CN121057737A - Protein (PHD) inhibitor crystals containing prolyl hydroxylase domain and uses thereof - Google Patents

Abstract

Crystalline forms of small molecule inhibitors of prolyl hydroxylase domain containing Proteins (PHDs), pharmaceutical compositions comprising them and methods of use thereof in the treatment of anemia.Compound 1

Description

Crystallization and Applications of Protein (PHD) Inhibitors Containing Prolyl Hydroxylase Domains

Cross-references

This patent application claims the benefit of International Patent Application No. PCT/CN2023/091785, filed on April 28, 2023, which is incorporated herein by reference in its entirety.

background

Hypoxia-inducible factor (HIF) mediates gene expression that responds to changes in cellular oxygen concentration. HIF is a heterodimer containing an oxygen-regulating subunit (HIF-α) and a constitutively expressed subunit (HIF-β). HIF prolyl hydroxylase (also known as a prolyl hydroxylase-containing protein (PHD)) exists in three isoforms in humans (PHD1, PHD2, and PHD3). PHDs function as oxygen sensors regulating the HIF degradation pathway. In short, PHDs are responsible for the hydroxylation of HIFα (the HIF subunit), the initiation of which ultimately leads to HIFα degradation via the proteasome. Three PHD subunits exist, including PHD1, PHD2, and PHD3. Inhibition of PHDs has been indicated as a promising therapy for HIFα-related diseases such as anemia.

PHD inhibitors coordinate erythropoiesis by inducing the synthesis of renal and hepatic erythropoietin (“EPO”) that stimulates erythrocyte production in the bone marrow and by regulating iron metabolism (an essential component of functional erythrocytes). PHD inhibitors can also inhibit the production of hepcidin, which has a negative impact on iron mobilization. It is also presumed that PHD inhibitors can upregulate the expression of several iron metabolism genes, such as DMT1 and DCYTB. Because HIF prolyl hydrolase plays a central role in cellular oxygen sensing, PHD inhibitors could be used to treat cardiovascular diseases, metabolic diseases, hematological disorders, lung diseases, kidney diseases, liver diseases, wound healing disorders, and cancer.

Overview

This article discloses 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthidine-6-carboxamide: (Compound 1) or its pharmaceutically acceptable salt in solid form.

In some implementations, the solid form is a crystalline form.

In some implementations, the solid form is crystalline compound 1 in the form of a free base.

In some implementations, the solid form is crystalline compound 1 free base type A.

In some implementations, the solid form is a crystalline compound 1 in the form of a salt.

In some embodiments, the solid form is crystalline compound 1 HCl salt type A, compound 1 HCl salt type B, or compound 1 toluenesulfonate type A.

This article also discloses pharmaceutical compositions comprising a therapeutically effective amount of the crystalline form disclosed herein and pharmaceutically acceptable excipients.

This document also discloses a method for treating an individual’s disease or condition, the method comprising administering to the individual the crystalline form or pharmaceutical composition disclosed herein, wherein the disease or condition is anemia.

Brief description of the attached diagram

The features of the invention are set forth in detail in the appended claims. The features of the invention can be better understood by referring to the detailed description set forth in the following exemplary embodiments (which utilize the principles of the invention) and the accompanying drawings:

Figure 1 shows the X-ray powder diffraction (XRPD) pattern of the free base A type of compound 1.

Figure 2 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of the free base A type of compound 1.

Figure 3 shows the X-ray powder diffraction (XRPD) pattern of compound 1 HCl salt type A.

Figure 4 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HCl salt type A.

Figure 5 shows the X-ray powder diffraction (XRPD) pattern of compound 1 HCl salt type B.

Figure 6 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HCl salt type B.

Figure 7 shows the X-ray powder diffraction (XRPD) pattern of compound 1 toluenesulfonate type A.

Figure 8 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 toluenesulfonate type A.

Detailed description

While small molecule inhibitors are typically evaluated first for their activity in solution, solid-state characteristics such as polymorphism are also important. Polymorphs of drug substances can possess different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly impact the ability to process or manufacture drug substances and drug products. Furthermore, differences in these properties can and often lead to different pharmacokinetic profiles in different polymorphs of a drug. Therefore, polymorphism is often an important factor in regulatory reviews of the 'sameness' of drugs from different manufacturers.

Compound 1

Compound 1 is 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthidine-6-carboxamide: (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 toluenesulfonate.

Solid form of compound 1

In one respect, this article provides 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthidine-6-carboxamide: (Compound 1) or its pharmaceutically acceptable salt in solid form.

In some implementations, the solid form is a crystalline form.

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

In some embodiments, the solid form is a salt of compound 1 HCl. In some embodiments, the solid form is a crystalline salt of compound 1 HCl. In some embodiments, the solid form is crystalline salt of compound 1 HCl type A. In some embodiments, the solid form is crystalline salt of compound 1 HCl type B.

In some embodiments, the solid form is compound 1 toluenesulfonate. In some embodiments, the solid form is crystalline compound 1 toluenesulfonate. In some embodiments, the solid form is crystalline compound 1 toluenesulfonate type A.

Compound 1 Free base type A

This document discloses a free base of compound 1, type A. In some embodiments, the crystalline form is a free base of compound 1, characterized by having at least one of the following properties:

(a) An X-ray powder diffraction (XRPD) pattern that is essentially the same as that shown in Figure 1, as determined using Cu Kα radiation;

(b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 8.5 ± 0.2°2θ, 16.2 ± 0.2°2θ, and 20.3 ± 0.2°2θ;

(c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 2;

(d) Differential scanning calorimetry (DSC) thermogram with an endothermic peak at a peak temperature of approximately 215°C;

(e) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as that shown in Figure 2; or

(f) Its combination.

In some embodiments, the crystalline form is a free base of compound 1, characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 8.5 ± 0.2°2θ, 16.2 ± 0.2°2θ, and 20.3 ± 0.2°2θ;

(b) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak at a peak temperature of approximately 215°C; or

(c) Its combination.

In some embodiments, the crystalline form is a free base of compound 1, characterized by having at least one of the following properties:

(a) An X-ray powder diffraction (XRPD) pattern that is essentially the same as that shown in Figure 1, as determined using Cu Kα radiation;

(b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 8.5 ± 0.2°2θ, 16.2 ± 0.2°2θ, and 20.3 ± 0.2°2θ;

(c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 2;

(d) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as shown in Figure 2; or

(e) Its combination.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1, as determined using Cu Kα radiation.

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

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

In some embodiments of the free base of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 14.2 ± 0.2° 2θ, 18.6 ± 0.2° 2θ, and 22.3 ± 0.2° 2θ.

In some embodiments of the free base of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 22.8 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 26.9 ± 0.2° 2θ.

In some embodiments of the free base of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 18.0 ± 0.2° 2θ, 23.9 ± 0.2° 2θ, 28.1 ± 0.2° 2θ, and 30.6 ± 0.2° 2θ.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, having at least ten 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.

In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, having at least eleven 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.

In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermograms are essentially the same as those shown in Figure 2.

In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram has an endothermic peak with a peak temperature of about 215°C.

In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) chromatogram is essentially the same as that shown in Figure 2.

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

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

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

In some embodiments of the free base of compound 1, the crystalline form is thermodynamically stable.

Table 1. List of XRPD peaks for the free base A type of compound 1.

Compound 1 HCl salt type A

This document discloses a type A HCl salt of compound 1. In some embodiments, the crystalline form is an HCl salt of compound 1, characterized by having at least one of the following properties:

(a) An X-ray powder diffraction (XRPD) pattern that is essentially the same as that shown in Figure 3, as determined using Cu Kα radiation;

(b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 7.9 ± 0.2°2θ, 10.8 ± 0.2°2θ, and 15.9 ± 0.2°2θ;

(c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 4;

(d) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as shown in Figure 4; or

(e) Its combination.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 3, as determined using Cu Kα radiation.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with the peaks shown in Table 2, as determined using Cu Kα radiation.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, with peaks at 7.9 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, and 15.9 ± 0.2° 2θ.

In some embodiments of the HCl salt of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 9.0 ± 0.2° 2θ, 13.1 ± 0.2° 2θ, and 24.6 ± 0.2° 2θ.

In some embodiments of the HCl salt of compound 1, X-ray powder diffraction (XRPD) patterns, such as those measured using Cu Kα radiation, also include a peak at 21.0 ± 0.2° 2θ.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the differential scanning calorimetry (DSC) thermograms are essentially the same as those shown in Figure 4.

In some embodiments of the HCl salt of compound 1, the thermogravimetric analysis (TGA) chromatogram is essentially the same as that shown in Figure 4.

Table 2: List of XRPD peaks for Compound 1 HCl salt type A

Compound 1 HCl salt type B

This document discloses a type B HCl salt of compound 1. In some embodiments, the crystalline form is an HCl salt of compound 1, characterized by having at least one of the following properties:

(a) The same X-ray powder diffraction (XRPD) pattern as shown in Figure 5, as determined using Cu Kα radiation.

(b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 4.8 ± 0.2°2θ, 20.0 ± 0.2°2θ, and 27.2 ± 0.2°2θ;

(c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 6;

(d) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as shown in Figure 6; or

(e) Its combination.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 5, as determined using Cu Kα radiation.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with the peaks shown in Table 3, as determined using Cu Kα radiation.

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

In some embodiments of the HCl salt of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 16.8 ± 0.2° 2θ, 22.2 ± 0.2° 2θ, and 27.7 ± 0.2° 2θ.

In some embodiments of the HCl salt of compound 1, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 13.7 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, and 19.3 ± 0.2° 2θ.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of the HCl salt of compound 1, the differential scanning calorimetry (DSC) thermograms are essentially the same as those shown in Figure 6.

In some embodiments of the HCl salt of compound 1, the thermogravimetric analysis (TGA) chromatogram is essentially the same as that shown in Figure 6.

Table 3. XRPD peak list of compound 1 HCl salt type B

Compound 1 Toluenesulfonate Type A

This document discloses compound 1 toluenesulfonate type A. In some embodiments, the crystalline form is compound 1 toluenesulfonate, characterized by having at least one of the following properties:

(a) An X-ray powder diffraction (XRPD) pattern that is essentially the same as that shown in Figure 7, as determined using Cu Kα radiation;

(b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 5.1 ± 0.2°2θ, 16.9 ± 0.2°2θ, and 20.2 ± 0.2°2θ;

(c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 8;

(d) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as shown in Figure 8; or

(e) Its combination.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 7, as determined using Cu Kα radiation.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern with the peaks shown in Table 4, as determined using Cu Kα radiation.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as measured using Cu Kα radiation, with peaks at 4.8 ± 0.2° 2θ, 20.0 ± 0.2° 2θ, and 27.2 ± 0.2° 2θ.

In some embodiments of compound 1 toluenesulfonate, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 16.0 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, and 23.7 ± 0.2° 2θ.

In some embodiments of compound 1 toluenesulfonate, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 19.1 ± 0.2° 2θ and 21.6 ± 0.2° 2θ.

In some embodiments of compound 1 toluenesulfonate, X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation also include peaks at 25.6 ± 0.2° 2θ and 26.3 ± 0.2° 2θ.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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.

In some embodiments of compound 1 toluenesulfonate, the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, having at least nine 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.

In some embodiments of compound 1 toluenesulfonate, the differential scanning calorimetry (DSC) thermograms are essentially the same as those shown in Figure 8.

In some embodiments of compound 1 toluenesulfonate, the thermogravimetric analysis (TGA) chromatogram is essentially the same as that shown in Figure 8.

In some embodiments of compound 1 toluenesulfonate, the ratio of compound 1 to p-toluenesulfonic acid is approximately 1:1.02.

Table 4. XRPD peak list of compound 1 toluenesulfonate type A

Treatment

This article discloses a method for treating an individual’s disease or condition, the method comprising administering to the individual a crystalline form disclosed herein, wherein the disease or condition is anemia.

anemia

Anemia is a common and serious complication of chronic kidney disease, characterized by a relative deficiency in EPO production and reduced iron utilization in hemoglobin (“Hb”) synthesis. According to Informa, there were 168 million prevalent cases of anemia worldwide in 2020 due to chronic kidney disease. This number is projected to rise to 182 million by 2027, according to the same source.

Currently, anemia caused by chronic kidney disease is managed through iron supplementation, and in more severe cases, through the administration of supraphysiological doses of erythropoietin-stimulating agents (“ESAs”) combined 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 PHD inhibitors are available and can be considered effective treatments for patients with anemia caused by chronic kidney disease. However, erythropoietin-induced cardiovascular side effects and potential off-target toxicity may raise safety concerns regarding long-term treatment. New therapies are needed to address both impaired EPO production and functional iron deficiency simultaneously.

Dosage

In some embodiments, a composition containing the compounds described herein is administered for preventative and/or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially relieve at least one symptom of the disease or condition. The effective dose for this purpose depends on the severity and duration of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, and the judgment of the attending physician. The therapeutically effective dose may optionally be determined by methods including, but not limited to, dose escalation and/or dose range clinical trials.

In preventative applications, a composition containing the compounds described herein is administered to a patient who is susceptible to a particular disease, disorder, or condition, or who is at risk of such a disease, condition, or condition. Such an amount is defined as a “preventatively effective amount or dose.” In this application, the precise amount also depends on the patient’s health condition, weight, etc. When used on a patient, the effective amount for this purpose depends on the severity and course of the disease, disorder, or condition, previous treatments, the patient’s health condition and response to the medication, and the judgment of the attending physician. In one aspect, preventative treatment comprises administering a pharmaceutical composition containing the compounds described herein or a pharmaceutically acceptable salt thereof to a mammal who has previously experienced at least one symptom or risk factor of a treated disease and is currently in remission, the pharmaceutical composition being to prevent recurrence of symptoms of the disease or condition.

In some implementation schemes where the patient’s condition does not improve, the compound may be administered long-term, based on the physician’s judgment, that is, for an extended period of time, including throughout the patient’s life, to improve, or otherwise control or limit, the symptoms of the patient’s disease or condition.

In any of the foregoing aspects, there are additional embodiments in which an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is administered to a mammal by: (a) systemic administration; and/or (b) oral administration to a mammal; and/or (c) intravenous administration to a mammal; and/or (d) injection administration to a mammal; and/or (e) local administration to a mammal; and/or (f) non-systemic or non-local administration to a mammal.

Application route

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and local administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of a reservoir preparation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered via implantation (e.g., subcutaneous or intramuscular injection) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered using a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In these embodiments, the liposomes target the organ and are selectively absorbed therefrom. In yet another embodiment, the compounds described herein are provided in the form of an immediate-release formulation, an extended-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

Pharmaceutical Compositions/Formulations

The compounds described herein, alone or in pharmaceutical compositions in combination with acceptable carriers, excipients, or diluents, are administered to individuals in need according to standard pharmaceutical practice. In one embodiment, the compounds described herein are administered to animals. The compounds are administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes of administration.

In another aspect, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in publications such as: 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference.

In some implementations, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combination thereof.

The pharmaceutical compositions described herein may be administered to an individual via appropriate routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, powders, lozenges, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

Pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers thereof are prepared in a conventional manner, for example by way of example only, through conventional mixing, dissolving, granulation, tableting, grinding, emulsifying, encapsulating, embedding or pressing methods.

Orally administered pharmaceutical compositions are obtained by the following steps: mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture (if desired) after adding suitable excipients to obtain tablets or tablet 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 gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants are added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or salts thereof, such as sodium alginate. In some embodiments, dyes or pigments are added to the coating of the tablets or tablets for identifying or characterizing different combinations of active compound dosages.

Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). 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 optionally a stabilizer. In 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.

Pharmaceutical compositions intended for parenteral use are formulated as infusion or injection solutions. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise sterile aqueous solutions, dispersions, or sterile powders 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, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition also comprises a preservative to prevent microbial growth.

definition

Unless otherwise stated, the following terms as used in this application have the definitions given below. The use of the term "comprising," as well as other forms such as "include," "includes," and "included," is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it has no lasting adverse effect on the general health of the individual being treated.

As used herein, the term "administration," etc., refers to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the term "effective amount" or "therapeutic effective amount" means an adequate amount of an active agent or compound administered that provides relief to one or more symptoms of the disease or condition being treated. Results include reduction and/or relief of signs, symptoms, or causes of the disease or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use means the amount of the composition of the compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in any individual case may optionally be determined using techniques such as dose-escalation studies.

As used herein, the term "enhancement" refers to increasing or prolonging the potency or duration of a desired effect. Therefore, regarding the effect of an enhancing therapeutic agent, the term "enhancement" refers to increasing or prolonging the effect of another therapeutic agent on the system in terms of potency or duration. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

The terms "individual" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates such as chimpanzees and other apes and monkey species; farm 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 respect, the mammal is human.

As used herein, the term “treatment” includes relieving, reducing or improving at least one symptom of a disease or condition, preventing other symptoms, inhibiting a disease or condition, for example, preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving the condition caused by a disease or condition, or preventing and/or therapeutically terminating the symptoms of a disease or condition.

The term "about" refers to a statistically significant range of a value, such as a specified concentration range, time range, molecular weight, particle size, temperature, or pH. Such a range can be within an order of magnitude, typically within 10% of the indicated value or range, more typically within 5%, and even more typically within 3%. Sometimes, such a range can be within the typical experimental error range of standard methods used to measure and/or determine a specified value or range. The permissible variation covered by the term "about" depends on the specific system under study and will be readily understood by those skilled in the art. Whenever a range is recorded in this application, each integer within that range is also considered an embodiment of the invention. In the context of this disclosure, whether or not the term "about" is used, it means within 10% of the specified value or range, appropriately within 5%, and particularly within 1%.

If multiple diffraction patterns are available, particle statistics (PS) and/or preferred orientation (PO) can be evaluated. Consistency in relative intensity across XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, if available, the observed XRPD pattern can be compared to an XRPD pattern calculated based on the single-crystal structure. Two-dimensional scattering patterns using an area detector can also be used to evaluate PS/PO. If the effects of PS and PO are determined to be negligible, the XRPD pattern represents the average powder intensity of the sample, and the dominant peak can be identified as the "representative peak." Generally, the more data collected to determine the representative peak, the greater the confidence in classifying those peaks.

A "characteristic peak" is a subset of representative peaks in terms of their presence and is used to distinguish one crystalline polymorph from another (a polymorph is a crystalline form with the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks (within ±0.2°2θ) (if any) are present in one of the compound's crystalline polymorphs compared to all other known crystalline polymorphs of the compound. Not all crystalline polymorphs of a compound must have at least one characteristic peak.

The term "preferred orientation" as used in this paper refers to the extreme case where the grains in the solid form are not randomly distributed. In XRPD, the ideal sample is homogeneous, and the grains are randomly distributed in the bulk solid. In a truly random sample, every possible reflection from a given set of planes has an equal number of grains contributing to it. However, this is not the case when the solid form is in a preferred orientation. Therefore, comparing the intensity of a random orientation diffraction pattern with a preferred orientation diffraction pattern may look completely different. Quantitative analysis based on intensity ratios is significantly distorted by preferred orientation. Careful sample preparation is crucial to reducing the occurrence of preferred orientation.

The term "substantially identical" as used herein with reference to the accompanying drawings is intended to mean that the drawings are considered to represent the type and kind of characteristic data that would be obtained by a person skilled in the art in view of acceptable deviations in the art. Such deviations may be caused by factors related to variations in sample size, sample preparation, specific instrumentation 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 temperature and peak temperature measured by methods such as differential scanning calorimetry (DSC) may differ from experiment to experiment. For example, a person skilled in the art can readily 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 when the characteristic peak variations do not exceed ±0.2° 2-θ.

As used herein, salts of Compound 1 include compounds in which the corresponding acid is in an ionized, non-ionized, associated, or non-associated form. In some embodiments, the corresponding acid is in an ionized and/or associated form. In some embodiments, the corresponding acid is in a non-ionized and/or non-associated form. Salts of Compound 1 also include salts in the form of monobasic acids, dibasic acids, etc.

Example

The following embodiments are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

Example 1: Preparation of Compound 1

To a solution of methyl 2-(bromomethyl)-6-chloronicotinate (5 g, 18.9 mmol) and methyl 2-(p-toluylsulfonylamino)acetate (4.6 g, 18.9 mmol) in DMF (50 mL), _K₂CO₃ (5.02 g, 47.4 _mmol ) and NaI (0.28 g, 1.86 mmol) were added. The mixture was stirred at 50°C under a _nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with _H₂O (80 mL × 3). The organic layer was washed with brine (80 mL × 3), dried over _MgSO₄ , filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography to give methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonylamino)methyl)nicotinate (6 g, crude) as a yellow solid.

To a solution of methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)nicotinate (6 g, 14 mmol) in DMSO (60 mL) _{, K₂CO₃} (11.6 g, 84.3 mmol) was added. The mixture was stirred at 50°C under a _nitrogen atmosphere for 4 hours. The mixture was diluted with _H₂O (60 mL), and the aqueous layer was adjusted to pH 6 with 1 M HCl. The precipitated solid was filtered and dried to give methyl 2-chloro-5-hydroxy-1,7-naphthidine-6-carboxylate (1.5 g, 45% yield) as a yellowish-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.72 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H).

To a solution of methyl 2-chloro-5-hydroxy-1,7-naphthyl-6-carboxylate (1 g, 4.19 mmol) in MeOH (30 mL), 5-(aminomethyl)pyridin-2-carboxynitrile (0.84 g, 6.29 mmol) and TEA (2.91 mL, 20.95 mmol) were added, and the reaction 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 give 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyl-6-carboxamide (1.1 g, 3.24 mmol, 77% yield) as a yellow solid.

To a solution of 2-chloro-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyl-6-carboxamide (8 g, 23.55 mmol, 1.0 eq) in DMSO (80 mL), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (4.7 g, 36.66 mmol, 1.5 eq) and TEA (13 mL, 93.53 mmol, 4.0 eq) were added, and the reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled and poured into water (160 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated NaCl solution (80 mL × ₃ ), dried over _Na₂SO₄ , and concentrated. When the solution volume was concentrated to approximately 40 mL, a large amount of yellow precipitate formed. The mixture was filtered, the filter cake was washed with EA (40 mL), and dried to give compound 1. LCMS: Retention time: 1.021 min, (M+H) = 403.2. ^1H NMR: (400 MHz, DMSO- _d⁶ ) δ 13.35 (s, 1H), 9.75 (t, J = 6.3 Hz, 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 = 6.4 Hz, 2H), 3.85 (d, J = 6.6 Hz, 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).

Example 2: PHD2 enzyme assay method

Preparation of DMSO stock solution of compound 1: Compound 1 was reconstituted into a 20 mM stock solution using DMSO.

Compound storage: Compound 1 in DMSO will be stored in a desiccator at room temperature for short-term storage (up to 3 months).

Preparation of working stock solution:

The control substance roxadustat (FG-4592) was serially diluted 3-fold from 400 μM in DMSO for a total of 10 doses.

The compound was serially diluted 3-fold from 400 μM in DMSO for a total of 10 doses.

Prepare a 200× positive control (400 μM, FG-4592) and a 200× medium control (100% DMSO).

Centrifuge the compound plate at 1000 rpm for 1 minute.

Compound screening:

a) Use an Echo 655 to transfer 40 nl of compound dilution to each well of the assay plate;

b) Seal the test plate and centrifuge the compound plate at 1000 rpm for 1 minute.

c) Prepare 4 μL of 2x PHD2 enzyme working solution and add it to a single well of the assay plate.

d) Seal the test plate and centrifuge the compound plate at 1000 rpm for 1 minute. Incubate the plate at room temperature for 30 minutes.

e) Prepare 4 μL of 2x PHD2 substrate working solution and add it to each well of the assay plate.

f) Prepare 4 μL of 2x PHD2 termination solution and add it to each well of the assay plate.

g) Prepare 4x detection solution using AlphaScreen streptavidin donor beads, AlphaScreen protein A acceptor beads, and hydroxy-HIF-1α (Pro564) (D43B5) XP® rabbit mAb.

h) Add 4 μL of 4x detection solution to each well of the assay plate. Repeat step d.

i) Read the Alphascreen signal on the Envision HTS reader.

Data Analysis

Calculate the ALPHASCREEN signal (ALPcmpd) for each aperture.

The method for calculating % suppression is as follows:

: The average ALP of the positive control group across the entire plate.

: The average ALP of the negative control on the entire plate.

Calculate the _IC50 and plot the effect-dose curve of the compound:

_IC50 was calculated by fitting the %inhibition value and the logarithm of the compound concentration to a nonlinear regression (dose-response-variable slope) using Graphpad 8.0.

Y = base + (top - base) / (1 + 10^((LogIC50 - X) * Hill slope))

X: Logarithm of inhibitor concentration; Y: % inhibition.

Example 3: EPO Elisa Determination

Dissolve the compound powder in 100% DMSO. Store the compound stock solution in a nitrogen cabinet.

Experimental methods

Cell seeding: Add 100µl of cell suspension containing 20k Hep3B cells to each well.

Preparation of compound concentration gradients: Compound 1 was prepared at a maximum dose of 100 µM, diluted 3-fold, with 8 doses, in single or duplicate forms. A 200x final concentration solution was prepared in a 96-well plate by diluting the compound 200/3x with cell culture medium and then pipetting 50 μL into each well. 50 μL of DMSO-containing medium was added to the lowest control well to achieve a final concentration containing 5‰ DMSO, and 50 μL of the highest concentration control compound was added to the highest control well. The plates were incubated at 37°C for 24 h.

Wash the reaction plate twice with 400 μL of 1x washing buffer in each well.

Add 100 µL of diluted standard (including standard blank control) to the appropriate well.

Add 50 µL of sample and 50 µL of sample diluent to the sample well.

Add 50 µL of 1x biotin-conjugated antibody to all wells and incubate at room temperature for 1 hour.

Wash the reaction plate 6 times with 400 µL of 1x washing buffer in each well.

Add 100 µL of 1x strepto-biotin-HRP to each well. Incubate at room temperature for 15 minutes.

Wash the reaction plate 6 times with 400 µL of 1x washing buffer in each well.

Add 100 µL of TMB substrate solution to each well. Incubate at room temperature for 10 minutes.

Add 100 µL of termination solution to each well.

Use EnSight to read OD450.

Data Analysis

Use GraphPad Prism 5.

% activity = (compound signal-minimum signal)/(maximum signal-minimum signal)*100.

The highest signal is obtained from the highest reference aperture.

The lowest signal is obtained from the lowest signal aperture.

The logarithm of concentration was used as the X-axis and the percentage of inhibition as the Y-axis. The EC50 value for each compound was obtained by fitting a dose-response curve to the GraphPadPrism 5 log(inhibitor) and response-variable slope using the analysis software GraphPadPrism ₅ .

The data from Examples 2 and 3 are shown below.

PHD2 (nM): 0<A≤5; 5<B≤20; 20<C≤100; 100<D≤1,000; 1,000<E<100,000

HEP3B EPO determination (EC50, nM): 0 < A ≤ 2,500; 2,500 < B ≤ 5,000; 5,000 < C ≤ 7,500; 7,500 < D ≤ 10,000; 10,000 < E ≤ 100,000

Example 4: Preparation of the free base A type of compound 1

At 25°C, approximately 30 mg of Compound 1 was equilibrated for 11 days in 0.5 mL of ethanol, methyl ethyl ketone, acetone, ethyl acetate, acetonitrile, or dichloromethane using a stirring rod on a magnetic stir plate at a rate of 500 rpm. The solid precipitate was collected for XRPD, DSC, TGA, and ^1H -NMR.

The XRPD plot of the free base A type of compound 1 is shown in Figure 1. The main peak and its related intensities in the XRPD plot are shown in Table 1. The free base A type of compound 1 is anhydrous.

The DSC and TGA results shown in Figure 2 indicate that the free base A type of compound 1 has the initiation of an endothermic event at approximately 215°C.

Example 5: Selective preparation of the free base A type of compound 1

Approximately 30 mg of Compound 1 was equilibrated for about 10 cycles in 0.45–1.0 mL of acetone, acetonitrile, dichloromethane, tetrahydrofuran, or isopropanol at a heating/cooling rate of 0.1°C/min under temperature cycling from 5°C to 50°C. Equilibration was performed on a magnetic stirring plate using a magnetic stir bar at 400 rpm. The residual solids were collected by centrifugation at 14,000 rpm and analyzed by XRPD. The XRPD plot of the solids was the same as in Table 1 and confirmed to be the free base A type of Compound 1.

Example 6: Selective preparation of the free base A type of compound 1

Approximately 30 mg of Compound 1 was equilibrated at 5°C in 0.45–1.0 mL of acetone, acetonitrile, dichloromethane, tetrahydrofuran, or isopropanol. The system was cooled to 5°C at a rate of 0.1°C/min. Equilibration was then performed on a magnetic stirring plate at 400 rpm using a magnetic stir bar. The residual solid was collected by centrifugation at 14,000 rpm. The solid precipitate was collected for XRPD analysis. The XRPD pattern of the solid was identical to that in Table 1 and confirmed to be the free base A type of Compound 1.

Example 7: Selective preparation of the free base A type 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 50°C for 30 min using a magnetic stir bar with a stirring rod, and then filtered. A certain amount of n-heptane was gradually added until a large amount of solid precipitated out. The entire sample was kept at 25°C and stirred at 500 rpm/min. The residual solid was collected by centrifugation at 14,000 rpm and studied by XRPD. The XRPD plot of the solid was the same as that in Table 1, confirming it to be the free base A type of Compound 1.

Example 8: Selective preparation of the free base A type 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 pinholes and placed in a fume hood until the liquid completely evaporated. Alternatively, the vial was dried with nitrogen gas until the liquid completely evaporated. The solid obtained from the system was then characterized by XRPD. The XRPD plot of the solid was the same as that in Table 1, and it was confirmed to be the free base A type of Compound 1.

Example 9: Preparation of Compound 1 HCl Salt Type A

Approximately 25 mg of the 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 300 rpm at 50°C. 1.1 equivalents of hydrochloric acid were diluted with 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 maintained at 25°C with stirring for 4 days. The resulting suspension was centrifuged (8000 rpm, 10 min), and the residual solid was dried under vacuum at 30°C. The solid was characterized by XRPD, DSC, and TGA.

The XRPD plot of compound 1 HCl salt (type A) is shown in Figure 3. The main peaks and their relative intensities in the XRPD plot are shown in Table 2. The DSC and TGA results are shown in Figure 4.

Example 10: Preparation of Compound 1 HCl Salt Type B

Approximately 25 mg of the 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 300 r/min at 50°C. 1.1 equivalents of hydrochloric acid were diluted with ethyl acetate and slowly added to the solution of compound 1. After stirring for 2 hours, the system was cooled to 25°C and stirred at 25°C for 4 days. The resulting suspension was centrifuged (8000 r/min, 10 mins), and the residual solid was dried under vacuum at 30°C. The solid was characterized by XRPD, DSC, TGA, and ^1H -NMR.

The XRPD plot of compound 1 HCl salt type B is shown in Figure 5. The main peaks and their relative intensities in the XRPD plot are shown in Table 3. The DSC and TGA results are shown in Figure 6.

Example 11: Preparation of Compound 1 Toluenesulfonate Type A

Approximately 25 mg of the 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 300 r/min at 50°C. 1.1 equivalents of p-toluenesulfonic acid were 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 stirred at 25°C for 4 days. The resulting suspension was centrifuged (8000 r/min, 10 mins), and the residual solid was dried under vacuum at 30°C. The solid was characterized by XRPD, DSC, TGA, and ^1H -NMR.

The XRPD plot of compound 1 toluenesulfonate A type is shown in Figure 7. The main peaks and their relative intensities in the XRPD plot are shown in Table 4. The DSC and TGA results are shown in Figure 8. ^1H -NMR shows that the ratio of compound 1 to p-toluenesulfonic acid is approximately 1:1.02.

Analytical methods

Differential scanning calorimetry (DSC)

Add an accurate amount of sample (0.5 ~ 1.5 mg) to the standard aluminum TA-Instruments sample tray/Tzero aluminum tray. Seal the sample tray with the standard cap/Tzero pinhole cap and record the DSC curve on a TA-Instruments Q2000/Discovery DSC 2500 equipped with an RCS cooling unit.

X-ray powder diffractometer (XRPD)

Thermogravimetric analysis (TGA)

Place approximately 2–10 mg of sample on an open/sealed aluminum tray. Details of the TGA (DiscoveryTGA 5500 or TGA Q5000) method used in the test are listed below:

High Performance Liquid Chromatography (HPLC) - Related Substances

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Claims (17)

1,2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-((6-cyanopyridin-3-yl)methyl)-5-hydroxy-1,7-naphthyl-6-carboxamide: (Compound 1) in solid form or a pharmaceutically acceptable salt thereof. 2. The solid form of claim 1, wherein the solid form is a crystalline form. 3. The solid form of claim 1 or 2, wherein the solid form is the crystalline compound 1 in the form of a free base. 4. The solid form of claim 3, wherein the solid form is the free base A type of crystalline compound 1. 5. The solid form of claim 1 or 2, wherein the solid form is a crystalline compound 1 in salt form. 6. The solid form of claim 5, wherein the solid form is crystalline compound 1 HCl salt type A, compound 1 HCl salt type B, or compound 1 toluenesulfonate type A. 7. The crystalline form of claim 2, wherein the crystalline form is the free base of compound 1, characterized by having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern that is essentially the same as that shown in Figure 1, as determined using Cu Kα radiation; (b) The X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, has peaks at 8.5 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram that is essentially the same as that shown in Figure 2; (d) A thermogravimetric analysis (TGA) chromatogram that is essentially the same as shown in Figure 2; or (e) Its combination. 8. The crystalline form of claim 7, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1, as determined using Cu Kα radiation. 9. The crystalline form of claim 7 or 8, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with the peaks shown in Table 1, as determined using Cu Kα radiation. 10. The crystalline form of any one of claims 7-9, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, having peaks at 8.5 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, and 20.3 ± 0.2° 2θ. 11. The crystalline form of any one of claims 7-10, wherein the X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, further includes peaks at 14.2 ± 0.2° 2θ, 18.6 ± 0.2° 2θ, and 22.3 ± 0.2° 2θ. 12. The crystalline form of any one of claims 7-11, wherein the X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα radiation, further includes peaks at 22.8 ± 0.2° 2θ, 25.9 ± 0.2° 2θ, and 26.9 ± 0.2° 2θ. 13. The crystalline form of any one of claims 7-12, wherein the X-ray powder diffraction (XRPD) pattern, as measured using Cu Kα 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. 14. The crystalline form of any one of claims 7-9, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern as determined using Cu Kα radiation, 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. 15. The crystalline form of any one of claims 7-14, wherein the crystalline form is anhydrous. 16. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 2-15 and a pharmaceutically acceptable excipient. 17. A method of treating an individual's disease or condition, the method comprising administering to the individual the crystalline form of any one of claims 2-15 or the pharmaceutical composition of claim 16, wherein the disease or condition is anemia.