Crystalline prolyl hydroxylase domain-containing protein (PHD) inhibitors and their use

Abstract

Crystalline form of small molecule prolyl hydroxylase domain-containing protein (PHD) inhibitors, their pharmaceutical compositions, and methods of use thereof in the treatment of anemia. TIFF2026513421000019.tif27170 Compound 1.

Description

[Technical Field]

[0001] Related applications This application claims the benefits of international application PCT / CN2023 / 091785, filed on 28 April 2023, the entire disclosure thereof of which is incorporated herein by reference. [Background technology]

[0002] Hypoxia-inducible factors (HIFs) mediate gene expression in response to changes in cellular oxygen concentration. HIFs are heterodimers with an oxygen-regulating subunit (HIF-α) and a constitutively expressed subunit (HIF-β). HIF prolyl hydroxylase, also known as prolyl hydroxylase domain-containing protein (PHD), exists in humans as three isoforms (PHD1, PHD2, and PHD3). PHDs function as oxygen sensors that regulate the hypoxia-inducible factor ("HIF") degradation pathway. Briefly, PHDs are involved in the hydroxylation of HIFα, a subunit of HIF that ultimately initiates a pathway leading to proteasome degradation of HIFα. Three subtypes of PHD exist, including PHD1, PHD2, and PHD3. Inhibition of PHDs has been shown as a promising treatment for HIFα-related disorders such as anemia.

[0003] PHD inhibitors regulate erythropoiesis by inducing erythropoietin (EPO) synthesis in the kidneys and liver, which stimulates red blood cell production in the bone marrow, and by regulating iron metabolism, an essential component of functional red blood cells. PHD inhibitors may also suppress the production of hepatic hepcidin, which adversely affects iron mobilization. Furthermore, it is hypothesized that PHD inhibitors may upregulate the expression of several iron metabolism genes, such as DMT1 or DCYTB. Because HIF prolyl hydrolase plays a central role in cellular oxygen sensing, PHD inhibitors may be particularly useful in the treatment of cardiovascular diseases, metabolic disorders, hematological disorders, lung diseases, kidney diseases, liver diseases, wound healing disorders, and cancer. [Overview of the project] [Means for solving the problem]

[0004] This specification refers to the solid form of 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide: [ka] Compound 1 or pharmaceutically acceptable salts thereof are disclosed.

[0005] In some embodiments, the solid state is crystalline.

[0006] In some embodiments, the solid form is crystalline compound 1 as a free base.

[0007] In some embodiments, the solid form is a crystalline compound 1 of the free base A type.

[0008] In some embodiments, the solid form is crystalline compound 1 as a salt.

[0009] In some embodiments, the solid form is the HCl salt type A of crystalline compound 1, the HCl salt type B of compound 1, or the tosylate type A of compound 1.

[0010] Furthermore, this specification also discloses pharmaceutical compositions comprising therapeutically effective amounts of crystalline forms and pharmaceutically acceptable excipients disclosed herein.

[0011] Furthermore, this specification discloses methods for treating a disease or disorder, including administering a crystalline form or a pharmaceutical composition disclosed herein to a subject, wherein the disease or disorder is anemia.

[0012] The features of the present invention are specifically described in the appended claims. A better understanding of the features of the present invention can be obtained by referring to the following detailed description of exemplary embodiments in which the principles of the present invention are utilized and the accompanying drawings thereof.

Brief Description of Drawings

[0013] [Figure 1] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of free base Compound A1.

[0014] [Figure 2] Figure 2 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of free base Compound A1.

[0015] [Figure 3] Figure 3 shows the X-ray powder diffraction (XRPD) pattern of HCl salt Compound A1.

[0016] [Figure 4] Figure 4 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of HCl salt Compound A1.

[0017] [Figure 5] Figure 5 shows the X-ray powder diffraction (XRPD) pattern of HCl salt Compound B1.

[0018] [Figure 6] Figure 6 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of HCl salt Compound B1.

[0019] [Figure 7] Figure 7 shows the X-ray powder diffraction (XRPD) pattern of tosylate Compound A1.

[0020] [Figure 8]Figure 8 shows the differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) thermogram of tosylate type A compound 1. [Modes for carrying out the invention]

[0021] While small molecule inhibitors are often initially evaluated for their activity when dissolved in solution, solid-state properties such as polymorphism are also important. Polymorphism of active pharmaceutical ingredients (APIs) can encompass a variety of physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly affect the ability to process or manufacture the API and the drug. Furthermore, differences in these properties can, and often do, result in different pharmacokinetic profiles for different polymorphic forms of the drug. Therefore, polymorphism is often a crucial factor in regulatory reviews of the "identity" of drugs from various manufacturers.

[0022] compound 1 Compound 1 is 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide: [ka] This is compound 1. In some embodiments, compound 1 is in the form of a free base. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 is in the form of an HCl salt. In some embodiments, compound 1 is in the form of a tosylate.

[0023] Solid form of compound 1 In one embodiment, the solid form of 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide: [ka] Compound 1 or pharmaceutically acceptable salts thereof are provided herein.

[0024] In some embodiments, the solid state is crystalline.

[0025] In some embodiments, the solid form is the free base of crystalline compound 1. In some embodiments, the solid form is the free base A of crystalline compound 1.

[0026] In some embodiments, the solid form is HCl salt compound 1. In some embodiments, the solid form is HCl salt crystalline compound 1. In some embodiments, the solid form is HCl salt type A crystalline compound 1. In some embodiments, the solid form is HCl salt type B crystalline compound 1.

[0027] In some embodiments, the solid form is the tosylate of compound 1. In some embodiments, the solid form is the tosylate of crystalline compound 1. In some embodiments, the solid form is the tosylate type A of crystalline compound 1.

[0028] Free base type A of compound 1 This specification discloses the free base A of compound 1. In some embodiments, the crystalline form of the free base of compound 1 is characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1; (b) X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°2θ, 16.2±0.2°2θ, and 20.3±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; (d) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature of approximately 215°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 2; or (f) combinations of those.

[0029] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°2θ, 16.2±0.2°2θ, and 20.3±0.2°2θ, as measured using CuKα rays; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature of approximately 215°C; or (c) combinations of those.

[0030] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1; (b) X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°2θ, 16.2±0.2°2θ, and 20.3±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 2; or (e) A combination of those.

[0031] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, as measured using CuKα radiation.

[0032] In some embodiments of free base compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks as shown in Table 1, as measured using CuKα radiation.

[0033] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°²θ, 16.2±0.2°²θ, and 20.3±0.2°²θ, as measured using CuKα radiation.

[0034] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα radiation, further includes peaks at 14.2±0.2°²θ, 18.6±0.2°²θ, and 22.3±0.2°²θ.

[0035] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα radiation, further includes peaks at 22.8±0.2°²θ, 25.9±0.2°²θ, and 26.9±0.2°²θ.

[0036] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα radiation, further includes peaks at 18.0±0.2°²θ, 23.9±0.2°²θ, 28.1±0.2°²θ, and 30.6±0.2°²θ.

[0037] In some embodiments of free base compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0038] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least two peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0039] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least three peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0040] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least four peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0041] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least five peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0042] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least six peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0043] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least seven peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0044] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least eight peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0045] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least nine peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0046] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least 10 peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0047] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least 11 peaks selected from 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, as measured using CuKα radiation.

[0048] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 2.

[0049] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram shows an endothermic peak with a peak temperature of approximately 215°C.

[0050] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 2.

[0051] In some embodiments of the free base of compound 1, the crystalline form is anhydrous.

[0052] In some embodiments of the free base of compound 1, the crystalline form is stable.

[0053] In some embodiments of the free base of compound 1, the crystalline form is chemically stable.

[0054] In some embodiments of the free base of compound 1, the crystalline form is thermodynamically stable. Table 1: XRPD Peak Table for Free Base Type A of Compound 1 [Table 1]

[0055] HCl salt type A of compound 1 This specification discloses the HCl salt A of compound 1. In some embodiments, the crystalline form of the HCl salt of compound 1 is characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 3; (b) X-ray powder diffraction (XRPD) pattern with peaks at 7.9±0.2°2θ, 10.8±0.2°2θ, and 15.9±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 4; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 4; or (e) A combination of those.

[0056] In some embodiments of the HCl salt of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 3, as measured using CuKα radiation.

[0057] In some embodiments of the HCl salt of compound 1, the crystalline morphology exhibits an X-ray powder diffraction (XRPD) pattern with peaks as shown in Table 2, as measured using CuKα radiation.

[0058] In some embodiments of the HCl salt of compound 1, the crystalline morphology exhibits an X-ray powder diffraction (XRPD) pattern with peaks at 7.9±0.2°²θ, 10.8±0.2°²θ, and 15.9±0.2°²θ, as measured using CuKα radiation.

[0059] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 9.0±0.2°2θ, 13.1±0.2°2θ, and 24.6±0.2°2θ.

[0060] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) pattern further includes a peak at 21.0 ± 0.2°²θ, as measured using CuKα rays.

[0061] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0062] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least two peaks selected from 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0063] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least three peaks selected from 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0064] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least four peaks selected from 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0065] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least five peaks selected from 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0066] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least six peaks selected from 7.9±0.2°2θ, 9.0±0.2°2θ, 10.8±0.2°2θ, 13.1±0.2°2θ, 15.9±0.2°2θ, 21.0±0.2°2θ, and 24.6±0.2°2θ, as measured using CuKα radiation.

[0067] In some embodiments of the HCl salt of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 4.

[0068] In some embodiments of the HCl salt of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 4. Table 2: XRPD peak table for HCl salt type A of compound 1 [Table 2]

[0069] Compound 1 HCl salt type B This specification discloses the HCl salt form B of compound 1. In some embodiments, the crystalline form of the HCl salt of compound 1 is characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 5; (b) X-ray powder diffraction (XRPD) pattern with peaks at 4.8±0.2°2θ, 20.0±0.2°2θ, and 27.2±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 6; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 6; or (e) A combination of those.

[0070] In some embodiments of the HCl salt of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 5, as measured using CuKα radiation.

[0071] In some embodiments of the HCl salt of compound 1, the crystalline morphology exhibits an X-ray powder diffraction (XRPD) pattern with peaks as shown in Table 3, as measured using CuKα radiation.

[0072] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 4.8±0.2°²θ, 20.0±0.2°²θ, and 27.2±0.2°²θ, as measured using CuKα radiation.

[0073] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 16.8±0.2°2θ, 22.2±0.2°2θ, and 27.7±0.2°2θ.

[0074] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 13.7±0.2°2θ, 17.5±0.2°2θ, and 19.3±0.2°2θ.

[0075] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0076] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least two peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0077] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least three peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0078] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least four peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0079] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least five peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0080] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least six peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0081] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least seven peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0082] In some embodiments of the HCl salt of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least eight peaks selected from 4.8±0.2°2θ, 13.7±0.2°2θ, 16.8±0.2°2θ, 17.5±0.2°2θ, 19.3±0.2°2θ, 20.0±0.2°2θ, 22.2±0.2°2θ, 27.2±0.2°2θ, and 27.7±0.2°2θ, as measured using CuKα radiation.

[0083] In some embodiments of the HCl salt of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 6.

[0084] In some embodiments of the HCl salt of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 6. Table 3: XRPD peak table for HCl salt type B of compound 1. [Table 3]

[0085] Tosylate type A of compound 1 This specification discloses the tosylate A form of compound 1. In some embodiments, the crystalline form of the tosylate of compound 1 is characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 7; (b) X-ray powder diffraction (XRPD) pattern with peaks at 5.1±0.2°2θ, 16.9±0.2°2θ, and 20.2±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 8; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 8; or (e) A combination of those.

[0086] In some embodiments of the tosylate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 7, as measured using CuKα radiation.

[0087] In some embodiments of the tosylate of compound 1, the crystalline morphology exhibits an X-ray powder diffraction (XRPD) pattern with peaks as shown in Table 4, as measured using CuKα radiation.

[0088] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 4.8±0.2°2θ, 20.0±0.2°2θ, and 27.2±0.2°2θ, as measured using CuKα radiation.

[0089] In some embodiments of tosylate compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 16.0±0.2°2θ, 20.8±0.2°2θ, and 23.7±0.2°2θ.

[0090] In some embodiments of the tosylate of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 19.1±0.2°²θ and 21.6±0.2°²θ.

[0091] In some embodiments of the tosylate of compound 1, the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 25.6±0.2°²θ and 26.3±0.2°²θ.

[0092] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks at 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0093] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least two peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0094] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least three peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0095] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least four peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0096] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least five peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0097] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least six peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0098] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least seven peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0099] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least eight peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0100] In some embodiments of the tosylate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having at least nine peaks selected from 5.1±0.2°2θ, 16.0±0.2°2θ, 16.9±0.2°2θ, 19.1±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 23.7±0.2°2θ, 25.6±0.2°2θ, and 26.3±0.2°2θ, as measured using CuKα radiation.

[0101] In some embodiments of the tosylate of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 8.

[0102] In some embodiments of the tosylate of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 8.

[0103] In some embodiments of the tosylate of compound 1, the ratio of compound 1 to p-toluenesulfonic acid is approximately 1:1.02. Table 4: XRPD peak table for tosylate type A of compound 1 [Table 4]

[0104] Treatment method This specification discloses a method for treating a disease or disorder, the method comprising administering a crystalline form disclosed herein to a subject, the disease or disorder being anemia.

[0105] anemia Anemia is a common and serious complication of chronic kidney disease, characterized by a relative deficiency in EPO production and reduced iron availability for hemoglobin ("Hb") synthesis. According to Informa, 168 million people worldwide were diagnosed with anemia due to chronic kidney disease in 2020. The same source estimates that this number will increase to 182 million by 2027.

[0106] Currently, anemia resulting from chronic kidney disease (PHD) is managed with iron supplementation, and in more severe cases, with the administration of superphysiological doses of erythropoiesis-stimulating agents ("ESAs") in combination with adjuvant iron therapy. High doses of ESAs increase the risk of serious adverse events, including myocardial infarction, congestive heart failure, stroke, and death. Several inhibitors of PHD are available and may be useful as effective treatments for patients with anemia resulting from chronic kidney disease. However, cardiovascular side effects and potential off-target toxicities caused by erythropoietin induction can raise safety concerns for long-term treatment. New therapies are needed to address both impaired EPO production and functional iron deficiency.

[0107] Administration In certain embodiments, compositions comprising the compound(s) described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to treat, or at least partially halt, at least one symptom of the disease or condition. The effective dose for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the attending physician. The therapeutically effective dose may, at the discretion of the physician, be determined by methods including, but are not limited to, dose escalation and / or dose determination clinical trials.

[0108] For prophylactic use, compositions containing the compounds described herein are administered to patients who are susceptible to or at other risk of a particular disease, disorder, or condition. Such amounts are defined as “a prophylactically effective amount or dose.” In this use, the exact amount will also vary depending on the patient’s health condition and weight, etc. When used in patients, the effective amount for this use will vary depending on the severity and course of the disease, disorder, or condition, previous treatments, the patient’s health condition and response to the drug, and the judgment of the attending physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom or risk factor of the disease under treatment and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0109] In certain embodiments where the patient's condition does not improve, the compound may, at the physician's discretion, be administered over a long period, i.e., over the patient's entire life, to improve, control, or limit the symptoms of the patient's disease or condition.

[0110] In any of the embodiments described herein, an effective amount of the compound or a pharmaceutically acceptable salt thereof is a further embodiment in which (a) it is administered systemically to a mammal; and / or (b) it is administered orally to a mammal; and / or (c) it is administered intravenously to a mammal; and / or (d) it is administered by injection to a mammal; and / or (e) it is administered topically to a mammal; and / or (f) it is administered non-systemically or topically to a mammal.

[0111] Route of administration Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. In addition, as merely an example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0112] In certain embodiments, the compounds described herein are often administered topically rather than systemically, for example, by direct injection of the compound into an organ, in depot or sustained-release formulations. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered by a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0113] Pharmaceutical composition / formulation The compounds described herein are administered in pharmaceutical compositions, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, to subjects requiring them, in accordance with standard pharmaceutical practices. In one embodiment, the compounds of the present invention may be administered to animals. These compounds can be administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0114] In another embodiment, pharmaceutical compositions comprising compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and at least one pharmaceutically acceptable excipient are provided herein. The pharmaceutical compositions are formulated in the conventional manner using one or more pharmaceutically acceptable excipients that facilitate the treatment of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), for which such disclosures are incorporated herein by reference.

[0115] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, fragrances, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0116] The pharmaceutical compositions described herein are administered to a target by an appropriate route of administration, including, but are not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, oral, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multi-particle formulations, and mixtures of immediate-release and controlled-release formulations.

[0117] Pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, may be manufactured, for example, by conventional methods such as conventional mixing, dissolution, granulation, sugar-coated tablet production, paste formation, emulsification, encapsulation, encapsulation, or compression processes.

[0118] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described herein, after adding appropriate excipients as necessary to obtain a tablet or sugar-coated tablet core, optionally grinding the resulting mixture, and processing the granular mixture. Suitable excipients include, for example, fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate are added. In some embodiments, dyes or pigments are added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of doses of the active compound.

[0119] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, and sealed soft capsules formed from gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and an optional stabilizer. In the soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0120] Parenteral pharmaceutical compositions are formulated for infusion or injection. In some embodiments, a pharmaceutical composition suitable for injection or infusion comprises a sterile aqueous solution or dispersion or sterile powder containing the compounds described herein or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline solution, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, non-toxic glyceryl esters; and any combination thereof. In some embodiments, the pharmaceutical composition further comprises an antiseptic to prevent microbial growth.

[0121] definition Unless otherwise specified, the following terms used in this application have the definitions set forth below. The use of the term “including,” as well as other forms such as “include,” “includes,” and “included,” is not limited to these. Section headings used herein are for summary purposes only and should not be construed as limiting the subject matter described.

[0122] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not cause any permanent adverse effects on the overall health of the subject being treated.

[0123] As used herein, terms such as “administer,” “administering,” and “administration” refer to methods that can be used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art will be familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0124] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of the drug or compound administered to alleviate, to some extent, one or more symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desirable changes in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to provide a clinically significant relief of the symptoms of the disease. The appropriate “effective” dose in individual cases is determined, at the discretion of the present invention, using techniques such as dose-escalation studies.

[0125] As used herein, the terms “enhance” or “enhancing” mean increasing or extending a desired effect in terms of either potency or duration. Therefore, with respect to enhancing the effect of a therapeutic agent, “enhancing” refers to the ability to increase or extend the effect of another therapeutic agent on a system in terms of either potency or duration. As used herein, “enhancing dose” refers to an amount sufficient to enhance the effect of another therapeutic agent on a desired system.

[0126] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, members of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, a mammal is a human.

[0127] As used herein, the terms “treat,” “treating,” and “treatment” include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing further symptoms, suppressing a disease or condition, for example, preventing the onset of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, reducing a condition caused by a disease or condition, or suppressing symptoms of a disease or condition preventively and / or therapeutically.

[0128] The term "approximately" means within a statistically significant range of values, such as a stated concentration range, time frame, molecular weight, particle size, temperature, or pH. Such a range may be within an order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, and even more typically within 3%. Sometimes such a range may be within the experimental error typical of the standard methods used to measure and / or determine a given value or range. The acceptable variation encompassed by the term "approximately" depends on the particular system under study and will be readily apparent to those skilled in the art. Wherever a range is referenced in this application, all positive integers within that range are also contemplated as embodiments of the disclosure. In the context of the disclosure, whether or not words such as "approximately" are used, "approximately" means within 10% of a given value or range, appropriately within 5%, and especially within 1%.

[0129] When multiple diffraction patterns are available, particle statistics (PS) and / or selective orientation (PO) can be evaluated. Consistency of relative intensities between XRPD patterns from multiple diffractometers indicates good directional statistics. Alternatively, the observed XRPD pattern can be compared, if possible, with an XRPD pattern calculated based on the single-crystal structure. Two-dimensional scattering patterns using a surface detector can also be used to evaluate PS / PO. If the effects of both PS and PO are deemed negligible, the XRPD pattern represents the average intensity of the sample powder, and prominent peaks can be identified as "representative peaks." Generally, the more data collected to determine representative peaks, the more confidently those peaks can be classified.

[0130] "Characteristic peaks," as long as they exist, are a subset of representative peaks and are used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms with the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks (if any) exist for one crystalline polymorph of a compound within ±0.2°2θ of all other known crystalline polymorphs of that compound. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0131] As used herein, the term “selective orientation” refers to an extreme case of the non-random distribution of microcrystals in solid form. In XRPD, an ideal sample is homogeneous, and microcrystals are randomly distributed in the bulk solid. In a truly random sample, each possible reflection from a given set of planes has an equal number of microcrystals contributing to it. However, this is not the case when the solid form is selectively oriented. Therefore, comparing the intensities of randomly oriented diffraction patterns and selectively oriented diffraction patterns can look quite different. Quantitative analysis based on intensity ratios is greatly distorted by selective orientation. Careful sample preparation is important to reduce the incidence of selective orientation.

[0132] As used herein in reference to drawings, the term “substantially identical” means that the drawing is considered representative of the type and nature of characteristic data that can be obtained by a person skilled in the art, taking into account the deviations permissible in the art. Such deviations may be caused by factors relating to variations in sample size, sample preparation, specific equipment used, operating conditions, and other experimental conditions known in the art. For example, a person skilled in the art will understand that the endothermic onset and peak temperatures measured by differential scanning calorimetry (DSC) may vary significantly from experiment to experiment. For example, a person skilled in the art can easily identify whether two X-ray diffraction patterns or two DSC thermograms are substantially identical. In some embodiments, two X-ray diffraction patterns are considered substantially identical if their characteristic peaks do not vary by more than ±0.2°²-θ.

[0133] As used herein, salts of compound 1 include compounds in which the corresponding acid is ionized, non-ionized, associated, or non-associative. In some embodiments, the corresponding acid is ionized and / or associated. In some embodiments, the corresponding acid is non-ionized and / or non-associative. Salts of compound 1 also include salt forms such as monoacids and diacids. [Examples]

[0134] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Example 1: Preparation of Compound 1 [ka]

[0135] To a 50 mL DMF solution containing methyl 2-(bromomethyl)-6-chloronicotinate (5 g, 18.9 mmol) and methyl 2-(p-tolylsulfonylamino)acetate (4.6 g, 18.9 mmol), K2CO3 (5.02 g, 47.4 mmol) and NaI (0.28 g, 1.86 mmol) were added. This mixture was stirred at 50°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with H2O (80 mL x 3). The organic layer was washed with brine (80 mL x 3), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel chromatography to obtain methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)nicotinate (6 g, crude) as a yellow solid.

[0136] 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)nicotinate methyl (6 g, 14 mmol) was added to a DMSO solution (60 mL) with K2CO3 (11.6 g, 84.3 mmol). The mixture was stirred at 50°C for 4 hours under an N2 atmosphere. The mixture was diluted with H2O (60 mL), and the aqueous solution was adjusted to pH 6 with 1 M HCl. The precipitated solid was filtered and dried to obtain 2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate methyl (1.5 g, yield 45%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.72(d,J=0.9Hz,1H),7.91(d,J=8.8Hz,1H),3.95(s,3H).

[0137] To a 30 mL MeOH solution containing methyl 2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate (1 g, 4.19 mmol), 5-(aminomethyl)pyridine-2-carbonitrile (0.84 g, 6.29 mmol) and TEA (2.91 mL, 20.95 mmol) were added, and the reaction mixture was stirred overnight at 75°C. The reaction mixture was filtered through a standard funnel, the filter cake was washed with 10 mL of MeOH, and dried under vacuum to obtain 2-chloro-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (1.1 g, 3.24 mmol, yield 77%) as a yellow solid.

[0138] To an 80 mL DMSO solution containing 2-chloro-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyrizine-6-carboxamide (8 g, 23.55 mmol, 1.0 equivalent), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (4.7 g, 36.66 mmol, 1.5 equivalent) and TEA (13 mL, 93.53 mmol, 4.0 equivalent) were added, and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled and poured into water (160 mL). The mixture was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with saturated NaCl solution (80 mL x 3), dried over Na2SO4, and concentrated. When the volume of the solution was concentrated to approximately 40 mL, a large amount of yellow solid precipitated. The mixture was filtered, the filter cake was washed with EA (40 mL), and dried to obtain compound 1. LCMS: Retention time: 1.021 min, (M+H) = 403.2. 1 H NMR:(400MHz,DMSO-d6)δ 13.35(s,1H),9.75(t,J=6.3Hz,1H),8.76(s,1H),8.42(s,1H),8.25(d,1H),8.02-8.00(m,2H),7.19-6.98(m,1H),5.19-5.17(m,1H), 4.75(s,1H),4.63(d,J=6.4Hz,2H),3.85(d,J=6.6Hz,1H),3.74-3.72(m,1H),3.62-3.60(m,1H),3.31-3.30(m,1H),2.01-1.92(m,2H).

[0139] Example 2: PHD2 Enzyme Assay Procedure Preparation of compound DMSO stock: Compound 1 was reconstituted into a 20 mM stock using DMSO. Compound storage: Compound 1 in DMSO was stored at room temperature in a desiccator for short-term storage (maximum 3 months).

[0140] Preparation of work stock: • Reference roxadustat (FG-4592) was sequentially diluted 3-fold in DMSO from 400 μM over 10 steps. The compound was sequentially diluted 3-fold in DMSO over 10 steps, starting from 400 μM. A 200× positive control (400 μM, FG-4592) and a 200× vehicle control (100% DMSO) were prepared. The compound plate was centrifuged at 1000 rpm for 1 minute.

[0141] Compound screening: a) Using an Echo 655, 40 nl of compound dilution was transferred to each well of the assay plate; b) The assay plate and the centrifuged compound plate were sealed at 1000 rpm for 1 minute. c) Prepare 4 μL of 2×PHD2 enzyme working solution and add it to each well of the assay plate. d) The assay plate and the compound plate were sealed by centrifuging at 1000 rpm for 1 minute. The plates were incubated at room temperature for 30 minutes. e) Prepare 4 μl of 2×PHD2 substrate working solution and add it to each well of the assay plate. f) Prepare 4 μL of 4× stop solution and add it to each well of the assay plate. g) A 4× detection solution containing AlphaScreen streptavidin donor beads, AlphaScreen protein A acceptor beads, and Hydroxy-HIF-1α(Pro564)(D43B5)XP(registered trademark) Rabbit mAb was prepared. h) 4 μL of 4× detection solution was added to each well of the assay plate. Repeat step d. i) The alpha screen signal was read using the Envision HTS plate reader.

[0142] Data Analysis The ALPHASCREEN signal (ALPcmpd) is calculated for each well. The inhibition rate is calculated as follows:

number

number

number

[0143] Example 3: EPO Elisa assay The compound powder was dissolved in 100% DMSO. The stock solution of the compound was stored in a nitrogen cabinet.

[0144] Experimental method Cell seeding: Add 100 μl of cell suspension, with 20k Hep3B cells per well. Preparation of compound concentration gradient: The highest dose of compound at 100 μM was administered 1.3 times, 8 times, as a single or double dose. A solution 200 times the final concentration was prepared in a 96-well plate, the compound was diluted 200 / 3× with cell culture medium, and 50 μL was pipetteed into the wells. 50 μL of medium containing DMSO was added to the smallest control well to reach the final concentration containing 5‰ DMSO, and 50 μL of the highest concentration of the reference compound was added to the largest control well. Incubate at 37°C for 24 hours. The reaction plate was washed twice with 400 μL of 1× Wash Buffer per well. 100 μL of diluted standard solution (including standard blank control) was added to the appropriate wells. 50 μL of the sample and 50 μL of the sample dilution were added to the sample wells. Add 50 μL of 1× biotin-conjugated antibody to all wells and incubate at room temperature for 1 hour. The reaction plate was washed six times with 400 μL of 1×Wash Buffer per well. • 100 μL of 1×Streptavidin-HRP was added to each well. Incubate at room temperature for 15 minutes. The reaction plate was washed six times with 400 μL of 1×Wash Buffer per well. 100 μL of TMB substrate solution was added to each well. Incubate at room temperature for 10 minutes. 100 μL of stop solution was added to each well. • The OD450 was read using EnSight.

[0145] Data Analysis Use GraphPad Prism 5. Active % = (composite signal - minimum signal) / (maximum signal - minimum signal) × 100.

[0146] The maximum signal was obtained from the largest control well. The minimum signal was obtained from the minimum control well.

[0147] The logarithmic value of the concentration is plotted on the X-axis, and the inhibition rate on the Y-axis. The dose-response curve was fitted using the analysis software GraphPad Prism 5 log(inhibitor)vs. response-Variable slope to determine the EC of each compound. 50 Obtain a value.

[0148] The data for Examples 2 and 3 are shown below. [Table 5]

[0149] Example 4: Preparation of free base A of compound 1 Approximately 30 mg of compound 1 was equilibrated in 0.5 mL of ethanol, methyl ethyl ketone, acetone, ethyl acetate, acetonitrile, or dichloromethane at 25°C for 11 days using a stirring bar on a magnetic stirring plate at a speed of 500 rpm. The solid precipitate was subjected to XRPD, DSC, TGA, and 1 Collected for 1H-NMR.

[0150] Figure 1 shows the XRPD pattern of the free base A of compound 1. Table 1 shows the major peaks in the XRPD pattern and their associated intensities. The free base A of compound 1 is anhydrous.

[0151] The DSC and TGA results shown in Figure 2 indicate that the free base A of compound 1 initiates an endothermic event at approximately 215°C.

[0152] Example 5: Another preparation of free base A of compound 1 Approximately 30 mg of compound 1 was equilibrated in 0.45–1.0 mL of acetone, acetonitrile, dichloromethane, tetrahydrofuran, or isopropanol under a temperature cycle of 5°C–50°C at a heating / cooling rate of 0.1°C / min for approximately 10 cycles. This equilibration was performed at a speed of 400 rpm using a stirring bar on a magnetic stirring plate. The residual solid was collected by centrifugation at 14,000 rpm and examined by XRPD. The XRPD pattern of the solid was the same as in Table 1, confirming that it was the free base A type of compound 1.

[0153] Example 6: Another preparation of free base A of compound 1 Approximately 30 mg of compound 1 was equilibrated at 50°C in 0.45–1.0 mL of acetone, acetonitrile, tetrahydrofuran, dichloromethane, or isopropanol. This system was cooled to 5°C at a rate of 0.1°C / min. This equilibration was performed at a speed of 400 rpm using a stirring bar on a magnetic stirring plate. The residual solid was collected by centrifugation at 14,000 rpm. The solid precipitate was collected for XRPD testing. The XRPD pattern of the solid was the same as in Table 1, confirming that it was the free base A type of compound 1.

[0154] Example 7: Another preparation of free base A of compound 1 Approximately 30 mg of compound 1 was weighed into a 2 ml vial, and then 1 ml of tetrahydrofuran, dimethylformamide, or 1,4-dioxane was added. The mixture was stirred at 500 rpm for 30 minutes at 50°C using a stirring bar on a magnetic stirring plate, and then filtered. A constant amount of n-heptane was added in stages until a large amount of solid precipitated. All samples were continuously stirred at 25°C and 500 rpm / min. The residual solid was collected by centrifugation at 14,000 rpm and examined by XRPD. The XRPD pattern of the solid was the same as in Table 1, confirming that it was the free base A type of compound 1.

[0155] Example 8: Another preparation of free base A of compound 1 Approximately 30 mg of compound 1 was weighed into a 2.0 mL glass vial, and then 1.0 mL of tetrahydrofuran or dichloromethane was added to obtain a clear solution. The vial was then covered with aluminum foil with a pinhole and placed in a fume hood until the liquid had completely evaporated. Alternatively, the vial was blow-dried with nitrogen until the liquid had completely evaporated. The solid obtained from the system was then characterized by XRPD. The XRPD pattern of the solid was the same as in Table 1, confirming that it was the free base A type of compound 1.

[0156] Example 9: Preparation of HCl salt type A of compound 1 Approximately 25 mg of free base A of compound 1 was weighed into a 2 mL glass vial, and then 300 μL of methyl ethyl ketone was added. The vial was placed on a hot plate and stirred at a rate of 300 r / min at 50°C. 1.1 equivalents of hydrochloric acid were diluted with methyl ethyl ketone and slowly filled into the compound 1 solution. After stirring for 2 hours, the system was cooled to 25°C and stirred continuously at 25°C for 4 days. The resulting suspension was centrifuged (8000 r / min, 10 min), and the residual solids were vacuum-dried at 30°C. The solids were characterized by XRPD, DSC, and TGA.

[0157] Figure 3 shows the XRPD pattern of compound 1's HCl salt type A. Table 2 shows the major peaks in the XRPD pattern and their associated intensities. Figure 4 shows the DSC and TGA results.

[0158] Example 10: Preparation of HCl salt form B of compound 1 Approximately 25 mg of free base A of compound 1 was weighed into a 2 mL glass vial, and then 300 μL of ethyl acetate was added. The vial was placed on a hot plate and stirred at a rate of 300 r / min at 50°C. 1.1 equivalents of hydrochloric acid were diluted with ethyl acetate and slowly added to the compound 1 solution. After stirring for 2 hours, the system was cooled to 25°C and stirred continuously at 25°C for 4 days. The resulting suspension was centrifuged (8000 r / min, 10 min), and the residual solid was vacuum-dried at 30°C. The solid was then subjected to XRPD, DSC, TGA, and 1 Characterized by 1H-NMR.

[0159] The XRPD pattern of the B-type HCl salt of Compound 1 is shown in Figure 5. The main peaks in the XRPD pattern and their related intensities are shown in Table 3. The results of DSC and TGA are shown in Figure 6.

[0160] Example 11: Preparation of the tosylate A-type of Compound 1 Approximately 25 mg of the free base A-type of Compound 1 was weighed in a 2 mL glass vial, and then 300 μL of methyl ethyl ketone was added. The vial was placed on a hot plate and stirred at 50 °C at a speed of 300 r / min. 1.1 equivalents of p-toluenesulfonic acid was pre-dissolved in methyl ethyl ketone and slowly added to the solution of Compound 1. After stirring for 2 hours, the system was cooled to 25 °C and stirring was continued at 25 °C for 4 days. The resulting suspension was centrifuged (8000 r / min, 10 minutes), and the residual solid was dried in vacuo at 30 °C. The solid was characterized by XRPD, DSC, TGA, and 1 1H-NMR.

[0161] The XRPD pattern of the tosylate A-type of Compound 1 is shown in Figure 7. The main peaks in the XRPD pattern and their related intensities are shown in Table 4. The results of DSC and TGA are shown in Figure 8. 1 1H-NMR indicates that the ratio of Compound 1:p-toluenesulfonic acid is approximately 1:1.02.

[0162] Analysis method Differential scanning calorimetry (DSC) An accurate amount of the sample (0.5 - 1.5 mg) was added to a standard aluminum TA-Instrument sample pan / Tzero aluminum pan. The sample pan was closed with a standard lid / Tzero lid with a pinhole, and a DSC curve was recorded with a TA-Instruments Q2000 / Discovery DSC 2500 equipped with an RCS cooling unit. [Table 6] [Table 7]

[0163] Thermogravimetric analysis (TGA) Approximately 2–10 mg of the sample was placed in an open aluminum pan / sealed aluminum pan. Details of the TGA (Discovery TGA 5500 or TGA Q5000) method used in the study are as follows: [Table 8] [Table 9]

Claims

1. 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide: 【Chemistry 1】 (Compound 1) or a pharmaceutically acceptable salt thereof in solid form.

2. The solid form according to claim 1, wherein the solid form is a crystalline form.

3. The solid form according to claim 1 or 2, wherein the solid form is a crystalline compound 1 as a free base.

4. The solid form according to claim 3, wherein the solid form is the free base A type of crystalline compound 1.

5. The solid form according to claim 1 or 2, wherein the solid form is a crystalline compound 1 as a salt.

6. The solid form according to claim 5, wherein the solid form is the HCl salt type A of crystalline compound 1, the HCl salt type B of compound 1, or the tosylate type A of compound 1.

7. The crystalline form according to claim 2, wherein the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) Measurements using CuKα radiation show substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1; (b) X-ray powder diffraction (XRPD) pattern with peaks at 8.5±0.2°2θ, 16.2±0.2°2θ, and 20.3±0.2°2θ, as measured using CuKα rays; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 2; or (e) A combination of those.

8. The crystal morphology according to claim 7, wherein, according to measurements using CuKα rays, the crystal morphology has substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 1.

9. The crystal morphology according to claim 7 or 8, wherein, according to measurements using CuKα rays, the crystal morphology has an X-ray powder diffraction (XRPD) pattern having the peaks shown in Table 1.

10. The crystal morphology according to any one of claims 7 to 9, wherein the crystal morphology has an X-ray powder diffraction (XRPD) pattern having peaks at 8.5±0.2°2θ, 16.2±0.2°2θ, and 20.3±0.2°2θ, as measured using CuKα rays.

11. The crystalline form according to any one of claims 7 to 10, wherein the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 14.2 ± 0.2°²θ, 18.6 ± 0.2°²θ, and 22.3 ± 0.2°²θ.

12. The crystal morphology according to any one of claims 7 to 11, wherein the X-ray powder diffraction (XRPD) pattern further includes peaks at 22.8 ± 0.2°²θ, 25.9 ± 0.2°²θ, and 26.9 ± 0.2°²θ, as measured using CuKα rays.

13. The crystalline form according to any one of claims 7 to 12, wherein the X-ray powder diffraction (XRPD) pattern, as measured using CuKα rays, further includes peaks at 18.0 ± 0.2°²θ, 23.9 ± 0.2°²θ, 28.1 ± 0.2°²θ, and 30.6 ± 0.2°²θ.

14. The crystal morphology according to any one of claims 7 to 9, wherein the crystal morphology has an X-ray powder diffraction (XRPD) pattern having peaks at 8.5±0.2°2θ, 14.2±0.2°2θ, 16.2±0.2°2θ, 18.0±0.2°2θ, 18.6±0.2°2θ, 20.3±0.2°2θ, 22.3±0.2°2θ, 22.8±0.2°2θ, 23.9±0.2°2θ, 25.9±0.2°2θ, 26.9±0.2°2θ, 28.1±0.2°2θ, and 30.6±0.2°2θ, according to measurements using CuKα rays.

15. The crystalline form according to any one of claims 7 to 14, wherein the crystalline form is anhydrous.

16. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form described in any one of claims 2 to 15 and a pharmaceutically acceptable excipient.

17. A method for treating a target disease or disorder, comprising administering to the target a crystalline form described in any one of claims 2 to 15, or a pharmaceutical composition described in claim 16, wherein the disease or disorder is anemia.

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