric analysis (TGA) thermogram to that shown in FIG. Fig.14 In some embodiments, the crystalline Compound 1 Form A has a DSC thermogram with an exotherm starting at about 210° C. In some embodiments, the crystalline Compound 1 Form A is non-hygroscopic. In some embodiments, the crystalline Compound 1 Form A is obtained from ethyl acetate. In some embodiments, the crystalline Compound 1 Form A is solvated. In some embodiments, the crystalline Compound 1 Form A is non-solvated.

[0165] Crystalline Compound 1, Free Base Form B

[0166] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the free base and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is Form B. In some embodiments, crystalline Compound 1 is Form B characterized by at least one of the following properties:

[0167] (a) with Fig.15 substantially the same X-ray powder diffraction (XRPD) pattern as shown;

[0168] (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 6.6°2θ, 10.1°2θ, 14.0°2θ, 16.6°2θ, 19.7°2θ, 22.2°2θ, 24.1°2θ and 26.2°2θ;

[0169] (c) with Fig.16 Thermogravimetric analysis (TGA) substantially similar to that shown;

[0170] (d) with Fig.16 DSC thermograms substantially similar to those shown;

[0171] (e) a DSC thermogram having an endothermic peak at about 177°C followed by an exothermic signal; or

[0172] (f) combinations thereof.

[0173] In some embodiments, crystalline Compound 1 Form B is characterized as having at least two properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form B is characterized as having at least three properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form B is characterized as having at least four properties selected from (a) to (e). In some embodiments, crystalline Compound 1 Form B is characterized as having properties (a) to (e).

[0174] In some embodiments, crystalline Compound 1 Form B has Fig.15 In some embodiments, the crystalline compound 1 Form B has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. In some embodiments, the crystalline compound 1 Form B has an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 6.6°2θ, 10.1°2θ, 14.0°2θ, 16.6°2θ, 19.7°2θ, 22.2°2θ, 24.1°2θ, and 26.2°2θ. In some embodiments, the crystalline compound 1 Form B has an X-ray powder diffraction (XRPD) pattern substantially the same as shown. Fig.16 In some embodiments, the crystalline compound 1 Form B has a substantially similar thermogravimetric analysis (TGA) thermogram to that shown in FIG. Fig.16 In some embodiments, the crystalline compound 1 Form B has a DSC thermogram with an endothermic peak at about 177°C, followed by an exothermic signal. In some embodiments, the crystalline compound 1 Form B is non-hygroscopic. In some embodiments, the crystalline compound 1 Form B is obtained from acetic acid. In some embodiments, the crystalline compound 1 Form B is solvated. In some embodiments, the crystalline compound 1 Form B is an acetic acid solvate. In some embodiments, the crystalline compound 1 Form B is non-solvated.

[0175] Preparation of crystalline compound 1

[0176] In some embodiments, compound 1 is prepared as described in US2021 / 0139486, which is incorporated herein by reference in its entirety. In some embodiments, the crystalline form of compound 1 is prepared as outlined in the examples. It is noted that the solvents, temperatures, and other reaction conditions set forth herein may vary.

[0177] In certain embodiments, provided herein is a method for preparing a solid form of compound 1, comprising 1) obtaining a saturated solution of compound 1 in a solvent at a first temperature (e.g., about 50°C); 2) adding an antisolvent to the saturated solution at a first temperature; 3) cooling to a second temperature (e.g., about -5°C to room temperature); and 4) collecting solids if there is precipitation, evaporating the solvent to collect solids if there is no precipitation; and 5) optionally drying. In certain embodiments, provided herein is a method for preparing a solid form of compound 1, comprising 1) obtaining a saturated solution of compound 1 in a solvent at about 50°C; 2) adding an antisolvent to the saturated solution at about 50°C; 3) cooling to about room temperature; and 4) collecting solids if there is precipitation, evaporating the solvent to collect solids if there is no precipitation; and 5) optionally air drying. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:9. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:4. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:2. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:1. In certain embodiments, the method for preparing a solid form of Compound 1 is an anti-solvent recrystallization experiment.

[0178] In another embodiment, the crystalline Compound 1 Form 3 is substantially pure. In certain embodiments, substantially pure crystalline Compound 1 Form 3 is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1 Form 3 is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0179] In another embodiment, the crystalline Compound 1 Form 2 is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1 Form 2 is substantially free of other solid forms, such as an amorphous solid. In certain embodiments, the substantially pure crystalline Compound 1 Form 2 has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0180] In another embodiment, the crystalline Compound 1 Form 1 is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1 Form 1 is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of the substantially pure crystalline Compound 1 Form 1 is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0181] Suitable solvent

[0182] The therapeutic agent that can be applied to mammals (e.g., humans) must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are referred to as good manufacturing practices (GMP). The GMP guidelines outline the acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvents in the final product. In some embodiments, the solvent disclosed herein is a solvent suitable for use in a GMP facility and in compliance with industrial safety considerations. The solvent category is defined in, for example, the International Council for Harmonization of Technical Registration of Pharmaceuticals for Human Use (ICH) "Impurities: Guidelines for Residual Solvents Q3C (R6)," (October 2016).

[0183] Solvents are divided into three categories. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents that have limited use during the manufacturing process of therapeutic agents. Class 3 solvents are solvents with low toxicity potential and pose a low risk to human health. Data for Class 3 solvents show that they are less toxic in acute or short-term studies and have tested negative in genotoxicity studies.

[0184] Class 1 solvents to avoid include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0185] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, isopropylbenzene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene, and xylene.

[0186] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, methyl tert-butyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and triethylamine.

[0187] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the APIs. In some cases, it is not possible to completely remove the solvents by practical manufacturing techniques. Appropriate selection of solvents for the synthesis of APIs can improve yields or determine characteristics such as crystal form, purity, and solubility. Therefore, solvents are a critical parameter in the synthesis process.

[0188] In some embodiments, the composition comprising compound 1 comprises an organic solvent. In some embodiments, the composition comprising compound 1 comprises a residual amount of an organic solvent. In some embodiments, the composition comprising compound 1 comprises a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, methyl tert-butyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and triethylamine. In some embodiments, the Class 3 solvent is selected from acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, heptane, isopropanol and ethanol.

[0189] In some embodiments, the composition comprising compound 1 comprises a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from acetonitrile, chlorobenzene, chloroform, isopropylbenzene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene and xylene. In some embodiments, the Class 2 solvent is selected from acetonitrile, tetrahydrofuran and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0190] In some embodiments, the composition comprising Compound 1 comprises a residual amount of a solvent for which adequate toxicological data have not been found. In some embodiments, the organic solvent is a solvent for which adequate toxicological data have not been found. In some embodiments, the solvent is selected from 2-butanone and 2-methyltetrahydrofuran.

[0191] Certain terms

[0192] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any subject matter claimed. In this application, unless otherwise explicitly stated, the use of the singular includes the plural. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly states otherwise. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms (such as "include", "includes" and "included") is not restrictive. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "included") is not intended to exclude that in certain other embodiments, for example, embodiments of any composition of matter, composition, method or process, etc. described herein may "consist of" or "consist essentially of" the described features. The term "about" when referring to a number or a numerical range means that the referenced number or numerical range is an approximation within the range of experimental variability (or within the range of statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

[0193] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated herein by reference in their entirety.

[0194] As used herein, the terms "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated or abrogating the biological activity or properties of the compound, and being relatively nontoxic.

[0195] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay of onset, slowing of progression, or shortening of duration, whether permanent or temporary, persistent or transient, attributable to or associated with the administration of the compound or composition.

[0196] "Bioavailability" refers to the percentage of administered Compound 1 that is delivered to the systemic circulation of an animal or human subject. The total exposure of the drug (AUC) when administered intravenously (0-∞) ) is generally defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is administered orally compared to intravenous injection.

[0197] "Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that the plasma concentration of Compound 1 can vary significantly between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of Compound 1 can vary from subject to subject. Similarly, a maximum plasma concentration (C 最大 ) or the time to reach maximum plasma concentration (T 最大 ) or the total area under the plasma concentration-time curve (AUC (0-∞) ) may vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

[0198] As used herein, the terms "co-administered," "co-administered," and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0199] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the administered agent or compound that will alleviate one or more symptoms of the disease or condition being treated to a certain extent. The result can be a reduction and / or alleviation of signs, symptoms or causes of the disease, or any other desired biological system changes. For example, an "effective amount" for therapeutic use is an amount of a composition including a compound as disclosed herein, which needs to provide a clinically significant reduction in disease symptoms without excessive adverse side effects. The appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a preventive effective amount. The "effective amount" of the compound disclosed herein is an amount that effectively achieves the desired pharmacological effect or therapeutic improvement without excessive adverse side effects. It should be understood that the "effective amount" or "therapeutically effective amount" may vary from subject to subject, due to the metabolism of compound 1, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, the therapeutically effective amount can be determined by a dose escalation clinical trial.

[0200] The term "enhance" or "enhancing" refers to increasing or prolonging the potency or duration of a desired effect. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong the effect (potency or duration) of a therapeutic agent during the treatment of a disease, disorder, or condition. As used herein, an "enhancing effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in treating a disease, disorder, or condition. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drug, and the judgment of the treating physician.

[0201] As used herein, the term "prophylactically effective amount" refers to the amount of the composition applied to a patient that will alleviate to some extent one or more symptoms of the disease, condition or disorder being treated. In such prophylactic applications, such an amount may depend on the patient's health status, weight, etc. As an example, such a prophylactically effective amount may be determined by a dose escalation clinical trial.

[0202] As used herein, the term "subject" refers to an animal that is the subject of treatment, observation or experiment. By way of example only, the subject can be, but is not limited to, a mammal, including, but not limited to, a human.

[0203] As used herein, the term "target activity" refers to a biological activity that can be regulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0204] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or stopping symptoms of a disease or condition. The term "treat" includes, but is not limited to, prophylactic and / or therapeutic treatment.

[0205] As used herein, IC 50 Refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of a particular response induced, stimulated or potentiated by that particular test compound.

[0206] Pharmaceutical compositions / preparations

[0207] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants) that assist in processing the active compound into a pharmaceutically usable preparation. Appropriate formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.

[0208] As used herein, a pharmaceutical composition refers to a mixture of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) and other chemical components (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). Pharmaceutical compositions facilitate administration of the compound to a mammal. In practicing the treatment or use methods provided herein, a therapeutically effective amount of Compound 1 is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, disorder or condition to be treated. Preferably, the mammal is a human. The therapeutically effective amount can vary greatly depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or as a component of a mixture in combination with one or more therapeutic agents.

[0209] In some embodiments, the pharmaceutical composition comprises 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 adipate (Form 1) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 adipate (Form 2) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 adipate (Form 3) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 oxalate (Form 1) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of the phosphate salt of compound 1 (Form 1) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of the mesylate salt of compound 1 (Form 1) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of the free base of compound 1 (Form A) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a crystalline form of the free base of compound 1 (Form B) and a pharmaceutically acceptable excipient.

[0210] The term "drug combination" as used herein refers to a product produced by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to an active ingredient (e.g., Compound 1) and an adjuvant being administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to an active ingredient (e.g., Compound 1) and an adjuvant being administered to a patient simultaneously, in parallel, or sequentially as an independent entity, without specific intermediate time limits, wherein such administration provides effective levels of the two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more active ingredients.

[0211] Pharmaceutical compositions comprising the compounds described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0212] Dosage form

[0213] The pharmaceutical compositions described herein can be formulated for administration to mammals by any conventional means, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous or intramuscular), oral, intranasal, rectal or transdermal administration routes. As used herein, the term "subject" or "individual" is used to refer to an animal, preferably a mammal, including humans or non-humans. The terms individual, patient and subject can be used interchangeably.

[0214] In addition, the pharmaceutical compositions described herein comprising Compound 1 can be formulated into any suitable dosage form, including but not limited to solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsed release formulations, multi-particulate formulations, and mixed immediate release and controlled release formulations.

[0215] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable excipients (if necessary) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate can be added.

[0216] Pharmaceutical preparations that can be used orally include push-in capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-in capsules can contain a mixture of active ingredients with fillers (such as lactose), binders (such as starches) and / or lubricants (such as talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oils, liquid paraffin or liquid polyethylene glycol). In addition, stabilizers can be added. The dosage of all oral preparations should be suitable for such administration.

[0217] In some embodiments, the solid dosage forms disclosed herein can be tablets (including dispersible tablets, fast-melting tablets, bite-disintegrating tablets, fast-disintegrating tablets, effervescent tablets or caplets), pills, powders (including aseptically packaged powders, dispersible powders or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC or "sprinkling capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulse release formulations, multi-particulate dosage forms, micropellets, granules or aerosols. In other embodiments, the pharmaceutical preparation is in the form of a powder. In yet other embodiments, the pharmaceutical preparation is in the form of a tablet, including but not limited to a fast-melting tablet. In addition, the pharmaceutical preparations described herein can be administered in a single capsule or multiple capsule dosage forms. In some embodiments, the pharmaceutical preparation is administered in two, three or four capsules or tablets.

[0218] In some embodiments, solid dosage forms (e.g., tablets, effervescent tablets, and capsules) are prepared by mixing particles of Compound 1 with one or more pharmaceutical excipients to form a bulk mixed composition. When these bulk mixed compositions are referred to as homogeneous, it means that the particles of Compound 1 are evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms (such as tablets, pills, and capsules). A single unit dose may also include a film coating that disintegrates upon oral ingestion or contact with a diluent. These preparations can be manufactured by conventional pharmacological techniques.

[0219] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0220] The pharmaceutical solid dosage forms described herein may include compound 1 and one or more pharmaceutically acceptable additives, such as compatible carriers, adhesives, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. In yet other aspects, a film coating is provided around the preparation of compound 1 using a standard coating procedure, such as the procedure described in Remington's Pharmaceutical Sciences, 20th edition (2000). In one embodiment, the particles of compound 1 are partially or entirely coated. In another embodiment, the particles of compound 1 are partially or entirely microencapsulated. In yet another embodiment, the particles of compound 1 are not microencapsulated and are not coated.

[0221] Suitable carriers for the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0222] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0223] In order to release Compound 1 from the solid dosage form matrix as effectively as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. When water is absorbed into the dosage form, the disintegrant helps the dosage form matrix to rupture by swelling or capillary action. Disintegrants suitable for the solid dosage forms described herein include, but are not limited to, natural starches (such as corn starch or potato starch), pregelatinized starches (such as National 1551 or ) or sodium carboxymethyl starch (such as or ), cellulose (such as wood products), methyl crystalline cellulose (such as PH101, PH102, PH105, P100, Ming and Solka- ), methylcellulose, cross-linked carboxymethylcellulose, or cross-linked cellulose (such as cross-linked sodium carboxymethylcellulose (Ac-Di- )), cross-linked carboxymethyl cellulose or cross-linked cross-linked carboxymethyl cellulose, cross-linked starch (such as sodium carboxymethyl starch), cross-linked polymers (such as cross-linked polyvinyl pyrrolidone), alginates such as alginic acid or a salt of alginic acid (such as sodium alginate), clays such as In some embodiments provided herein, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch (such as sodium carboxymethyl starch), cross-linked polymers (such as cross-linked polyvinyl pyrrolidone), sodium alginate, clay or gum. In some embodiments provided herein, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0224] Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they help form plugs that can be filled into soft or hard shell capsules; and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blending uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g. ), hydroxypropyl methylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. ), ethyl cellulose (e.g. ) and microcrystalline cellulose (e.g. ), microcrystalline glucose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, cross-linked polyvinylpyrrolidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (such as sucrose (e.g. ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose), natural or synthetic gums (such as gum arabic, gum tragacanth, gum ghatti, mucilage from isapol husks), starch, polyvinylpyrrolidone (e.g. CL, CL, XL-10 and K-12), larch arabogalactan, Polyethylene glycol, wax, sodium alginate, etc.

[0225] In general, the binder level used in powder-filled gelatin capsule formulations is 20-70%. The level of binder used in tablet formulations varies, whether it is direct compression, wet granulation, roller compaction or the use of other excipients, such as fillers, which themselves can act as a medium binder. A skilled formulator in the art can determine the binder level of a formulation, but it is common to use binder levels as high as 70% in tablet formulations.

[0226] Lubricants or glidants suitable for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as calcium, magnesium, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax TM , PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, etc. In some embodiments provided herein, the lubricant is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate and wax. In some embodiments provided herein, the lubricant is magnesium stearate.

[0227] Diluents suitable for solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0228] The term "water-insoluble diluent" refers to compounds commonly used in pharmaceutical formulations, such as calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose (e.g., a density of about 0.45 g / cm 3 , such as Avicel, powdered cellulose) and talc.

[0229] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, etc.

[0230] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g. (BASF) etc. In some embodiments provided herein, the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, stearic acid monoglyceride, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0231] Suspending agents suitable for use in the solid dosage forms described herein include, but are not limited to, polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30), polyethylene glycol (e.g., polyethylene glycol having a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polysorbate-80, hydroxyethyl cellulose, sodium alginate, gums (such as, for example, tragacanth and acacia, guar gum, xanthans, including xanthan gum gum)), sugars, cellulosic materials (such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0232] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0233] It should be recognized that there is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above should only be used as examples of the types of additives that can be included in the solid dosage forms described herein, rather than as limitations. Those skilled in the art can easily determine the amount of such additives based on the specific properties desired.

[0234] In other embodiments, one or more layers of the pharmaceutical preparation are plasticized. Illustratively, plasticizers are generally high boiling solids or liquids. Approximately 0.01% to approximately 50% by weight (w / w) of the coating composition can be added as a suitable plasticizer. Plasticizers include but are not limited to diethyl phthalate, citrate, polyethylene glycol, glycerine, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate and castor oil.

[0235] Compressed tablets are solid dosage forms prepared by compressing a bulk mixture of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of Compound 1 from the formulation. In other embodiments, the film coating helps patient compliance (e.g., coating or sugar coating). including The film coating, including , typically comprises about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets include one or more excipients.

[0236] Capsules can be prepared, for example, by placing a bulk mixture of compound 1 preparations into capsules. In some embodiments, preparations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In some embodiments, preparations (non-aqueous suspensions and solutions) are placed in hard shell gelatin capsules. In other embodiments, preparations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules comprising HPMC. In other embodiments, preparations are placed in sprinkle capsules, wherein the capsules can be swallowed as a whole, or the capsules can be opened and the contents are sprinkled on food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three or four) capsules. In some embodiments, the entire dose of the preparation is delivered in capsule form.

[0237] In various embodiments, particles of Compound 1 and one or more excipients are dry mixed and compressed into a mass (such as a tablet) having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0238] In another aspect, the dosage form may include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH regulators, corrosion accelerators, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0239] Materials useful for microencapsulation as described herein include materials that are compatible with Compound 1 and that sufficiently isolate Compound 1 from other incompatible excipients. Materials that are compatible with Compound 1 are those that delay the release of Compound 1 in vivo.

[0240] Exemplary microencapsulation materials that can be used to delay the release of formulations including the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as or Nisso HPC), low-substituted hydroxypropyl cellulose ether (L-HPC), hydroxypropyl methyl cellulose ether (HPMC) (such as Seppifilm-LC, Metolose SR, -E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843), methylcellulose polymers (such as -A), Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethyl cellulose (EC) and its mixtures (such as E461, -EC, ), polyvinyl alcohol (PVA) (such as Opadry AMB), hydroxyethyl cellulose (such as ), carboxymethyl cellulose and carboxymethyl cellulose (CMC) salts (such as -CMC), polyvinyl alcohol and polyethylene glycol copolymers (such as Kollicoat ), monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic acid polymers, and mixtures of acrylic acid polymers and cellulose ethers (such as EPO, L30D-55, FS 30D L100-55, L100, S100, RD100, E100, L12.5, S12.5, NE30D and NE 40D), cellulose acetate phthalate, sepifilm (such as a mixture of HPMC and stearic acid), cyclodextrin, and mixtures of these materials.

[0241] In yet other embodiments, plasticizers such as polyethylene glycol (e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800), stearic acid, propylene glycol, oleic acid, and triacetin) are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material that can be used to delay the release of the pharmaceutical composition is from USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methylcellulose (methocel).

[0242] Microencapsulated compound 1 can be formulated by several methods, illustrative examples of which include, for example, spray drying processes, spinning disk solvent processes, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solid-gas interfacial polymerization, pressure extrusion, or spray solvent extraction baths. In addition, several chemical techniques can also be used, for example, complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in-situ polymerization, drying in liquids, and desolvation in liquid media. In addition, other methods such as rolling, extrusion / spheronization, coacervation, or nanoparticle coating can also be used.

[0243] In one embodiment, the particles of Compound 1 are microencapsulated prior to being formulated into one of the above forms. In yet another embodiment, a portion or majority of the particles are coated using a standard coating procedure such as that described in Remington's Pharmaceutical Sciences, 20th Edition (2000) prior to further formulation.

[0244] In other embodiments, the solid dosage form formulation of Compound 1 is plasticized (coated) with one or more layers. Illustratively, plasticizers are generally high boiling solids or liquids. Approximately 0.01% to approximately 50% by weight (w / w) of a suitable plasticizer for the coating composition may be added. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate, and castor oil.

[0245] In other embodiments, powders including formulations with Compound 1 can be formulated to include one or more pharmaceutical excipients and flavoring agents. For example, such powders can be prepared by mixing the formulation and optional pharmaceutical excipients to form a bulk mixture composition. Other embodiments also include suspending agents and / or wetting agents. The bulk mixture is uniformly subdivided into unit dose packages or multi-dose packaging units.

[0246] In yet other embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are particles or coarse powders containing a medicament in a dry mixture generally consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salt of the composition described herein is added to water, acid and alkali react to release carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that causes the release of carbon dioxide can replace the combination of sodium bicarbonate with citric acid and tartaric acid, as long as the ingredient is suitable for pharmaceutical use and causes pH to be about 6.0 or higher.

[0247] In some embodiments, solid dosage forms described herein can be formulated into enteric coating delayed release oral dosage forms, that is, formulated into the oral dosage forms of pharmaceutical compositions as described herein, which utilize enteric coating to affect the release in the small intestine of the gastrointestinal tract. Enteric coating dosage forms can be compressed or molded or extruded tablets / molds (coated or uncoated), which contain particles, powders, pills, beads or particles of active ingredients and / or other composition components, and the particles, powders, pills, beads or particles themselves are coated or uncoated. Enteric coating oral dosage forms can also be capsules (coated or uncoated), which contain pills, beads or particles of solid carriers or compositions, and the pills, beads or particles themselves are coated or uncoated.

[0248] The term "delayed release" as used herein refers to delivery such that release can be accomplished at some generally predictable location in the intestinal tract that is further away than where it would have been accomplished had there been no delayed release change. In some embodiments, the method for delayed release is coating. Any coating should be applied to a sufficient thickness so that the entire coating is insoluble in gastrointestinal fluids at a pH below about 5, but dissolves at a pH of about 5 and above 5. Any anionic polymer that is expected to exhibit a pH-dependent solubility curve can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymer described herein is an anionic carboxylic acid polymer. In other embodiments, polymers and compatible mixtures thereof and some of their properties include, but are not limited to:

[0249] Shellac, also known as purified shellac, is a refined product obtained from the resinous secretions of insects. The coating dissolves in a medium with a pH>7;

[0250] Acrylic polymers. The properties of acrylic polymers, primarily their solubility in biological fluids, can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract, but are permeable and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach, but dissolve in the intestine;

[0251] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; and reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP psuedolatex with particles <1 μm. Other components in Aquateric may include Pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance may vary based on the degree and type of substitution. For example, HPMCP (such as HP-50, HP-55, HP-55S or HP-55F grades) are suitable. Performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF) (which dissolves at pH 5), AS-MG (MF) (which dissolves at pH 5.5), and AS-HG (HF) (which dissolves at higher pH). These polymers are provided in the form of granules or fine powders for aqueous dispersions; polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH>5 and has a relatively low permeability to water vapor and gastric fluid.

[0252] In some embodiments, the coating can and usually does contain a plasticizer and possible other coating excipients, such as a colorant, talc and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. Specifically, anionic carboxylic acid acrylic polymers will usually contain 10-25% by weight of plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques, such as spraying or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

[0253] In addition to plasticizers, colorants, anti-adherents, surfactants, defoamers, lubricants (such as carnauba wax or PEG) may be added to the coating to dissolve or disperse the coating material and improve coating properties and coated products.

[0254] In other embodiments, the formulations described herein including Compound 1 are delivered using a pulsatile dosage form. The pulsatile dosage form can provide one or more immediate release pulses at a predetermined time point or at a specific site after a controlled lag time. Other types of controlled release systems can also be used. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices, lipid-based non-polymer systems including sterols (such as cholesterol, cholesterol esters and fatty acids) or neutral fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional adhesives, etc. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2nd Edition, Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Edition, pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

[0255] In some embodiments, a pharmaceutical formulation comprising particles of Compound 1 and at least one dispersing agent or suspending agent is provided for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and when mixed with water, a substantially uniform suspension is obtained.

[0256] It should be appreciated that there is overlap between the above listed additives used in the aqueous dispersions or suspensions described herein, as a given additive is often classified in different ways by different practitioners in the art, or is often used for any of several different functions. Therefore, the above listed additives should only be used as examples of the types of additives that can be included in the formulations described herein, rather than as limitations. The amount of such additives can be readily determined by those skilled in the art based on the specific properties desired.

[0257] method

[0258] In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein. In some embodiments, a method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein. In some embodiments, a method of treating an autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, intestinal disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo and atopic dermatitis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is rheumatoid arthritis. In some embodiments, it is a method of treating an inflammatory or autoimmune disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is multiple sclerosis. In some embodiments, it is a method of treating an inflammatory or autoimmune disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is psoriasis. In some embodiments, it is a method of treating an inflammatory or autoimmune disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is lupus. In some embodiments, it is a method of treating an inflammatory or autoimmune disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is intestinal disease. In some embodiments, it is a method of treating an inflammatory or autoimmune disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a crystalline form of compound 1 described herein, wherein the disease, disorder or condition is Crohn's disease. In some embodiments are methods of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or condition is ulcerative colitis. In some embodiments are methods of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or condition is ankylosing spondylitis.In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or condition is vitiligo. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or condition is atopic dermatitis.

[0259] Dosage and treatment regimen

[0260] In some embodiments, crystalline Compound 1 is used to prepare a medicament for treating a disease or condition that would benefit from TYK2 inhibition. In addition, a method for treating any disease or condition described herein in an individual in need of such treatment involves administering to the individual a therapeutically effective amount of a pharmaceutical composition containing crystalline Compound 1 or a pharmaceutically acceptable solvate thereof.

[0261] In some embodiments, compositions containing crystalline Compound 1 are administered for prophylactic, therapeutic, or maintenance therapy. In some embodiments, compositions containing Compound 1 are administered for therapeutic applications. In some embodiments, compositions containing Compound 1 are administered for prophylactic applications.

[0262] In therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health status, weight and response to the drugs, and the judgment of the treating physician.

[0263] In preventive applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount also depends on the patient's health, weight, etc. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health status and response to drugs, and the judgment of the treating physician.

[0264] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0265] In some embodiments, crystalline Compound 1 is administered once a day. In some embodiments, crystalline Compound 1 is administered twice a day. In some embodiments, crystalline Compound 1 is administered three times a day. In some embodiments, crystalline Compound 1 is administered four times a day.

[0266] In cases where the patient's condition does not improve, then at the physician's discretion, the compound may be administered chronically, i.e., for an extended period of time, including throughout the course of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0267] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level at which the improved disease, disorder or condition is maintained as the symptoms change. However, once any symptoms recur, the patient may require long-term intermittent treatment.

[0268] The amount of a given medicament corresponding to this amount will vary according to factors such as the specific compound, the disease or condition and its severity, the characteristics of the subject or host to be treated (e.g., body weight), but can still be determined in a manner recognized in the art according to the specific circumstances of the case, including, for example, the specific medicament administered, the route of administration, the condition treated, and the subject or host treated. However, in general, the dosage used for treatment of adults is generally in the range of about 0.02 to about 5000 mg per day, in some embodiments, about 1 to about 1500 mg per day. The desired dosage can be conveniently provided in a single dose, or as a divided dose administered simultaneously (or over a short period of time) or administered at appropriate intervals (e.g., twice, three times, four times or more sub-doses per day).

[0269] The pharmaceutical compositions described herein can be unit dosage forms suitable for single administration of precise doses. In a unit dosage form, a preparation is divided into unit doses containing an appropriate amount of one or more compounds. A unit dose can be in a packaged form containing a discrete amount of preparation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions can be packaged in non-reclosable single-dose containers. Alternatively, a reclosable multi-dose container can be used, in which case a preservative is typically included in the composition. By way of example only, preparations for parenteral injection can be present in a unit dosage form with a preservative added, including but not limited to ampoules, or in a multi-dose container.

[0270] The daily dose suitable for the compounds described herein is about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dose is about 0.1 mg / kg to about 10 mg / kg. The specified daily dose of large mammals (including but not limited to humans) is conveniently administered in a single dose or divided dose in the range of about 0.5 mg to about 1000 mg, including but not limited to up to four times a day or in an extended release form. Suitable unit dosage forms for oral administration include about 1 to about 500 mg of active ingredient. In one embodiment, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg or about 500 mg. The aforementioned range is only suggestive, because there are many variables related to individual treatment regimens, and it is not uncommon to have considerable deviations from these recommended values. Such dosage may vary according to many variables including but not limited to the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated and the judgment of the physician.

[0271] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as LD 50 and ED 50 The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within the range that includes the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0272] Kits / Products

[0273] For use in the therapeutic methods described herein, kits and articles are also described herein. Such kits include carriers, packages or containers that are separated to receive one or more containers, such as vials, tubes, etc., each of which includes one of the individual elements for the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed of a variety of materials, such as glass or plastic.

[0274] The articles provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products include, for example, U.S. Pat. No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0275] In some embodiments, the compound or composition described herein is presented in a package or dispenser device, which may contain one or more unit dosage forms containing active ingredients. The compound or composition described herein is packaged separately, or packaged with another compound or another ingredient or additive. In some embodiments, the package contains one or more containers, in which the ingredients of one or more pharmaceutical compositions are contained. In some embodiments, the package includes metal or plastic foil, such as blister packaging. In some embodiments, the package or dispenser device is accompanied by an application instruction, such as an application instruction for a compound or composition for treating a tumor disease. In some embodiments, the package or dispenser is accompanied by a notice related to the container, the form of which is specified by a government agency that manages drug manufacturing, use or sales, and the notice reflects the approval of the administration agency for the drug form used for human or veterinary administration. In some embodiments, such a notice is, for example, a prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. In some embodiments, the composition includes a compound described herein formulated in a compatible drug carrier, which is placed in an appropriate container and labeled for the condition indicated for treatment.

[0276] For example, the container includes crystalline Compound 1, optionally in a composition or in combination with another agent as disclosed herein.Such kits optionally include an identifying description or label or instructions related to its use in the methods described herein.

[0277] Kits typically include a label listing the contents and / or instructions for use, and a package insert with instructions for use. A set of instructions is also typically included.

[0278] In one embodiment, the label is located on or associated with the container. In one embodiment, the label is located on the container when the letters, numbers or other characters constituting the label are attached, molded or etched into the container itself; the label is associated with the container when the label is present in a container or carrier that holds the container, such as as a package insert. In one embodiment, the label is used to indicate that the contents will be used for a specific therapeutic application. The label also indicates instructions for use of the contents, such as in the methods described herein.

[0279] In certain embodiments, the pharmaceutical composition is presented in a package or dispenser device containing one or more unit dosage forms containing a compound provided herein. For example, the package contains metal or plastic foil, such as a blister package. In one embodiment, the package or dispenser device is accompanied by instructions for use. In one embodiment, the package or dispenser is also accompanied by a notice associated with the container, the form of which is specified by a government agency that manages drug manufacturing, use or sales, and the notice reflects the approval of the administration agency for the form of the drug used for human or veterinary administration. Such a notice is, for example, a prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. In one embodiment, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in an appropriate container, and labeled for use in the treatment of indicated conditions.

[0280] Example

[0281] List of abbreviations

[0282] As used throughout the specification of the present invention, unless otherwise indicated, the following abbreviations should be understood to have the following meanings:

[0283] ACN or MeCN Acetonitrile

[0284] Bn Benzyl

[0285] BOC or Boc tert-butyl carbamate

[0286] t-Bu tert-butyl

[0287] Cy Cyclohexyl

[0288] DCE Dichloroethane (ClCH2CH2Cl)

[0289] DCM Dichloromethane (CH2Cl2)

[0290] DIPEA or DIEA diisopropylethylamine

[0291] DMAP 4-(N,N-dimethylamino)pyridine

[0292] DMF Dimethylformamide

[0293] DMA N,N-Dimethylacetamide

[0294] DMSO Dimethyl sulfoxide

[0295] eq or equiv equivalent

[0296] Et Ethyl

[0297] Et2O Diethyl ether

[0298] EtOH

[0299] EtOAc Ethyl acetate

[0300] HPLC High Performance Liquid Chromatography

[0301] IPA Isopropyl Alcohol

[0302] Me Methyl

[0303] MeOH Methanol

[0304] MS mass spectrometry

[0305] GC Gas chromatography

[0306] h hour

[0307] KF Karl Fischer

[0308] min

[0309] MsOH Methanesulfonic acid

[0310] NMP N-Methylpyrrolidine

[0311] NMR Nuclear Magnetic Resonance

[0312] RP-HPLC Reverse Phase High Performance Liquid Chromatography

[0313] rt room temperature

[0314] TFA Trifluoroacetic acid

[0315] THF Tetrahydrofuran

[0316] TLC Thin layer chromatography

[0317] V Volume

[0318] I. Synthesis of Compound 1 Free Base Polymorphs

[0319]

[0320] Example 1A: Synthesis of Compound 1 Free Base Form A

[0321] To a solution of intermediate A (84 g, 0.152 mol, 1.0 eq) (prepared according to US2021 / 0139486) in DCM (1000 mL) was added triethylsilane (26.5 g, 0.228 mol, 1.5 eq). After stirring for 10 min, TFA (200 mL) was added to the mixture, and the reaction solution was stirred at rt. for 0.5 hours. TfOH (45 mL) was added, and the reaction solution was stirred at rt for 2 hours. The reaction mixture was poured into saturated NaHCO3 (250 mL). The solid was collected by filtration and dried under vacuum. The solid was ground with EtOH (250 mL) and collected by filtration. The solid was ground with EtOAc (2×250 mL). The solid was collected by filtration and dried under vacuum to obtain compound 1 free base, Form A (39.6 g, 60%), as a yellow solid. LCMS: m / z is calculated as [M+H] + =432.2; 1 HNMR(400MHz,DMSO-d6)δ8.30(s,1H),8.17(dd,J=11.8,3.2Hz,1H),8.01(s, 1H),7.75(s,1H),7.55(q,J=4.4Hz,1H),6.62(d,J=3.2Hz,1H),6.35(dd,J=9. 6,3.0Hz,1H),5.94(s,1H),4.71(ddd,J=65.2,8.4,5.8Hz,1H),4.31(q,J=4. 8Hz, 4H), 2.88 (d, J = 4.7Hz, 3H), 2.63 (m, 1H), 1.03 (m, 1H), 0.88–0.73 (m, 1H).

[0322] Example 1B: Synthesis of Compound 1 Free Base Form B

[0323] Compound 1 free base Form A (4 g) was added to acetic acid (40 mL) and the mixture was stirred at room temperature for 2 h. The solid was collected by filtration and washed with cold acetic acid (15 mL). The solid was dried under high vacuum at 45 ° C for 6 h to obtain Compound 1 free base Form B.

[0324] II. Characterization of Polymorphs

[0325] Example 2: X-ray powder diffraction (XRPD)

[0326] XRPD patterns were identified using an X-ray diffractometer (PANalytical Empyrean). The system was equipped with a PIXcel1D detector. The sample was scanned from 3 to 40° 2θ with a step size of 0.013° 2θ. The tube voltage and current were 45 KV and 40 mA, respectively.

[0327] Alternatively, XRPD patterns were collected using a Bruker D8 Advance diffractometer. The X-ray source was a Cu tube operating at 40 kV and 40 mA. The axial soller was 4.1° and the divergence slit was 0.6 mm. Powder samples were prepared on a zero-background Si holder, using manual gentle pressure to keep the sample surface flat. Each sample was analyzed from 3 to 45° 2θ, with an effective step size of 0.02° 2θ and an exposure time of 0.2 s.

[0328] XRPD analysis of Compound 1 adipate salt form 1 ( Figure 1 ) showed that it was crystalline, and its characteristic peaks were located at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ.

[0329] XRPD analysis of Compound 1 adipate salt form 2 ( Figure 3 ) showed that it was crystalline, and its characteristic peaks were located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ.

[0330] XRPD analysis of Compound 1 adipate salt form 1 ( Figure 5 ) showed that it was crystalline, and its characteristic peaks were located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ.

[0331] XRPD analysis of Compound 1 oxalate form 1 ( Figure 7 ) showed that it was crystalline, and its characteristic peaks were located at 5.4°2θ, 8.8°2θ, 12.9°2θ, 16.3°2θ, 17.8°2θ, 20.0°2θ, 21.7°2θ, 23.9°2θ, 26.4°2θ, 27.3°2θ and 28.4°2θ.

[0332] XRPD analysis of Compound 1 Phosphate Form 1 ( Fig. 9 ) showed that it was crystalline, and its characteristic peaks were located at 8.7°2θ, 14.3°2θ, 15.8°2θ, 17.0°2θ, 17.3°2θ, 21.1°2θ, 21.4°2θ and 22.3°2θ.

[0333] XRPD analysis of Compound 1 mesylate salt Form 1 ( Fig.11) showed that it was crystalline, and its characteristic peaks were located at 7.5°2θ, 15.5°2θ, 17.8°2θ, 18.9°2θ, 19.3°2θ, 21.6°2θ, 22.2°2θ, 23.2°2θ, 24.7°2θ and 27.8°2θ.

[0334] XRPD analysis of compound 1 free base form A ( Fig.13 ) showed that it was crystalline, and its characteristic peaks were located at 8.5°2θ, 11.8°2θ, 12.3°2θ, 13.3°2θ, 17.1°2θ, 19.4°2θ, 23.7°2θ and 26.8°2θ.

[0335] XRPD analysis of compound 1 free base form B ( Fig.15 ) showed that it was crystalline, and its characteristic peaks were located at 6.6°2θ, 10.1°2θ, 14.0°2θ, 16.6°2θ, 19.7°2θ, 22.2°2θ, 24.1°2θ and 26.2°2θ.

[0336] Example 3: Polarized Light Microscopy (PLM)

[0337] Optical microscopy was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, JPN) or a Motic BA310Met (Motic, CN) optical microscope equipped with a polarizer under a 50× objective.

[0338] PLM analysis of Compound 1 adipate salt Form 1 showed plate-like crystals with a particle size of 10 μm-100 μm.

[0339] PLM analysis of Compound 1 adipate salt Form 2 showed irregularly shaped crystals with agglomerated and particle sizes less than 10 μm.

[0340] PLM analysis of Compound 1 adipate salt Form 3 showed irregularly shaped crystals with agglomerated and particle sizes less than 20 μm.

[0341] PLM analysis of Compound 1 oxalate Form 1 showed irregularly shaped crystals with high crystallinity and a particle size less than 10 μm.

[0342] PLM analysis of Compound 1 Phosphate Salt Form 1 showed irregularly shaped crystals with high crystallinity and a particle size less than 10 μm.

[0343] PLM analysis of Compound 1 mesylate salt Form 1 showed microcrystalline prisms.

[0344] PLM analysis of Compound 1 Form A showed microcrystalline clusters.

[0345] PLM analysis of Compound 1 Form B showed microcrystalline prisms.

[0346] Example 4: Thermogravimetric analysis (TGA)

[0347] TGA was performed on a Discovery TGA 55 (TA Instruments, US). The sample was placed in a tared aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated from room temperature (RT) to the final temperature at a rate of 10°C / min.

[0348] TGA of Compound 1 adipate salt form 1 ( Figure 2 ) shows no weight loss before 150°C.

[0349] TGA of Compound 1 adipate salt form 2 ( Figure 4 ) shows no weight loss before decomposition, which starts at about 150°C.

[0350] TGA of Compound 1 adipate salt form 3 ( Figure 6 ) shows a weight loss of about 0.2% before 100°C.

[0351] TGA of Compound 1 Oxalate Form 1 ( Figure 8 ) shows no weight loss before 150°C.

[0352] TGA of Compound 1 Phosphate Form 1 ( Fig.10 ) shows no weight loss before 150°C.

[0353] TGA of Compound 1 Mesylate Form 1 ( Fig.12 ) shows a weight loss of about 0.5% before 100°C.

[0354] TGA of Compound 1 Form A ( Fig.14 ) shows a weight loss of about 1.7% before 100°C.

[0355] TGA of Compound 1 Form B ( Fig.16 ) shows a weight loss of about 10.6% before 150°C.

[0356] Example 5: Differential Scanning Calorimetry (DSC)

[0357] DSC was performed using Discovery DSC 250 (TA Instruments, US). The sample was placed in an aluminum pinhole sealed pan and the weight was accurately recorded. The sample was then heated from 25°C to the final temperature at a rate of 10°C / min.

[0358] DSC analysis of Compound 1 adipate salt form 1 ( Figure 2) shows a single exothermic peak starting at 200 °C.

[0359] DSC analysis of Compound 1 adipate salt form 2 ( Figure 4 ) shows a single exothermic peak with an onset at 194 °C.

[0360] DSC analysis of compound 1 adipate salt form 3 ( Figure 6 ) shows a first exotherm starting at about 133°C, and a second exotherm starting at about 177°C.

[0361] DSC of Compound 1 Oxalate Form 1 ( Figure 8 ) shows an endotherm starting at about 190°C, followed by an exothermic signal.

[0362] DSC of Compound 1 Phosphate Form 1 ( Fig.10 ) shows a single exothermic peak starting at 200 °C.

[0363] DSC of Compound 1 mesylate salt form 1 ( Fig.12 ) shows an exotherm above 195°C.

[0364] DSC of Compound 1 Form A ( Fig.14 ) shows a single exothermic peak, starting at 210 °C.

[0365] DSC of Compound 1 Form B ( Fig.16 ) showed an endothermic peak at about 177°C, followed by an exothermic signal.

[0366] Example 6: Dynamic Vapor Sorption (DVS)

[0367] DVS data were collected on a Vsorp dynamic moisture sorption analyzer (ProUmid GmbH & Co. KG, Germany). The samples were placed in a tared sample chamber and weighed automatically.

[0368] Sample temperature: 25°C

[0369] Cycle: Full cycle

[0370] Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90

[0371] Desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0

[0372] Characterization of samples by XRPD after DVS experiments

[0373] Alternatively, DVS analysis is performed using a Surface Measurement System DVS Intrinsic analyzer. The instrument is calibrated with a standard weight. Approximately 15-20 mg of sample is loaded into a pan for analysis. Samples are analyzed at 25°C with a 10% relative humidity (RH) step length, from 50% to 95% RH (adsorption cycle), from 95% to 0% RH (desorption cycle), and from 0% to 50% RH (adsorption cycle). The movement from one step length to the next step length occurs after the equilibrium criterion of a 0.002% weight change (dm / dt) is met, or, if the equilibrium criterion is not met, then moves after ten hours. Samples after the DVS test are tested by XRPD.

[0374] DVS analysis of Compound 1 adipate salt Form 1 showed less than 0.2% water uptake at 80% RH and 25° C. Post-DVS analysis of XRPD showed no change. The material is non-hygroscopic.

[0375] DVS analysis of Compound 1 Oxalate Salt Form 1 showed a water uptake of 0.37% at 80% RH and 25° C. Post-DVS analysis of XRPD showed no change. The material is slightly hygroscopic.

[0376] DVS analysis of Compound 1 Phosphate Salt Form 1 showed a water uptake of 1.20% at 80% RH and 25° C. Post-DVS analysis of XRPD showed no change. The material is slightly hygroscopic.

[0377] DVS analysis of Compound 1 mesylate salt Form 1 showed a water absorption of 2.65% at 95% RH and 25° C. Post-DVS analysis of XRPD showed no change.

[0378] DVS analysis of Compound 1 Form A showed a water absorption of 5.08% at 95% RH and 25° C. Post-DVS analysis of XRPD showed no change.

[0379] DVS analysis of Compound 1 Form B showed a water absorption of 0.68% at 95% RH and 25° C. Post-DVS analysis of XRPD showed no change.

[0380] III. Polymorph Screening

[0381] Example 7: Evaporation method

[0382] 20 mg of the clear solution of Compound 1 was dissolved in the selected solvent and placed in a fume hood without sealing to allow the solvent to evaporate at 25° C. The obtained solid sample was directly subjected to XRPD characterization. The results are shown in Table 1.

[0383] Table 1

[0384] Solvents Volume (mL) XRPD results acetone 6 Form A + other forms 2-ME 0.9 Form A DMSO 0.1 Form A THF 4 Form A DME 6 Amorphous DMF 0.1 Form A NMP 0.1 Form A Acetic acid 2 Form B

[0385] Example 8: Rapid precipitation

[0386] 20mg compound 1 sample was dissolved in selected solvent (acetone, DMF, DMSO, 2-methoxyethanol (2-ME), NMP, THF, acetic acid, formic acid). Anti-solvent (MeOH, EtOH, EtOAc, IPA, butyl formate, heptane, diethyl ether, water, acetonitrile, toluene, chloroform) was added at 25°C until precipitation was formed. If no crystals were formed, the solution was cooled to 0°C in a refrigerator for crystallization. If no solid was formed, the solution was further moved to a -15°C refrigerator. The obtained precipitate was centrifuged and vacuum dried for XRPD characterization. The results are shown in Table 2.

[0387] Table 2

[0388]

[0389]

[0390] Example 9: Slurry method at 25°C

[0391] A 20 mg sample of Compound 1 was stirred in suspension in the selected single solvent or binary solvent mixture at 25°C for 7 days (5 days for acetic acid slurry). The results are shown in Table 3.

[0392] Table 3

[0393]

[0394] Example 10: Slurry method at 50°C

[0395] A 20 mg sample of Compound 1 was stirred in suspension in the selected single solvent or binary solvent mixture at 50° C. for 1 day. The results are shown in Table 4.

[0396] Table 4

[0397]

[0398]

[0399] Example 11: Vapor Diffusion

[0400] A 20 mg sample of Compound 1 was dissolved in an appropriate solvent. The vial containing the prepared clear solution was placed in a designated anti-solvent atmosphere to allow the vapor to diffuse at room temperature. The results are shown in Table 5.

[0401] Table 5

[0402]

[0403] III. Crystalline Salt Form

[0404] Example 12: Preliminary Salt Screening

[0405] An appropriate amount of compound 1 free alkali is suspended in different solvents at room temperature, and then solid acid or acid solution (about 1-2eq) is added to form salt. The suspension is stirred at room temperature for 3 days. If no precipitation occurs, the reaction solution is concentrated or some anti-solvents are added. Solid is collected by filtration and analyzed by XRPD.

[0406] Example 13A: Synthesis of Compound 1 Adipate Salt Form 1

[0407] Adipic acid (7.4 g, 2.0 eq) was suspended in acetone (200 mL) and water (10 mL). The suspension was stirred at room temperature for 15 min to form a clear solution. Compound 1 free alkali (10.8 g, 1.0 eq) was added to the solution in batches. The mixture was stirred at room temperature for 24 h. The solid was collected by filtration and rinsed with acetone (2x10 mL). The solid was dried under high vacuum for 24 h at 45 ° C to obtain Compound 1 adipate salt form 1 (11.45 g).

[0408] Example 13Ab: First Alternative Synthesis of Compound 1 Adipate Salt Form 1 (Acetone / Water 19 / 1)

[0409] At 25°C, compound 1 free base (0.25eq) and seed crystals (1%) were added to a solution of adipic acid (2.0eq) in acetone: water (19V: 1V). The suspension was stirred for 2h at 25°C. Compound 1 free base (0.25eq) was then added to the suspension. The suspension was stirred for 1h at 25°C. Compound 1 free base (0.25eq) was then added to the suspension. The suspension was stirred for 1h at 25°C. Compound 1 free base (0.25eq) was then added to the suspension. The suspension was stirred for 6h at 25°C. The solid was collected by filtration and dried under vacuum at 50°C for 3-5h to obtain compound 1 adipate salt form 1.

[0410] Example 13Ac: Second Alternative Synthesis of Compound 1 Adipate Salt Form 1 (DMSO / EtOAc / EtOH)

[0411] At 50 ° C, adipic acid (2.0 eq) was added to a solution of compound 1 free base (1.0 eq) in DMSO (2 V). The solution was cooled to room temperature and seed crystals (1%) were added. The suspension was stirred at room temperature for 2 h. EtOAc:EtOH (1:5, 12 V) was then added to the suspension and then added to the suspension at a rate of 1 V / h. The suspension was stirred at room temperature for 4 h. The solid was collected by filtration and washed with EtOAc (2×2 V). The solid was dried under vacuum at 40 ° C for 3 h to obtain compound 1 adipate salt form 1.

[0412] Example 13Ad: Third Alternative Synthesis of Compound 1 Adipate Salt Form 1 (DMSO / EtOH / Water)

[0413] At 25 ° C, adipic acid (2.0 eq), EtOH (1 V) and seed (1%) were added to a solution of compound 1 free base (1.0 eq) in DMSO (3 V). The suspension was stirred for 2 h at 25 ° C. EtOH (1 V) was then added to the suspension at a rate of 1 V / h, followed by water (6 V) at a rate of 2 V / h. The solid was collected by filtration and washed with water (2 × 2 V). The solid was dried under vacuum at 50 ° C for 3 h to obtain compound 1 adipate salt form 1.

[0414] Example 13B: Synthesis of Compound 1 Adipate Salt Form 3

[0415] Adipic acid (8.5 g, 2.0 eq) was suspended in acetone (400 mL). The suspension was stirred at room temperature for 15 min to form a clear solution. Compound 1 free alkali (12.5 g, 1.0 eq) was added to the solution in batches. Additional acetone (100 mL) was added. The mixture was stirred at room temperature for 3 days. The solid was collected by filtration and rinsed with acetone (2 × 50 mL). The solid was dried under high vacuum at 45 ° C for 24 h to obtain Compound 1 adipate salt form 3 (28.8 g).

[0416] Example 13C: Synthesis of Compound 1 Adipate Salt Form 2

[0417] Compound 1 adipate salt Form 3 (28.8 g) was suspended in TBME (290 mL) and stirred at room temperature for 5 h. The solid was collected by filtration and rinsed with TBME (2×50 mL), and the solid was dried under high vacuum at 45° C. for 2 h to give Compound 1 adipate salt Form 2 (28.1 g).

[0418] Example 13D: Synthesis of Compound 1 Oxalate Form 1

[0419] About 250 mg of Compound 1 free base and solid oxalic acid (1.1 eq.) were suspended in 3.0 mL of acetone. The suspension was stirred continuously at room temperature for 14 h. The solid was collected by filtration and dried in vacuum at 40 °C for 14 h to obtain Compound 1 oxalate salt Form 1.

[0420] Example 13E: Synthesis of Compound 1 Phosphate Form 1

[0421] About 250 mg of Compound 1 free base and concentrated phosphoric acid (1.1 eq.) were suspended in 3.0 mL of MeOH. The suspension was stirred continuously at room temperature for 14 h. The solid was collected by filtration and dried in vacuum at 40° C. for 14 h to obtain Compound 1 Phosphate Salt Form 1.

[0422] Example 13F: Synthesis of Compound 1 Mesylate Salt Form 1

[0423] To a slurry of Compound 1 free base (297 mg) in EtOH (12 mL) was added a 1.37 M solution of methanesulfonic acid in EtOH (1 mL). After stirring at room temperature for 4 h, the solid product was recovered by centrifugation and dried under vacuum at room temperature to give Compound 1 mesylate salt Form 1.

[0424] Example 14: Competitive Slurry Experiments of Compound 1 Adipate Salt Forms 1, 2 and 3

[0425] A mixed sample of Compound 1 adipate form 1 and Compound 1 adipate form 2 was suspended in a solvent (40 mg, 0.5 mL) and stirred at 50° C. or 25° C. for 2 h. The resulting solid was collected by filtration and analyzed by XRPD. As shown in Table 6, after slurrying in a solvent at 50° C. or 25° C. for 2 h, all mixed samples were converted to Form I.

[0426] Table 6

[0427] Solvents Solvent V (mL) Temperature(℃) XRPD results EtOAc 0.5 50 Form 1 ACN 0.5 50 Form 1 Toluene 0.5 50 Form 1 EtOAc 0.5 25 Form 1 ACN 0.5 25 Form 1

[0428] A mixed sample of Compound 1 adipate form 2 and Compound 1 adipate form 2 was suspended in a solvent (40 mg, 0.5 mL) and stirred at 50 ° C for 1 h. The resulting solid was collected by filtration and analyzed by XRPD. As shown in Table 7, after slurrying in the solvent for 2 h at 50 ° C or 25 ° C, all mixed samples were converted to Form I.

[0429] Table 7

[0430] Solvents Solvent V (mL) Temperature(℃) XRPD results EtOAc 0.5 50 Form 1 ACN 0.5 50 Form 1

[0431] From the competitive slurry experiments, Compound 1 adipate salt form 1 is the most stable form among the three Compound 1 adipate salt forms.

[0432] Example 15: Stability test of Compound 1 adipate salt form 1

[0433] About 10 mg of Compound 1 adipate salt form 1 obtained from acetone / water (19 / 1) (Example 13Ab), DMSO / EtOAc / EtOH (Example 13Ac) and DMSO / EtOH / water (Example 13Ad) was placed at 60°C / closed and 40°C / 75% RH (open) for 7 days. Two samples were prepared for each condition. On the 7th day, samples were analyzed by HPLC and XRPD to check purity and crystalline form, respectively. The results are summarized in Table 8.

[0434] Compound 1 adipate salt Form 1 remained physically and chemically stable for 1 week at both 60°C (closed) and 40°C / 75% RH (open). The crystalline form and HPLC purity of adipate salt Form I remained unchanged for 7 days under both test conditions.

[0435] Table 8

[0436]

[0437] IV. Biological Data

[0438] Example 16: Co-stimulation assay in lysed whole blood; JAK2:GM-CSF-stimulated STAT5 phosphorylation and JAK1 / TYK2-stimulated STAT1 phosphorylation assay

[0439] Human blood lysis using abcam's RBC lysis buffer

[0440] Dilute RBC Lysis Buffer to 1X in distilled water. Add 2 mL of blood to 38 mL of 1X RBC Lysis Buffer. Incubate in the dark at RT for 15 min. Spin at 300 g for 5 min to collect the pellet. Re-lyse if necessary. Resuspend the pellet in 5 mL of cRPMI.

[0441] Compound and cytokine treatment

[0442] Aliquot 80 μL of lysed human blood into the wells of a 96-deep well plate. Add 10 μL (10X concentration) of compound 1 at different concentrations to all wells except the control (unstained and unstimulated) and mix with the help of a 100 μL multichannel. Add 10 μL of RPMI medium to the control. Refer to the Appendix for the dilution and dilution range of compound 1. Incubate at 37°C in a water bath or CO2 incubator for 1 hour. Add 10 μL (10X concentration) of cytokine mixture (GM-CSF and IFNa) (final concentration 10 ng / mL of GM-CSF and 100 ng / mL of IFNa) to each well except the unstimulated and unstained controls and further incubate at 37°C in a water bath for 20 minutes.

[0443] RBC lysis and fixation

[0444] Add 900 μL of pre-warmed 1X Fixation / Lysis Solution (Appendix) and mix appropriately using 1000 μL multichannel, and incubate further in a 37°C water bath for 10 minutes (which includes the addition time). Centrifuge at 800 x g for 5 minutes at 40°C; remove 900 μL of supernatant and add 900 μL of 1X PBS. Centrifuge at 800 x g for 5 minutes at 40°C, remove 900 μL of supernatant. Wash once more with 900 μL PBS (optional), and resuspend the pellet in 100 uL PBS.

[0445] Permeabilization

[0446] The pellet was broken up by gentle tapping and resuspended in 1000 μL BD Phosflow Perm Buffer III and the plate was incubated on ice for 30 minutes. The plate was centrifuged at 800 x g for 5 minutes at 40°C. Washed twice more with 1000 μL BD Pharmingen staining buffer.

[0447] Antibody treatment

[0448] The pellet was broken by tapping gently. The pellet was resuspended in 100 μL staining buffer and 5 μL pSTAT5_AF488 Ab and 5 μL pSTAT1_PE were added to all wells except the unstained control and properly mixed using 200 μL multichannel and incubated overnight at 40°C. 900 μL wash buffer was added and centrifuged at 1800 rpm for 3 minutes at 40°C. Washed again with 1000 μL BD Pharmingen staining buffer. Finally, the pellet was resuspended in 300 μL BD Pharmingen staining buffer. The cells were transferred to a 96-well V-bottom plate and collected in a Beckman Coulter CytExpert. Cells were collected in a flow cytometer: the threshold was kept at 250 and the cell concentration should not exceed 100-500 cells / μL. At least 5,000-10,000 cells were collected. Compound 1 IFN-a / Jak1Tyk2 IC50 <1 μM.

[0449] appendix

[0450] Reagent preparation

[0451] Complete RPMI 1640 medium: RPMI 1640 medium + 10% FBS.

[0452] Cytokine dilutions: 1) 100 μg / mL GM-CSF stock solution. Prepare an intermediate dilution of 1 ug / mL by adding 2 μL of stock solution to 198 μL cRPMI. Further dilute to 100 ng / mL by adding 100 μL of intermediate stock solution to 900 uL cRPMI. 2) 200 μg / mL IFNa stock solution. Dilute the IFNa stock solution 1:200 by adding 5 uL of stock solution to 1000 uL of 100 ng / mL GM-CSF working stock solution as above to obtain a combined working stock solution of 1000 ng / mL IFNa and 100 ng / mL GM-CSF (10x). Keep it on ice until use.

[0453] Lysis / Fixation Buffer Preparation: Dilute 5X Lysis / Fixation Buffer to 1X using MQ water and store at 37 °C until use.

[0454] BD Phosflow perm buffer III: Keep on ice / in refrigerator.

[0455] Compound dilution

[0456]

[0457] Example 17: Pharmacokinetics of a crystalline form of Compound 1 following oral administration to male cynomolgus monkeys

[0458] Single-dose PK parameters in plasma were determined after oral gavage of compound 1 (compound 1 adipate form 1; compound 1 oxalate form 1; and compound 1 free base form A) in male cynomolgus monkeys. After the dose was administered, the gavage tube was flushed with 5 mL of vehicle. Plasma samples were collected at the following time points: 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. The concentration of compound 1 in plasma was determined. As shown in Table 9, compared with compound 1 free base form A, compound 1 adipate form 1 provides a faster T 最大 and higher AUC. Similarly, as shown in Table 10, Compound 1 adipate salt form 1 provides a faster T compared to Compound 1 oxalate salt form 1. 最大 , higher AUC and higher oral bioavailability (%F).

[0459] Table 9

[0460]

[0461]

[0462] *After the second dose

[0463] Table 10

[0464]

Claims

1. A crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea or a pharmaceutically acceptable salt or solvate thereof.

2. The crystalline form of claim 1, wherein the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is a salt of adipic acid (adipate salt), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt is Form 1 having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG1 ; (b) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG2 ; (d) DSC thermogram substantially similar to that shown in FIG2 ; (e) a DSC thermogram having an exotherm starting at about 200° C.; (f) non-hygroscopic; or (g) combinations thereof.

3. The crystalline form of claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1 .

4. The crystalline form of claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0°2θ, 9.3°2θ, 14.0°2θ, 21.1°2θ, 24.9°2θ and 25.6°2θ.

5. The crystalline form of claim 2, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 2 .

6. The crystalline form of claim 2, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG. 2 .

7. The crystalline form of claim 2, wherein the crystalline form has a DSC thermogram with an exotherm onset at about 200°C.

8. The crystalline form of claim 2, wherein the crystalline form is non-hygroscopic.

9. The crystalline form of claim 2, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), (e), and (f).

10. The crystalline form according to any one of claims 2 to 9, wherein the crystalline form is obtained from acetone / water.

11. The crystalline form according to any one of claims 2 to 10, wherein the crystalline form is non-solvated.

12. The crystalline form of claim 1, wherein the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is a salt of adipic acid (adipate salt) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt is Form 2 having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG3 ; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG4 ; (d) DSC thermogram substantially similar to that shown in FIG4 ; (e) a DSC thermogram having an exotherm onset at about 194° C.; (f) non-hygroscopic; or (g) combinations thereof.

13. The crystalline form of claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG3.

14. The crystalline form of claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0°2θ, 9.3°2θ, 13.3°2θ, 13.8°2θ, 18.3°2θ, 18.8°2θ, 20.6°2θ, 21.2°2θ and 25.6°2θ.

15. The crystalline form of claim 12, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

4.

16. The crystalline form of claim 12, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

4.

17. The crystalline form of claim 12, wherein the crystalline form has a DSC thermogram with an exotherm onset at about 194°C.

18. The crystalline form of claim 12, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), (e), and (f).

19. The crystalline form according to any one of claims 12 to 18, wherein the crystalline form is obtained from acetone.

20. The crystalline form of claim 1, wherein the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is a salt of adipic acid (adipate salt) and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt is Form 3 having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG5 ; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks located at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG6 ; (d) DSC thermogram substantially similar to that shown in FIG6 ; (e) a DSC thermogram having a first exotherm starting at about 133°C and a second exotherm starting at about 177°C; or (f) combinations thereof.

21. The crystalline form of claim 20, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 5.

22. The crystalline form of claim 20, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.9°2θ, 6.9°2θ, 8.9°2θ, 9.2°2θ, 11.7°2θ, 13.8°2θ, 17.9°2θ, 20.9°2θ, 21.9°2θ, 24.8°2θ and 25.8°2θ.

23. The crystalline form of claim 20, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

6.

24. The crystalline form of claim 20, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 6.

25. The crystalline form of claim 20, wherein the crystalline form has a DSC thermogram with a first exotherm onset at about 133°C and a second exotherm onset at about 177°C.

26. The crystalline form of claim 20, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), and (e).

27. The crystalline form according to any one of claims 20 to 26, wherein the crystalline form is obtained from methyl tert-butyl ether.

28. A crystalline form according to any one of claims 1 to 27 for use in medicine.

29. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 27 and a pharmaceutically acceptable excipient.

30. A method of treating an inflammatory or autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-27.

31. The method of claim 30, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

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