Crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, method of preparation thereof, and use thereof.

Abstract

Provided herein are various crystalline forms of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, methods for their production, and methods for their use for RET inhibition.

Description

[Technical Field]

[0001] This application claims the interests of U.S. Provisional Application No. 63 / 116,191, filed on November 20, 2020, which is incorporated herein by reference in its entirety for any purpose.

[0002] This disclosure relates to the crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (also known as HM06 or TAS953), a selective RET inhibitor useful in the treatment of cancer. This disclosure also relates to the crystalline forms of HM06 in both free base and salt forms, as well as methods for producing them. [Background technology]

[0003] Various protein kinases exist in vivo and are known to be involved in a wide range of functional regulation. RET is a receptor tyrosine kinase identified as one of the proto-oncogenes. RET binds to glial cell line-derived neurotrophic factor (GDNF) and the GDNF receptor to form a complex, which enables RET to perform physiological functions via intracellular phosphorylation signaling. (Bavetsias et al., "Aurora Kinase Inhibitors: Current Status and Outlook", Frontiers in Oncology, 2015, vol.5, Art.278.) Several studies have shown that in cancers such as lung cancer, thyroid cancer, breast cancer, pancreatic cancer, and prostate cancer, translocation, mutation, and overexpression of RET enhance its activation, thereby contributing to cell proliferation, tumorigenesis, or tissue invasion.(Kohno et al.,「KIF5B-RET fusions in lung adenocarcinoma,」Nature Med.,18(3):pp.375-377,(2012);Santoro et al.,「RET / PTC activation in papillary thyroid carcinoma:European Journal of Endocrinology Prize Lecture,」Eur J Endocrinol.,155:pp.645-653,(2006);Yeganeh et al.,「RET Prato Oncogene Mutation Detection and Medullary Thyroid Carcinoma Prevention,」Asian Pac J Cancer Prev.,16(6):pp.2107-2117,(2015);Gattelli et al.,「Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells,」EMBO Mol Med.,5:pp.1335-1350,(2013);Ito et a.,「Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers,」Surgery,138:pp.788-794,(2005);and Dawson et al.,「Altered Expression of RET Proto-oncogene Product in Prostatic Intraepithelial Neoplasia and Prostate Cancer,」J Natl Cancer Inst.,90:pp.519-523,(1998))。Furthermore, RET is known to be a poor prognostic factor for cancer, and several reports have shown that RET translocation and increased activation levels are inversely correlated with cancer prognosis (Cai et al., "KIF5B-RET Fusions in Chinese Patients With Non-Small Cell Lung Cancer," Cancer, 119:pp.1486-1494, (2013); Elisei et al., "Prognostic Significance of Somatic RET Oncogene Mutations in Sporadic Medullary Thyroid Cancer: A 10-Year Follow-Up Study," J Clin Endocrinol Metab., 93(3):pp.682-687, (2008); Gattelli et al., "Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells," EMBO Mol Med., 5:pp.1335-1350, (2013); and Zeng et al., "The Relationship between Over-expression of Glial Cell-derived Neurotrophic Factor and Its RET Receptor with Progression and Prognosis of Human Pancreatic Cancer, J.Int.Med.Res.,36:pp.656-664,(2008)). Therefore, inhibitors that can inhibit RET activity are considered useful as therapeutic agents for diseases associated with abnormal hyperactivity of the RET signaling pathway, including cancer.

[0004] Furthermore, many cancers can lead to metastatic brain tumors. Symptomatic metastatic brain tumors have been reported to occur in 8-10% of cancer patients, and in lung cancer, some reports indicate that brain metastases occur in 40-50% of cases upon autopsy (Qingbei Zeng, J Med Chem. 22; 58(20): 8200-15, (2015); Lakshmi Nayak, Curr Oncol Rep; 14(1): 48-54, (2012); Brunilde Gril, Eur J Cancer.; 46(7): 1204-10, (2010)). Therefore, it is desirable to find therapeutic agents that effectively treat cancer, including brain metastases.

[0005] Even more desirable is that therapeutic agents can be administered in a form that is easily absorbed by the body and has storage stability. The pharmaceutically active substances used in the preparation of therapeutic agents must be as pure as possible and their stability for long-term storage under various environmental conditions must be ensured. These properties are useful in preventing the appearance of unintended degradation products in the pharmaceutical composition, which may be potentially toxic or simply reduce the potency of the composition.

[0006] A major concern regarding the large-scale manufacturing of pharmaceutical compounds is the need for active substances to be in a stable crystalline form to ensure consistent processing parameters and pharmaceutical quality. Using an unstable crystalline form can lead to changes in crystal structure during manufacturing and / or storage, resulting in quality control problems and formulation irregularities. Such changes can affect the reproducibility of the manufacturing process and, therefore, may lead to final formulations that fail to meet the high-quality and stringent requirements imposed on the formulation of pharmaceutical compositions. In this regard, it should be kept in mind that, generally speaking, any change to a solid state of a pharmaceutical composition, which can improve physical and chemical stability, offers significant advantages over less stable forms of the same drug.

[0007] When a compound crystallizes from a solution or slurry, it may crystallize in different spatial lattice configurations; this property is called "polymorphism." Each crystalline form is a "polymorph." While the polymorphs of a given substance have the same chemical composition, they may differ from one another in terms of one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal shape, compressible behavior, flow properties, and / or solid-state stability.

[0008] The RET inhibitor 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (also known as HM06 or TAS0953) is reported in U.S. Patent No. 10,155,768. The molecular formula of the free base form of HM06 / TAS0953 is C 26 H 30 It is N6O3, has a molecular weight of 474.57, and the structural formula of the free base is as follows. [ka]

[0009] However, the crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide has not been disclosed to date. [Overview of the project]

[0010] Accordingly, disclosed herein are substantially crystalline forms of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base and HCl salt forms, methods for preparing said crystalline forms, and methods for using said forms.

[0011] This disclosure relates to a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. In one aspect of this disclosure, the crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is a free base. In one aspect of the present disclosure, the crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is an HCl salt, for example, a 1:1 or 1:2 HCl salt.

[0012] This disclosure also relates to a pharmaceutical composition comprising at least one substantially crystalline form described herein and a pharmaceutically acceptable excipient.

[0013] The disclosure further relates to a method for treating cancer in a human patient requiring treatment for cancer, comprising administering to the patient an effective amount of a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

[0014] Further objectives and benefits are partially described in the following description, partially evident therefrom, or can be acquired through practice. These objectives and benefits are realized and achieved by the elements and combinations specifically indicated in the attached claims.

[0015] Please understand that both the general explanation above and the detailed explanation below are illustrative and descriptive only, and do not limit the scope of the claims.

[0016] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more embodiments and, together with the description, serve to explain the principles described herein.

Brief Description of the Drawings

[0017] [Figure 1A] Shows the XRPD pattern of the HM06 crystalline free base form 1 obtained using CuKα radiation.

[0018] [Figure 1B] Shows the XRPD pattern of the HM06 crystalline free base form 2 obtained using CuKα radiation.

[0019] [Figure 1C] Shows the XRPD pattern of the HM06 crystalline free base form 3 obtained using CuKα radiation.

[0020] [Figure 1D] Shows the XRPD pattern of the HM06 crystalline free base form 4 obtained using CuKα radiation.

[0021] [Figure 1E] Shows the XRPD pattern of the HM06 crystalline free base form 5 obtained using CuKα radiation.

[0022] [Figure 1F] Shows the XRPD pattern of the HM06 HCl crystalline salt form A obtained using CuKα radiation.

[0023] [Figure 1G] Shows the superimposed XRPD patterns of five HM06 crystalline free base forms and the HM06 HCl crystalline salt form A obtained using CuKα radiation.

[0024] [Figure 2A] Shows the XRPD pattern of the crystalline HM06 1:1HCl form 1 obtained using CuKα radiation.

[0025] [Figure 2B] The XRPD pattern of crystalline HM06 1:1HCl form 1 obtained using CuKα radiation is shown.

[0026] [Figure 2C] The XRPD pattern of crystalline HM06 1:1HCl form 1 obtained using CuKα radiation is shown.

[0027] [Figure 2D] This is a DSC thermogram of HM06 1:1HCl form 1.

[0028] [Figure 2E] This provides a TGA profile for HM06 1:1HCl Form 1.

[0029] [Figure 3A] The XRPD pattern of crystalline HM06 1:2HCl form 1 obtained using CuKα radiation is shown.

[0030] [Figure 3B] This provides a TGA profile for HM06 1:2HCl Form 1.

[0031] [Figure 3C] This is a DSC thermogram of HM06 1:2HCl crystalline form 1.

[0032] [Figure 3D] This diagram illustrates the twinning of a crystal due to a space group transition from orthorhombic to monoclinic. Macroscopic views of the crystal from below and above are shown. Twin monoclinic crystals occur when molecules rearrange similarly in the top view (A) and the bottom view (B). The packing of the monoclinic crystal is equivalent in the two volumes, but not related by crystallographic symmetry. Instead, the twinning operation, which is a 180° rotation around an axis in a plane perpendicular to the intrinsic crystallographic b-axis of the monoclinic lattice, relates the diffraction patterns of the two volumes.

[0033] [Figure 3E] This provides an ORTEP diagram of a single crystal of HM06 1:2HCl form 1.

[0034] [Figure 4A] This shows the crystal packing diagram of HM06 1:2HCl form 1 along the "a-axis".

[0035] [Figure 4B] This shows the crystal packing diagram of HM06 1:2HCl form 1 along the "b axis".

[0036] [Figure 5A] The XRPD pattern of crystalline HM06 1:2HCl form 1-bis obtained using CuKα radiation is shown.

[0037] [Figure 5B] The XRPD pattern of HM06 1:2HCl crystalline form 1-bis obtained using CuKα radiation is shown.

[0038] [Figure 5C] This image shows the superimposed XRPD pattern profiles of HM06 1:2HCl form 1-bis under vacuum (time = 0) and in air for 2 to 20 minutes, in the range of 2θ = 25.5° to 27.5°.

[0039] [Figure 5D] This shows the superimposed XRPD pattern profiles of HM06 1:2HCl form 1-bis as the starting material, both under vacuum and after moisture has been absorbed from air.

[0040] [Figure 6A] The image shows a superimposed XRPD pattern (top pattern) of the HM06 1:2HCl Form 2 sample obtained after a slurry experiment using ethanol at 50°C. The standard reference patterns (bottom two patterns) for Form 1 and Form 2 are reported for comparison.

[0041] [Figure 6B] This shows the superimposed XRPD patterns (top two patterns) of the HM06 1:2HCl Form 2 sample obtained after a 50°C slurry experiment from ethanol. The standard reference patterns for Form 2 (bottom pattern) and Form 3 (second from the bottom pattern) are reported for comparison.

[0042] [Figure 6C] XRPD patterns of HM06 1:2HCl form 2, collected after 4-day slurry experiments from ethanol and scaled to 100 mg, are shown, obtained using CuKα radiation and used as an STD reference.

[0043] [Figure 6D] This is a DSC thermogram of HM06 1:2HCl Form 2.

[0044] [Figure 6E] This provides a TGA profile for HM06 1:2HCl Form 2.

[0045] [Figure 6F] XRPD patterns of samples collected after the microscale-up R01 (second pattern from the top) and R02 (top pattern) of Example 5 are provided. Standard reference XRPD patterns for Forms 2 and 3, provided as the two patterns below, are included for comparison.

[0046] [Figure 6G] The XRPD pattern of the sample collected after a microscale-up procedure using a concentration of 20 mg / mL is provided (top line). Standard reference XRPD patterns for Form 2 and Form 3, provided as the two bottom lines, are included for comparison.

[0047] [Figure 7A]This image shows a superimposed XRPD pattern (blue line) of crystalline HM06 1:2HCl Form 3 obtained after a 50°C slurry experiment from acetonitrile using CuKα radiation, along with the standard reference pattern of Form 1 (black line), Form 2 (green line), and Form 3 (pink line).

[0048] [Figure 7B] The XRPD pattern of HM06 1:2HCl form 3, collected after high-speed gradient precipitation from 1-propanol using CuKα radiation and then scaling to 100 mg, is shown.

[0049] [Figure 7C] This is a DSC thermogram of HM06 1:2HCl Form 3.

[0050] [Figure 7D] This provides the TGA profile for HM06 1:2HCl Form 3.

[0051] [Figure 8A] The XRPD pattern of HM06 1:2HCl form 4-bis obtained using CuKα radiation (upper pattern) is shown alongside the XRPD pattern of HM06 1:2HCl form 1 (lower pattern) for reference.

[0052] [Figure 8B] The XRPD pattern of HM06 1:2HCl form 4-bis is shown.

[0053] [Figure 8C] The image shows a superimposed XRPD patterns of HM06 1:2HCl Form 4-bis (bottom pattern) and the same sample analyzed after being stored in a sealed vial for 7 days (middle pattern). The XRPD pattern of HM06 1:2HCl Form 1 is provided for comparison (top pattern).

[0054] [Figure 8D]The XRPD pattern of HM06 1:2HCl form 4 obtained using CuKα radiation is shown.

[0055] [Figure 8E] This image shows a superimposed XRPD pattern of HM06 1:2HCl Form 4 (bottom pattern) and the XRPD pattern after storage overnight at 43% relative humidity (top pattern).

[0056] [Figure 9A] The XRPD patterns of HM06 1:2HCl Form 5-bis (top pattern) are shown in comparison to Form 5 (bottom pattern).

[0057] [Figure 9B] The XRPD pattern of HM06 1:2HCl form 5-bis obtained using CuKα radiation is shown.

[0058] [Figure 9C] The image shows a superimposed XRPD pattern of HM06 1:2HCl form 5-bis (upper blue pattern) and the XRPD pattern of the same sample analyzed after 18 hours of exposure (lower red pattern).

[0059] [Figure 9D] The XRPD pattern of HM06 1:2HCl Form 5-bis (top blue pattern) and the XRPD pattern of the same sample analyzed after 7 days in a sealed vial (middle pattern) are shown superimposed. The XRPD pattern of HM06 1:2HCl Form 1 is provided for comparison (bottom pattern).

[0060] [Figure 9E] The XRPD pattern of HM06 1:2HCl form 5 obtained using CuKα radiation is shown.

[0061] [Figure 9F] This is a DSC thermogram of HM06 1:2HCl Form 5.

[0062] [Figure 9G] This provides the TGA profile for HM06 1:2HCl Form 5.

[0063] [Figure 10] The XRPD pattern of HM06 1:2HCl form 6 is shown.

[0064] [Figure 11] This shows the superimposed XRPD patterns of isolated crystalline HM06 1:2HCl. [Modes for carrying out the invention]

[0065] As summarized above and described in detail below, this disclosure relates to the crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (also known as HM06 or TAS953). This disclosure also relates to the crystalline free base form and a method for producing its HCl salt form, for example, a dichloride (or 1:2) HCl salt.

[0066] [ka]

[0067] Methods for using crystalline forms for therapeutic treatment of cancer and other conditions are also disclosed herein.

[0068] Details of this disclosure are set forth in the attached specification below. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but only exemplary methods and materials are described herein. Other features, purposes, and advantages of this disclosure will become apparent from this specification and the claims. In this specification and the attached claims, singular forms include plural forms unless the context makes it clear otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains. All patents and publications referenced herein are incorporated herein by reference in their entirety.

[0069] This disclosure relates to a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. In at least one aspect of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is a free base.

[0070] In some embodiments of this disclosure, the substantially crystalline form of the free base of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is form 1. In at least one embodiment, the free base of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is characterized by an XRPD pattern substantially identical to that of Figure 1A. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 1 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 12.57°2θ, 13.36°2θ, 16.08°2θ, 18.86°2θ, 20.66°2θ, 21.73°2θ, 23.90°2θ, and 24.86°2θ.

[0071] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base is form 2. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 2 is characterized by substantially the same XRPD pattern as in Figure 1B. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 2 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 7.94°2θ, 10.47°2θ, 11.53°2θ, 15.75°2θ, 21.80°2θ, and 23.65°2θ.

[0072] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base is form 3. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 3 is characterized by an XRPD pattern substantially the same as that in Figure 1C. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 3 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 7.11°2θ, 7.83°2θ, 14.12°2θ, 16.15°2θ, 20.61°2θ, 21.19°2θ, 26.37°2θ, and 28.59°2θ.

[0073] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base is form 4. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 4 is characterized by an XRPD pattern substantially identical to that of Figure 1D. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 4 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 7.77°2θ, 9.48°2θ, 11.54°2θ, 16.34°2θ, 20.21°2θ, 23.24°2θ, and 24.77°2θ.

[0074] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base is form 5. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 5 is characterized by substantially the same XRPD pattern as in Figure 1E. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 5 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 9.51°2θ, 13.52°2θ, 18.71°2θ, 21.26°2θ, 21.49°2θ, 28.60°2θ, and 29.05°2θ.

[0075] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is a mixture of free base forms.

[0076] In some embodiments, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is the HCl salt form A. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide HCl salt form A is characterized by the same XRPD pattern as in Figure 1F. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide HCl salt form A is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 5.67°2θ, 7.19°2θ, 7.32°2θ, 10.90°2θ, 14.31°2θ, 14.59°2θ, 20.08°2θ, and 21.24°2θ.

[0077] In some embodiments of the present disclosure, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl salt. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl salt is Form 1. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl salt Form 1 is characterized by substantially the same XRPD pattern as in Figure 2A, Figure 2B, or Figure 2C. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl form 1 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 6.53°2θ, 7.37°2θ, 9.07°2θ, 14.60°2θ, 16.35°2θ, 21.26°2θ, and 26.12°2θ. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl form 1 has at least one feature selected from substantially the same DSC thermogram as in Figure 2D and substantially the same TGA profile as in Figure 2E.

[0078] In some embodiments of the present disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide is a mixture of HCl form A and 1:1 HCl form 1.

[0079] In some embodiments, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt.

[0080] In some embodiments, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is Form 1. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt Form 1 is characterized by substantially the same XRPD pattern as in Figure 3A. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl form 1 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 6.59°2θ, 7.40°2θ, 9.12°2θ, 14.57°2θ, 16.39°2θ, 26.06°2θ, 26.57°2θ, and 27.07°2θ. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl form 1 has at least one feature selected from substantially the same DSC thermogram as in Figure 3C and substantially the same TGA profile as in Figure 3B.

[0081] In some embodiments, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt, which is form 1-bis. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 1-bis is characterized by the same XRPD pattern as substantially the same as in Figure 5A or Figure 5B. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 1-bis is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 6.66°2θ, 7.63°2θ, 9.31°2θ, 10.74°2θ, 13.09°2θ, 16.45°2θ, 21.36°2θ, 26.70°2θ, and 29.01°2θ.

[0082] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 1 and Form 1-bis.

[0083] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 2. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 2 is characterized by substantially the same XRPD pattern as in Figure 6C. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 2 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 7.13°2θ, 12.21°2θ, 14.22°2θ, 15.50°2θ, 17.18°2θ, 21.60°2θ, 22.23°2θ, 23.26°2θ, 26.72°2θ, and 27.69°2θ. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 2 has at least one feature selected from substantially the same DSC thermogram as in Figure 6D and substantially the same TGA profile as in Figure 6E.

[0084] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 1 and Form 2.

[0085] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 3. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 3 is characterized by substantially the same XRPD pattern as in Figure 7B. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 3 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 5.44°2θ, 9.94°2θ, 14.85°2θ, 22.39°2θ, 22.84°2θ, and 27.96°2θ. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 3 has at least one feature selected from substantially the same DSC thermogram as in Figure 7C and substantially the same TGA profile as in Figure 7D.

[0086] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Forms 2 and 3.

[0087] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 4-bis. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 4-bis is characterized by substantially the same XRPD pattern as in Figure 8B. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 4-bis is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 4.35°2θ, 5.98°2θ, 6.20°2θ, 8.54°2θ, 17.39°2θ, 21.28°2θ, 21.58°2θ, and 21.89°2θ.

[0088] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 4. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 4 is characterized by substantially the same XRPD pattern as in Figure 8D. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 4 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 4.38°2θ, 6.15°2θ, 8.60°2θ, 9.62°2θ, 21.46°2θ, 21.90°2θ, and 26.14°2θ.

[0089] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 4-bis and Form 4.

[0090] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 1 and Form 4.

[0091] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 5-bis. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 5-bis is characterized by substantially the same XRPD pattern as in Figure 9B. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 5-bis is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 6.08°2θ, 6.82°2θ, 7.11°2θ, 7.51°2θ, 8.92°2θ, 9.35°2θ, 11.34°2θ, 17.29°2θ, 20.02°2θ, 21.21°2θ, 22.36°2θ, and 23.15°2θ.

[0092] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 5. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 5 is characterized by substantially the same XRPD pattern as in Figure 9E. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 5-bis is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 6.74°2θ, 7.11°2θ, 8.10°2θ, 13.10°2θ, 17.16°2θ, 23.28°2θ, 24.22°2θ, 25.15°2θ, and 26.24°2θ. In at least one embodiment, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 5 has at least one feature selected from substantially the same DSC thermogram as in Figure 9F and substantially the same TGA profile as in Figure 9G.

[0093] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 5-bis and Form 5.

[0094] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is form 6. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 6 is characterized by substantially the same XRPD pattern as in Figure 10. In at least one embodiment, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt form 6 is characterized by an XRPD pattern containing one or more peaks selected from peaks at approximately 5.88°2θ, 7.01°2θ, 8.81°2θ, 11.51°2θ, 13.12°2θ, 18.36°2θ, 21.4°2θ, and 22.92°2θ.

[0095] In some embodiments of this disclosure, the substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of Form 1, Form 2, and Form 3.

[0096] In some embodiments of the present disclosure, a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt is a mixture of at least one form selected from Form 1, Form 1-bis, Form 2, Form 3, Form 4-bis, Form 4, Form 5-bis, Form 5, and Form 6.

[0097] The substantially crystalline forms disclosed herein may be forms with at least 50% crystalline content, for example, forms with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline content.

[0098] This disclosure also relates to a pharmaceutical composition comprising at least one substantially crystalline form disclosed herein and a pharmaceutically acceptable excipient. For example, in some embodiments, the pharmaceutical composition may comprise a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt.

[0099] This disclosure further relates to a method for treating cancer in a human patient requiring treatment for cancer, comprising administering to the patient an effective amount of a substantially crystalline form of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. In at least one embodiment, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide free base form 1. In at least one embodiment, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:1HCl form 1. In at least one embodiment, the substantially crystalline form is 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropa-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl form 1.

[0100] [Table 1] [Examples]

[0101] Details of the experiment and equipment Unless otherwise specified, the following instruments and parameters were used to physically characterize the crystalline morphologies disclosed herein.

[0102] X-ray powder diffraction (XRPD) analysis [Table 2]

[0103] thermal analysis

[0104] DSC analysis was performed using DSC Mettler Toledo DSC1.

[0105] The samples were weighed in an aluminum pan sealed with an aluminum cover. The samples were heated from 25°C to 320°C at 10 K / min and then analyzed.

[0106] TG analysis was performed using Mettler Toledo TGA / DSC1.

[0107] The samples were weighed in an aluminum pan sealed with an aluminum through-cover. The samples were heated from 25°C to 320°C at 10 K / min and then analyzed. Example 1. Preparation and characterization of crystalline form 1 of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (HM06) free base.

[0108] Example 1A: Preparation of (HM06 free base form 1)

[0109] Free base form 1 of HM06 was prepared using a Sonogashira cross-coupling reaction mediated by Pd(PPh3)2Cl2 and CuI in ACN. More specifically, 4-amino-6-bromo-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (8.2 kg) (which can be prepared according to known methods such as Example 55 in U.S. Patent No. 10,155,768) was added to a reaction vessel at room temperature, and the following reagents, CuI (0.108 kg), Pd(PPh3)2Cl2 (0.402 kg), and CH3CN (82.5 L) were added. 4-(propa-2-in-1-yl)morpholine (6.683 kg) was added to the mass. TEA (7.9 L) was added. The mass was inactivated five times under vacuum and with N2 (500 mbar / 1030 mbar). The mass was heated to Tj 60°C (Ti: 56°C) under N2, stirred at Tj 60°C for 14 hours to obtain a solution, and then cooled to Ti 18-22°C. THF (82.2 L) was added and the mixture was heated to Ti 40°C. The heated mixture was filtered through an 8-10 μm mesh filter (PTFE) by applying precise pressure (at least 2 bar). The filtered mixture was cooled to Ti 20-25°C. The mixture was then passed through a resin (ISOLUTE® Si-Thiol; RATE: 220 L / h, mixed at Ti 25-25°C). The reaction vessel, filter, and resin cake were washed with THF (13 L). The wet resin was discarded. The solvent was distilled under vacuum at Tj: 45°C until Vmax was applied (by stopping stirring as needed). MeTHF (164.5 L) was added to the residue and stirred at room temperature to obtain a homogeneous suspension.

[0110] A 0.1 M solution of N-acetylcysteine ​​(2.6 kg) in water (161.6 L) was added to the organic suspension. The mixture was heated to Tj: 50°C (Ti: 45-48°C) and stirred for 3 hours. Then, stirring was stopped and the phases were separated for at least 20 minutes. After phase separation, the aqueous layer was back-extracted with MeTHF (81.9 L) at Ti: 45-48°C. The mixture was stirred for 30 minutes, then stirring was stopped and the layers were separated at Ti: 45-48°C for at least 20 minutes. Then, the layers were separated and the aqueous layer was discarded. The two organic layers were combined and then 20% NaCl (41 L) was added at Ti: 45-48°C. The mixture was stirred for 30 minutes, then stirring was stopped and the phases were separated for at least 20 minutes. The aqueous layer was removed and discarded. Water (66.4 L) was added to the organic layer at Ti: 45-48°C. The mixture was stirred at the same temperature for 30 minutes, then the stirring was stopped and the phases were allowed to separate for at least 20 minutes. The aqueous layer was removed again and discarded.

[0111] The organic layer was distilled under vacuum at Tj:45°C until Vmax was applied to obtain the residue. The residue was stripped overnight at Tj:45°C under Vmax without stirring. Acetone (17 L) was added to the residue at Ti:45°C and then heated to Ti:48°C (Ti:52°C). The mixture was stirred for at least 1 hour to obtain a homogeneous suspension. The suspension was cooled to Ti:-10°C (Tj:-15°C) over at least 3 hours. The product was then isolated by filtration at Tj:-10°C using a 20 μm mesh filter by applying vacuum and pressure (at least 2 bar). The filtration cake was washed with pre-cooled acetone (3.6 L; Ti:-10°C) by applying pressure (at least 2 bar) and vacuum until no further deliquidation was observed. The solid was dried at Tj:60°C for at least 24 hours to obtain the final product (6.8 kg). The product was stored at Tj:2-8°C.

[0112] Figure 1A shows the XRPD pattern of HM06 crystalline free base form 1 obtained using CuKα radiation. The peaks identified in Figure 1A include those listed in Table 2.

[0113] [Table 3]

[0114] Example 1B: Preparation and characterization of HM06 free base crystalline forms 2-5 and HCl salt crystalline form A

[0115] Five new crystalline phases of the free base, as well as the crystalline salt form of HCl, were observed after selected recrystallization experiments using the solvents listed in Table 3.

[0116] [Table 4]

[0117] Figure 1B shows the XRPD pattern of HM06 crystalline free base form 2 obtained using CuKα radiation. The peaks identified in Figure 1B include those listed in Table 4.

[0118] [Table 5]

[0119]

[0120] Figure 1C shows the XRPD pattern of HM06 crystalline free base form 3 obtained using CuKα radiation. The peaks identified in Figure 1C include those listed in Table 5.

[0121] [Table 6]

[0122] Figure 1D shows the XRPD pattern of crystalline free base form 4 of HM06 obtained using CuKα radiation. The peaks identified in Figure 1D include those listed in Table 6.

[0123] [Table 7]

[0124]

[0125] Figure 1E shows the XRPD pattern of HM06 crystalline free base form 5 obtained using CuKα radiation. The peaks identified in Figure 1E include those listed in Table 7.

[0126] [Table 8]

[0127]

[0128] Figure 1F shows the XRPD pattern of HM06 HCl salt form A obtained using CuKα radiation. The peaks identified in Figure 1F include those listed in Table 8.

[0129] [Table 9]

[0130] Figure 1G shows a superimposed XRPD patterns of five crystalline free base forms of HM06 and HM06 HCl salt form A obtained using CuKα radiation. Example 2. Synthesis and Characterization of Crystalline 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (HM06) 1:1HCl Salt Form 1

[0131] In a 100 ml round-bottom flask, 1.16 ml (1.1 equivalents) of 2 M HCl aqueous solution was added to 1 g of HMO6 free base. 40 ml of tetrahydrofuran was added, and the suspension was stirred at room temperature (25°C) for 2 days (800 RPM).

[0132] The sample was collected, filtered, and analyzed by XRPD. The remaining suspension was collected by suction and dried under vacuum (50 mbar) at 25°C for 1 day. The dried sample was analyzed by XRPD.

[0133] Figure 2A shows the XRPD pattern of crystalline HM06 1:1HCl form 1 obtained using CuKα radiation. Figures 2B and 2C also show the XRPD patterns of crystalline HM06 1:1HCl form 1 obtained using CuKα radiation. The peaks identified in Figures 2A to 2C for crystalline HM06 1:1HCl include those listed in Table 9. [Table 10]

[0134] thermal analysis The DSC profile of HM06 1:1HCl Form 1 recorded in a sealed pan showed events above 200°C due to sample melting and decomposition. Figure 2D is the DSC thermogram of HM06 1:1HCl Form 1. The lack of signal in the DSC profile and the change at baseline related to solvent release were likely due to the sealed pan used in combination with the effects of solvent release.

[0135] The TGA profile of HM06 1:1HCl form 1 showed a 4.8% weight loss in the range of 40°C to 170°C, consistent with the water loss recorded by EGA. Decomposition occurred after 200°C. Figure 2E provides the TGA profile of HM06 1:1HCl form 1. The heat flow recorded by TGA shows broad, large events occurring in the range of water loss, followed by a signal after 200°C due to melting, and then decomposition. Example 3. Preparation of HM06 1:2HCl [ka]

[0136] A. Synthesis of 1g HMO6 1:2HCl using an aqueous HCl solution 1 g of HMO6 free base was weighed and transferred to a 250 mL reactor equipped with a magnetic stirring bar. 50 mL of ethanol was then added, and the resulting mixture was heated until the solid was completely dissolved (T=80°C). Once no solid material was observed, the solution was cooled to 50°C. 532 μL (3 equivalents) of 37% HCl was slowly added to the reactor. Solid formation was immediately observed. The mixture was cooled to 25°C over 25 minutes, and then stirred for a further 1 hour. After this, the formed solid was isolated by vacuum filtration, washed with ethanol, and dried at 40°C and 30 mbar for 24 hours. 1.08 g of the product was recovered as a white solid in nearly quantitative yield.

[0137] B. Synthesis of 5G HM06 1:2HCl using aqueous HCl solution 5 g of HMO6 free base was weighed and transferred to a 250 mL reactor equipped with a magnetic stirring bar. 70 mL of ethanol was then added, and the resulting mixture was heated until the solid was completely dissolved (T=80°C). Once no solid material was observed, the solution was cooled to 50°C. A small amount of solid precipitate was observed, so the solution was heated again until completely dissolved, and then cooled to 60°C. No precipitate formation was observed at this temperature. Next, 2.5 mL (3 equivalents) of 37% HCl was dissolved in 10 mL of ethanol, and the resulting solution was slowly added to the reactor. Solid formation was immediately observed. The mixture was cooled to 25°C for 35 minutes, and then stirred for a further 1 hour. After this, the formed solid was isolated by vacuum filtration, washed with ethanol, and dried at 40°C and 30 mbar for 24 hours. 5.64 g of the product was recovered as a white solid in nearly quantitative yield.

[0138] C. Synthesis of 2.5g HMO6 1:2HCl using anhydrous HCl 2.5 g of HMO6 free base was weighed and transferred to a 250 mL reactor equipped with a magnetic stirring rod. 35 mL of ethanol was then added, and the resulting mixture was heated until the solid was completely dissolved (T=80°C). Once no solid material was observed, the solution was cooled to 50°C. 4.8 mL (3 equivalents) of 3.3 M anhydrous HCl in ethanol was mixed with 5 mL of ethanol, and the resulting solution was slowly added to the reactor. Solid formation was immediately observed. The mixture was cooled to 25°C in 35 minutes, and then stirred for a further 1 hour. After this, the formed solid was isolated by vacuum filtration, washed with an additional 10 mL of ethanol, collected, and dried at 25°C and 0.1 mbar for 24 hours. The solid was further dried at 100°C and 30 mbar for a further 72 hours. TG / EG analysis confirmed the recovery of the anhydrous compound. 2.69 g of the product was recovered as a white solid in nearly quantitative yield.

[0139] D. Stoichiometric measurements To measure the stoichiometry of the salt, chloride analysis was performed by ion chromatography. A 1:2HCl solution of HM06 was prepared by dissolving 149.2 mg of powder in HPLC-grade water in a volumetric flask (10 mL). Based on TGA analysis (weight loss associated with 5.9% water content) performed on a batch immediately prior to the chloride measurement, the amount of anhydrous salt administered was estimated to be 140.4 mg (94.1%).

[0140] Assuming a stoichiometry of 1:2 (HMO6:HCl), the molecular weight of the anhydrous salt is 547.5 g / mol, which corresponds to a concentration of HMO6 of 0.0256 mmol / mL in the prepared solution. The chloride concentration measured by ion chromatography was found to be 0.05056 mmol / mL, corresponding to a chloride / HMO6 molar ratio of 1.98, confirming that the stoichiometry of HMO6:HCl is 1:2.

[0141] Example 4. Preparation and Characterization of Polymorph 1 and Form 1-bis of HM06 1:2HCl Example 4A: Synthesis of HM06 1:2HCl Form 1

[0142] Free HM06 base (562.0 g) was added to hot ethanol (7885.5 mL), and the mixture was heated at Ti:75°C with stirring until the solid was completely dissolved. The solution was then polished and filtered on a 1 μm cartridge (PP or PTFE). A mixture of 33% HCl (283.4 mL) and EtOH (283.5 mL) was added to the pre-filtered solution over at least 1 hour with stirring, maintaining a temperature of Ti:65–75°C (target 70°C). The mixture was then cooled to Ti:20–25°C over at least 30 minutes, and then stirred at Ti:20–25°C for at least 1 hour. The mixture was then isolated by filtering it on a 20 μm mesh filter by applying pressure (at least 2 bar) and vacuum until no further liquid removal was observed. The filter cake was washed twice with EtOH (1070.8 mL × 2) by applying pressure (at least 2 bar) and vacuum until no further liquid removal was observed. The wet product was dried at Tj:40°C for at least 12 hours. Product HM06 1:2HCl form 1 was obtained (626 g). The product was stored at Tj:2~8°C.

[0143] Figure 3A shows the XRPD pattern of crystalline HM06 1:2HCl form 1 obtained using CuKα radiation. The peaks identified in Figure 3A include those listed in Table 10.

[0144] [Table 11]

[0145] Thermal analysis was performed after storage in a sealed container at low temperature (4–10°C) for two months. Figure 3B provides the TGA profile of HM06 1:2HCl form 1. A weight loss of 4.5% was observed in the range of 30–160°C, which, as confirmed by EGA, was attributed to water release. Above approximately 200°C, decomposition occurred. TGA showed further weight loss attributable to methanol release, as confirmed by EGA. Figure 3C is the DSC thermogram of HM06 1:2HCl form 1. As shown in the figure, the DSC showed a broad endothermic event at 25°C, continuing to approximately 160°C, attributable to water release. The next endothermic peak at 195.13°C (starting at 188.11°C) was related to the melting of the sample.

[0146] HM06 1:2HCl form 1 single crystal

[0147] Crystals of HM06 1:2HCl form 1 were obtained by slow evaporation. The crystals were large enough for single-crystal diffraction, but all were affected by non-merohedry twinning. This means that two crystals grew together to form the same macroscopic sample. Separation of the two crystals was impossible, and the collected data clearly indicated the presence of two reciprocal lattices (see Figure 3D). Structural resolution and refinement were affected by this situation.

[0148] We collected two datasets from two different crystals. In both cases, they were twins, with the second lattice being the same as the first lattice. * The results were obtained by rotating 180° along the line. In the first case, the crystal consisted of two nearly equal constituent elements, and non-Merohedry twinning negatively affected the data, making it impossible to refine the structure to obtain a good R value. The second data retrieval was characterized by one dominant constituent element and a second weaker constituent element. In this case, refinement was acceptable.

[0149] HM06 1:2HCl Form 1 has a space group P21\c and parameters a=6.8636(8)Å, b=16.7683(12)Å, c=24.5798(13)Å, β=94.163(7)° and V=2821.4(4). 3 It crystallizes as a monoclinic in [location]. The asymmetric unit consists of one diprotonated HM06, two chloride ions, and 1.35 water molecules at two positions (see Figure 3E). The chloride ions labeled with Cl2 have disordered occupancies of Cl2A, Cl2B, and Cl2C at three positions: 0.35, 0.36, and 0.29, respectively. - Furthermore, since oxygen atoms in water molecules can repel each other, the position of Cl2 probably depends on the number of water molecules in the lattice.

[0150] HM06 molecules form columns in the b-axis direction, exhibiting short contacts (molecular distance of 3.4 Å) due to the presence of π-stack interactions. The columns have a kind of cross-section, which likely prevents structural collapse due to the removal of water molecules (see, error! reference unknown. 4A and 4B). [Table 12]

[0151] Example 4B: HM06 1:2HCl Form 1-bis To determine the properties of the HM06 1:2HCl form 1 hydrate / anhydrous and to pinpoint the exact amount of water present in the crystal lattice, a series of preliminary dehydration / drying experiments were conducted, which led to the discovery of form 1-bis.

[0152] Figure 5A shows the XRPD pattern of crystalline HM06 1:2HCl form 1-bis obtained using CuKα radiation. The peaks identified in Figure 5A include those listed in Table 12.

[0153] [Table 13]

[0154] VP-XRPD measurements were performed using a Panalytical X'pert equipped with an Anton Paar TTK450 chamber, allowing for in-situ measurement of the powder under controlled temperature and / or vacuum.

[0155] The initial measurements were collected at room temperature and atmospheric pressure. The sample was then left under vacuum (0.07 mbar) for 15 minutes. Figure 5B shows the XRPD pattern of HM06 1:2HCl crystalline form 1-bis obtained using CuKα radiation. As shown in Figure 5B, the second pattern labeled form 1-bis differs from the pattern of the starting material (form 1) because the vacuum leads to dehydration of the sample.

[0156] Some peaks remain in the same position, while others are clearly shifted to higher theta values. It is important to note that this likely indicates that the release of water molecules is only affecting a portion of the crystal plane, and the structure does not change significantly. Based on the structural determination by SC-XRD, form 1-bis was considered to be a highly unstable anhydrous form that does not differ significantly from form 1. This behavior allows it to easily incorporate water molecules in a short time.

[0157] The absorption of moisture by morphology 1-bis was observed by tracking the pattern differences in the range of 2θ = 25.5° to 27.5° using XRPD (see Figure 5C). Under vacuum, the peak at 2θ = 26.7° was the highest, and after exposing the sample to air for 2 minutes, the peak at 2θ = 26.4° was the highest. The peak at 2θ = 26.4° shifted to 2θ = 26.2° after 20 minutes. HM06 1:2HCl crystalline morphology 1-bis absorbs moisture from the atmosphere as soon as the powder is exposed to air, reaching the diffraction pattern of the starting material in 20 minutes (see, error! reference source unknown. 5D). This experiment was performed under ambient conditions where the room's RH% was approximately 80%.

[0158] Example 5. Synthesis and Characterization of Crystalline HM06 1:2HCl Form 2 HM06 1:2HCl Form 2 was observed in a mixture with Form 1 in a high-temperature (50°C) slurry experiment using ethanol. 15 mg of HM06 1:2HCl Form 1 was suspended in 1.5 mL of ethanol and stirred at 50°C for 3 days. After this, the suspension was vacuum filtered under approximately 45-50% RH and analyzed by XRPD. The diffraction pattern is reported in Figure 6A as the upper pattern, compared to the XRPD pattern of Form 1 and the standard pattern of Form 2 (the two lower lines).

[0159] Reproduction and microscale-up procedure

[0160] 1. Reproduction steps The crystallization procedure was reproduced twice. Reproduction R01 yielded HM06 1:2HCl form 2 influenced by a trace amount of form 3, while reproduction R02 recovered pure form 2. For both experiments, the filtration step and plate preparation for XRPD analysis were performed under 7% RH. XRPD measurements were performed using Kapton film. The results and a summary of the relative XRPD patterns are reported in Table 13. [Table 14] 1 Powder isolation by vacuum filtration and preparation of sample plates covered with Kapton film were performed at 7% RH.

[0161] The XRPD patterns of the R01 and R02 results are shown in Figure 6B, compared with the standard reference patterns of Form 2 and Form 3.

[0162] Microscale-up procedure

[0163] To obtain enough powder for further testing and to explore the feasibility of the process, different microscale-up procedures were attempted. The first trial was performed with 100 mg of HM06 1:2HCl Form 1. The powder was suspended in 10 mL of ethanol (10 mg / mL) and stirred at 50°C for 4 days. After this, the suspension was vacuum filtered under 5% RH conditions, and XRPD plates covered with Kapton film were prepared under the same %RH conditions. HM06 1:2HCl Form 2 was isolated, and the collected XRPD patterns were used as the standard (STD) reference patterns for Form 2.

[0164] This procedure was reproduced twice, with the isolation step performed after 5 days under 5% RH conditions. The first reproduction (R01) yielded HM06 1:2HCl form 3 influenced by a trace amount of form 2, while the second reproduction (R02) yielded form 3 with one signal at 7.2° 2-theta due to form 2.

[0165] Taking this data into consideration, we attempted a further procedure. 100 mg of HM06 1:2HCl Form 1 was suspended in 5 mL of ethanol (20 mg / mL) and left to stand at 50°C for 10 days with stirring. From this procedure, Form 2, which had a small signal at 5.5° 2-theta, was isolated from Form 3.

[0166] A summary of the results obtained is reported in Table 14. [Table 15] 1 The experiment was conducted at a concentration of 20 mg / mL.

[0167] Figure 6C shows the XRPD pattern of HM06 1:2HCl form 2, obtained using CuKα radiation, scaled to 100 mg after a 4-day slurry experiment from ethanol, and used as a STD reference. Peaks identified in Figure 6C include those listed in Table 15.

[0168] [Table 16]

[0169] thermal analysis Figure 6D is a DSC thermogram of HM06 1:1HCl form 2, which shows an endothermic event at 219.8°C (starting at 205.5°C) consistent with sample melting. Decomposition occurred above approximately 200°C.

[0170] Figure 6E provides the TGA profile of HM06 1:1HCl Form 2, which did not show weight loss. The sample can be considered anhydrous. Release of methanol and HCl was detected during decomposition.

[0171] Figures 6F and 6G show the relative XRPD patterns from the microscale-up of Example 5 obtained using CuKα radiation.

[0172] Example 6: Synthesis and Characterization of Form 3 of HM06 1:2HCl 15 mg of HM06 1:2HCl Form 1 was suspended in 1.5 mL of acetonitrile and stirred at 50°C for 3 days. After this, the suspension was vacuum filtered under approximately 45-50% RH and analyzed by XRPD. Figure 7A shows the superimposed XRPD patterns of crystalline HM06 1:2HCl Form 3 obtained after the HT (50°C) slurry experiment from acetonitrile (top line), the standard reference pattern of Form 1 (black line), the standard reference pattern of Form 2 (bottom line), and the standard reference pattern of Form 3 (pink line), obtained using CuKα radiation.

[0173] Reproduction and microscale-up procedure Reproduction steps The crystallization procedure was reproduced twice, with the time extended to 9 days, and the recovered powder was treated under 7% RH conditions. XRPD plates were prepared using Kapton film. Reproduction R01 yielded a phase in which trace amounts of morphology 2 were observed. Reproduction R02 yielded morphology 3 and several further unassigned peaks.

[0174] Since pure form 3 was collected from a high-speed precipitation experiment using 1-propanol and used as a standard reference pattern, additional reproductions were attempted. All three high-gradient trials were prepared as follows. 1.5 mL of 1-propanol was added to 15 mg of HM06 form 1 1:2 HCl. The suspension was heated for several minutes to the boiling point of the solvent. A clear solution was immediately observed. It was crash-cooled to \(10^{\circ}C\) using an ice bath. Precipitation occurred immediately. The powder was collected by vacuum filtration and XRPD plates were prepared using Kapton films. All of these experiments were processed under controlled 4 - 5% RH conditions.

[0175] The summary of the obtained results is reported in Table 16.

Table 17

[0176] Microscale-up procedures

[0177] To obtain sufficient powder for further testing and to explore the feasibility of the process, different microscale-up procedures were attempted. All trials were processed under controlled %RH conditions between 5 - 7% values for both the isolation step and the preparation of the XRPD sample plates using Kapton films.

[0178] The first trial was performed with 100 mg of HM06 1:2HCl Form 1. The powder was suspended in 10 mL of acetonitrile (10 mg / mL) and stirred at 50°C for 4 days. After this, the suspension was filtered under vacuum and analyzed by XRPD. A mixture of Forms 2 and 3 was recovered. To attempt to obtain pure Form 3, the first reproduction R01 was planned, and the slurry time was extended to 12 days. In parallel, the same experiment was prepared, tested at a concentration of 20 mg / mL. From reproduction R01, Form 2 was collected, while in the other trial, a mixture of Forms 2 and 3 was obtained, and an unassigned peak at 6.3° 2-theta was observed.

[0179] Pure form 3 was achieved by rapid gradient precipitation from 1-propanol using 15 mg, and since form 3 could not be obtained despite reproducibility, a microscale-up procedure was performed. 100 mg of HM06 1:2HCl form 1 was suspended in 10 mL of 1-propanol. This was heated to the boiling point of the solvent. After a few minutes, the resulting clear solution was crush-cooled at 10°C and left to stand for 5 minutes under magnetic stirring. The powder was then isolated by filtration and analyzed by XRPD. Pure form 3 was achieved, and its XRPD pattern was used as a standard reference. A very small signal at 7.2° 2-theta was observed, presumably due to form 2. The filtration step and preparation of XRPD sample plates covered with Kapton film were performed at 4% RH.

[0180] Reproduction R01 was performed according to the procedure described in Table 17, and the drying process was applied. The samples were analyzed by XRPD. Since morphology 3 was obtained, the entire wet cake was treated at 40°C / 50mbar for 3 hours and then remeasured. Morphology 3 was achieved, but a weak signal at 7.2° 2-theta, attributable to morphology 2, was detected.

[0181] Two further reproductions (R02 and R03) were performed using the same procedure. Form 3 was collected, but a weak signal at 7.2° 2-theta, attributed to Form 2, was detected. For R03, no additional drying step was applied. Instead, the reproduced R02 was subjected to two staining steps, and both were then subjected to TGA-EGA analysis. The low crystallinity of R02 was due to the small amount used for XRPD analysis.

[0182] Based on these results, high-speed gradient precipitation from 1-propanol can be considered a suitable procedure for obtaining form 3.

[0183] A summary of the results obtained is reported in Table 17. [Table 18] 1 The experiment was conducted using a concentration of 20 mg / mL. 2 Powder isolation by vacuum filtration and preparation of sample plates covered with Kapton film were performed at 3–7% RH.

[0184] Figure 7B shows the XRPD pattern of HM06 1:2HCl form 3 collected after rapid gradient precipitation from 100 mg scaled 1-propanol using CuKα radiation. Peaks identified from HM06 1:2HCl form 3 in Figure 7B include those listed in Table 17. [Table 19]

[0185] Figure 7C is a DSC thermogram of HM06 1:2HCl form 3, showing an endothermic event at 214°C (starting at 202°C) caused by sample melting. Decomposition occurred above approximately 200°C.

[0186] Figure 7D provides the TGA profile of HM06 1:2HCl Form 3, which showed a very moderate weight loss of 0.7% up to 180°C. During decomposition, the generation of methanol and HCl was detected by EGA.

[0187] Example 7 Synthesis and Characterization of Form 4 and Form 4-bis of HM06 1:2HCl Form 04 and Form 04-Bis crystallization procedure

[0188] Form 4-bis was collected after evaporation experiments from methanol at 25°C under low pressure, following the procedure below.

[0189] A saturated solution of HM06 1:2HCl form 1 in methanol was prepared at approximately 50 mg / mL and stirred overnight (18 hours) at room temperature. This solution was then filtered and evaporated at 25°C / 700 mbar. Sample plates sealed with Kapton film were prepared under 40–45% RH. The collected XRPD patterns are reported in Figure 8A, compared to form 1. Several very weak signals of form 1 were present.

[0190] Reproduction steps The experiment was reproduced four times (reproductions R01-R04) following the procedure reported above. XRPD sample plates sealed with Kapton film were prepared under 40-45% RH. In all trials, morphology 1 was recovered. This procedure was repeated four more times, but in this case, samples were isolated under controlled %RH values ​​of 7-8% RH. In all samples analyzed, a new pattern labeled with morphology 4, influenced by the morphology 1 signal, was observed. From a qualitative standpoint, reproduction R05 showed the lowest amount of morphology 1. Table 18 shows the reproduction procedure and results. [Table 20] 1 Powder isolation by vacuum filtration and preparation of sample plates covered with Kapton film were performed at 7-8% RH.

[0191] Figure 8B shows the XRPD pattern of HM06 1:2HCl form 4-bis. The peaks identified in Figure 8B for HM06 1:2HCl form 4-bis include those listed in Table 19. [Table 21]

[0192] Stability evaluation The stability of Form 4-bis was evaluated after storage in a sealed vial for 7 days. Complete conversion to Form 1 was shown, as shown in Figure 8C.

[0193] Form 4: Crystallization Procedure As described in the previous section, HM06 1:2HCl form 4 was isolated as a mixture with form 1 from a replication experiment conducted to achieve form 4-bis.

[0194] Reproduction steps As described in the previous section and Table 18, form 4 was recovered from all four replication experiments (R05-R08) that were conducted. From a qualitative standpoint, replication R05 appeared to contain the smallest amount of form 1.

[0195] Figure 8D shows the XRPD pattern of HM06 1:2HCl form 4 obtained using CuKα radiation. The peaks identified in Figure 8D for HM06 1:2HCl form 4 include those listed in Table 20. [Table 22]

[0196] The HM06 1:2HCl form 4 exposed powder was stored overnight at room temperature under 43% RH. No significant changes were observed, as shown in Figure 8E.

[0197] Example 8: Synthesis and Characterization of Form 5 and Form 5-bis of HM06 1:2HCl Form 5 and Form 5-Bis Form 5 - Bis 1. Crystallization procedure Evaporation experiments of HM06 1:2HCl Form 1 in a 50 / 50 water / dimethylformamide mixture at 60°C separated a new XRPD pattern, and several signals from Form 5 were observed. Due to its similarity, this was labeled Form 5-bis. Sample processing was carried out under 40–45% RH conditions. Figure 9A shows the XRPD pattern of HM06 1:2HCl Form 5-bis in comparison with Form 5.

[0198] 2. Reproduction Steps The evaporation experiment was replicated twice, and the orange powder was collected. Both samples were analyzed by XRPD and showed a diffraction pattern of morphology 5, with several weak signals likely related to morphology 5-bis, as well as unassigned signals, particularly a signal with a distinct intensity at 18° 2-theta. Based on these results, morphology 5-bis was considered non-reproducible.

[0199] Figure 9B shows the XRPD pattern of HM06 1:2HCl form 5-bis. The peaks identified in Figure 9B for HM06 1:2HCl form 5-bis include those listed in Table 21. [Table 23]

[0200] 3. Stability Test The stability of the HM06 1:2HCl form 5-bis sample was assessed at room temperature after 18 hours of exposure to air and after 1 week in a sealed vial.

[0201] Form 5-bis was measured after the powder was exposed to room temperature for 18 hours. The %RH was approximately 45%. The XRPD pattern of this showed several changes, for example, no signal at the 6° and 12° thetas, and a peak rising at the 6.4° theta.

[0202] These changes could not be associated with a conversion to one of the other isolated polymorphs observed during this study, so the sample was considered unstable. Figure 9C shows the XRPD pattern of Form 5-bis (upper blue pattern), and that of the same sample analyzed after 18 hours of exposure (lower red pattern).

[0203] HM06 1:2HCl Form 5-bis was measured after 7 days at room temperature in a sealed vial. As shown in Figure 9D, the sample began to convert to Form 1.

[0204] Form 5 crystallization procedure / reproducibility procedure Evaporation experiments of HM06 1:2HCl Form 1 in dimethyl sulfoxide at 60 °C yielded Form 1 with signals that were not further assigned. To better understand the nature of these few new signals, the recrystallization procedure was reproduced twice (R01 and R02). Both samples showed a dark brown color, R02 was completely glassy, and only a small amount of powder could be recovered from R01. Analysis of the powder from R01 by XRPD showed a diffraction pattern with low crystallinity labeled as Form 5.

[0205] Figure 9E shows the XRPD pattern of HM06 1:2HCl Form 5 obtained using CuKα radiation. The peaks identified in Figure 9E for HM06 1:2HCl Form 5 include those listed in Table 22.

Table 24

[0206] Figure 9F is the DSC thermogram of HM06 1:2HCl Form 5, showing a broad endothermic event from 30 °C to 90 °C due to solvent release, as also observed by TGA-EGA. Two consecutive endothermic events at 158.7 °C (starting at 144.6 °C) and 164.8 °C (starting at 158.3 °C) were also observed.

[0207] Figure 9G provided the TGA profile of HM06 1:2HCl Form 5, showing a weight loss of moisture up to 130 °C. The occurrence of moisture could not be clearly attributed to dehydration or release of adsorbed water. Decomposition occurred above 200 °C. In EGA, the evolution of HCl as observed for other isolated forms was not detected. The formation of salts with lower HCl content cannot be excluded. The stoichiometry of the salt of Form 5 was not determined with certainty.

[0208] Example 9 Synthesis and Characterization of HM06 1:2HCl Form 6 After evaporating HM06 1:2HCl Form 1 in 1:1 acetonitrile / water solution at room temperature under low pressure, Form 6 was collected. After storage for 6 days under these conditions, conversion to Form 1 was observed. Further analysis was not performed since the phase was unstable after the batch showed an orange color.

[0209] Figure 10 shows the XRPD pattern of HM06 1:2HCl Form 6 using CuKα radiation. The peaks identified in Figure 10 for HM06 1:2HCl Form 6 include those listed in Table 23.

[0210] [Table 25]

[0211] Figure 11 reports the overlay of XRPD patterns for all isolated forms of HM06 1:2HCl.

[0212] Example 10: Storage Stability Test for HM06 1:2HCl Form 1 Samples of HM06 1:2HCl Form 1 were subjected to accelerated storage conditions and long-term storage. The results demonstrated that HM06 1:2HCl Form 1 was stable and retained its crystallinity.

[0213] 1. Accelerated Storage Conditions Samples of HM06 1:2HCl Form 1 from the same lot were stored at 40°C and 75% relative humidity for 24 months, with testing at regular intervals. Table 24 shows the analysis of the samples at 0, 1 month, 3 months, and 6 months. [Table 26] * All impurities exceeding 0.05% (A%) are reported. ** RRT (Relative Retention Time) 0.92~94

[0214] 2.24 months storage Samples of HM06 1:2HCl Form 1 from the same lot were stored at 25°C and 60% relative humidity for 6 months and tested at regular intervals. Table 25 shows the analysis of the samples at 0, 3, 6, 9, 12, 18, and 24 months. [Table 27] * Report all impurities exceeding 0.05% (A%); ** RRT0.92~0.94

[0215] The aforementioned written specification is considered sufficient for those skilled in the art to carry out the embodiments. The foregoing description and examples detail specific embodiments and illustrate the best mode intended by the inventors. However, it will be understood that no matter how detailed the foregoing description may be, the embodiments can be carried out in many ways and should be interpreted in accordance with the appended claims and any equivalents thereof.

[0216] As used herein, the term "about" refers to numerical values, including, for example, integers, fractions, and percentages, whether expressly indicated or not. Generally, the term "about" refers to a range of numerical values ​​that a person skilled in the art would consider equivalent to (e.g., having the same function or result as) the listed values ​​(e.g., ±5 to 10% of the listed range). When terms such as "at least" and "about" precede a list of numerical values ​​or ranges, these terms qualify all values ​​or ranges provided in that list. In some examples, the term "about" may include numerical values ​​that are rounded to the nearest significant figure.

Claims

1. A crystal of form 1 of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt, A crystal characterized by an XRPD pattern containing peaks (±5%) at 6.59°2θ, 7.40°2θ, 9.12°2θ, 14.57°2θ, 16.39°2θ, 26.06°2θ, 26.57°2θ, and 27.07°2θ.

2. A crystal of form 1 of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt, A crystal characterized by an XRPD pattern containing three or more peaks selected from peaks at 6.59°2θ, 7.40°2θ, 9.12°2θ, 14.57°2θ, 16.39°2θ, 26.06°2θ, 26.57°2θ, and 27.07°2θ.

3. The crystal according to claim 1 or 2, characterized by the same XRPD pattern as shown in Figure 3A below. 。

4. The crystal according to any one of claims 1 to 3, wherein the XRPD pattern is obtained using CuKα rays as the X-ray source.

5. A crystal according to any one of claims 1 to 4, having at least one feature selected from the same TGA profile as shown in Figure 3C, the DSC thermogram, and Figure 3B below. 。

6. Crystals of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropane-1-in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide 1:2HCl salt, comprising at least 50% of the crystals of Form 1 described in any one of Claims 1 to 5.

7. A pharmaceutical composition comprising at least one crystal according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

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